TYPE Review

PUBLISHED 04 October 2023

DOI 10.3389/fimmu.2023.1267091

The role of inflammation in

OPEN ACCESS autoimmune disease: a
EDITED BY
Jian Gao,
Shanghai Children’s Medical Center, China
therapeutic target
REVIEWED BY
Yong Ling, Yu Xiang 1†, Mingxue Zhang 2†, Die Jiang 3, Qian Su 4*
Nantong University, China
Peng Wang, and Jianyou Shi 1*
Anhui Medical University, China
1
Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan, Sichuan Academy
*CORRESPONDENCE of Medical Science & Sichuan Provincial People’s Hospital, Sichuan Provincial People’s Hospital,
Jianyou Shi School of Medicine, University of Electronic Science and Technology of China, Chengdu, China,
shijianyoude@126.com 2
State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of
Qian Su Traditional Chinese Medicine, Chengdu, Sichuan, China, 3 School of Life Science and Engineering,
20020248@163.com Southwest Jiaotong University, Chengdu, China, 4 Department of Health Management & Institute of
Health Management, Sichuan Provincial People’s Hospital, University of Electronic Science and
†
These authors have contributed Technology of China, Chengdu, China
equally to this work and share
first authorship

RECEIVED 26 July 2023

ACCEPTED 20 September 2023
Autoimmune diseases (AIDs) are immune disorders whose incidence and
PUBLISHED 04 October 2023
prevalence are increasing year by year. AIDs are produced by the immune
CITATION
Xiang Y, Zhang M, Jiang D, Su Q and Shi J
system’s misidentification of self-antigens, seemingly caused by excessive
(2023) The role of inflammation in immune function, but in fact they are the result of reduced accuracy due to
autoimmune disease: a therapeutic target. the decline in immune system function, which cannot clearly identify foreign
Front. Immunol. 14:1267091.
doi: 10.3389/fimmu.2023.1267091 invaders and self-antigens, thus issuing false attacks, and eventually leading to
COPYRIGHT
disease. The occurrence of AIDs is often accompanied by the emergence of
© 2023 Xiang, Zhang, Jiang, Su and Shi. This inflammation, and inflammatory mediators (inflammatory factors,
is an open-access article distributed under inflammasomes) play an important role in the pathogenesis of AIDs, which
the terms of the Creative Commons
Attribution License (CC BY). The use, mediate the immune process by affecting innate cells (such as macrophages)
distribution or reproduction in other and adaptive cells (such as T and B cells), and ultimately promote the occurrence
forums is permitted, provided the original
author(s) and the copyright owner(s) are
of autoimmune responses, so targeting inflammatory mediators/pathways is one
credited and that the original publication in of emerging the treatment strategies of AIDs. This review will briefly describe the
this journal is cited, in accordance with role of inflammation in the pathogenesis of different AIDs, and give a rough
accepted academic practice. No use,
distribution or reproduction is permitted introduction to inhibitors targeting inflammatory factors, hoping to have
which does not comply with these terms. reference significance for subsequent treatment options for AIDs.

KEYWORDS

autoimmunity, inflammation, pro-inflammatory factors, T cells, B cells

Abbreviations: AIDs, Autoimmune diseases; ACPAs, anti-citrullinated peptides/protein antibodies; RF,

rheumatoid factor; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; IgG, immunoglobulin G;
TH0, naïve T cells; TH2, helper T cells 2; TH1, helper T cells1; TH17, helper T cells 17; ILC2s, 2 groups of
innate lymphoid cells; IFN, type I interferon; pDC, plasmacyte-like dendritic cells; BAFF, B-cell activating
factor; SSc, Systemic sclerosis; SS, Sjogren syndrome; pSS, primary Sjogren syndrome; HLA, human leukocyte
antigen; AIH, Autoimmune hepatitis; IBD, inflammatory bowel disease; UC, Ulcerative colitis; CD, Crohn’s
disease; mAb, monoclonal antibody; ISR, injection site reaction; MTX, methotrexate; CAPSs, cryopyrin-
associated periodic syndromes; sJIA, systemic-onset juvenile idiopathic arthritis; PSO, plaque psoriasis.

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Xiang et al. 10.3389/fimmu.2023.1267091

1 Introduction which would trigger its own cytotoxic reaction, eventually resulting
in pathological changes in organ tissues, accompanied by
When talking about autoimmune diseases (AIDs), it is inflammation, which is also called pathological AIDs (2, 4).
necessary to mention the concept of “immune tolerance”, which Helper T cells produce cytokines or recruit inflammatory cells to
is an acquired feature during human development (1). Immune cause tissue damage, while autoantibodies cause cells’ damage or
tolerance is disrupted by immune system disorders leading to death and drive inflammation through mechanisms of interaction
malignant proliferation of autoreactive T and B lymphocyte with their antigen-binding sites (Fab) or crystallizable fragments
populations, which in turn produce an attack response to (Fc), formation of immune complexes, cytolysis or phagocytosis of
autoantigens (2, 3). This process is the basis and root cause of target cells, both of which mediate the emergence of AIDs (5, 10).
AIDs, mainly caused by the immune system’s ineffective judgment At present, there are more than 100 AIDs, including
of self and non-self (4). The occurrence of AIDs usually goes rheumatoid arthritis, Sjogren’s syndrome, systemic sclerosis,
through three stages, first of all, the immune system is blocked juvenile idiopathic arthritis, psoriasis. An important way to
under the stimulation of a variety of factors, at which time the classify AIDs is through systemic and organ-specific distinctions,
immune tolerance has been destroyed. In this process, the activated of which systemic representatives are systemic lupus erythematosus,
innate immune response triggers the emergence of adaptive which occurs in joints, kidneys, lungs, skin, and heart (2). Such
immune response, and T and B cells misrecognize antigens to diseases may have similarities in clinical, immunological and
cause abnormal immune function; Secondly, abnormal genetic characteristics, while organ-specific representatives are
proliferation of innate immune cells (macrophages, granulocytes, type 1 diabetes mellitus that occurs in the pancreas, but different
dendritic cells) secretes a large number of inflammatory factors to AIDs have specific disease characteristics (2, 11).
stimulate abnormal infiltration of T and B cells, and eventually
patients has progressive inflammation and tissue damage; Finally,
the control stage of AIDs is usually limiting the development of 2.2 Epidemiology and diagnosis
autoimmune responses from the internal and extrinsic mechanisms
of cells, and this stage would continue to have the possibility of For the general population, the prevalence of AIDs is about
remission and recurrence (5, 6). 4.5%, of which 2.7% in men and 6.4% in women with significant
In terms of maintaining immune homeostia and preventing differences. The risk of most AIDs in women is much higher than in
immune tolerance, regulatory T cells (Treg cells) are a key cell that men, indicating a bias of AIDs towards women (12). However, there
reduces the activation and proliferation of autoreactive T cells in the is a higher proportion of some disorders in men, including Guillain-
body through cell-to-cell contact and secretion of inhibitory Barré syndrome and ankylosing spondylitis, which show a higher
cytokines in various immune cell subsets mediated by the prevalence than in women (13). The main reason for the gender
regulatory factor Foxp3, one of the key transcription factors for differences in the manifestations of AIDs may be discrepant in the
Treg cell development and function, thereby alleviating the immune systems of men and women, in which diverse categories of
development of AIDs (7). However, due to the changes of Foxp3 lymphocytes are different. Women have more T lymphocytes and
or epigenetics, Treg cells might be unstable or plasticity (TH1-like, show a stronger autoimmune response, which might make women
TH2-like or TH17-like cells) to develop numerical or functional more susceptible to AIDs (14, 15). In addition, the prevalence of
deficits, leading to AIDs (8). Therefore, maintaining the balance Ulcerative colitis (UC) and Crohn’s disease (CD) is at a balanced
between autoimmune effects and immunomodulatory responses is level in the proportion of men and women, so there are
pivotal to treating AIDs (6, 9). Next, this review mainly discusses geographical differences in the incidence and prevalence of
the role of inflammation in AIDs and proposes therapeutic different AIDs in men and women. For example, celiac disease
strategies targeting inflammatory mediators/pathways. usually occurs more in women, but shows a higher prevalence in
men in India (16).
Currently, clinical symptoms, physical examination, laboratory
2 Autoimmune diseases tests, and radiological results are fundamental to the diagnosis of
AIDs. In the case of rheumatoid arthritis, the physical examination
2.1 Features and classification focuses on joint pain, swelling, redness, and rigidity, and laboratory
tests include inflammatory and serological markers (5, 17). In most
Autoimmune reactions are physiological and pathological, and AIDs, an antinuclear antibody (ANA) test can initially screen
physiological autoimmunity is usually a low-level recognition of suspected patients. A positive result indicates that the immune
exogenous antigens by immune cells - T cells and B cells. Because system is under false immune stress, and the higher the number, the
autoantigens have similarities with foreign antigens, the specific greater the probability of developing the autoimmune disease, but
recognition of the two is not well distinguished, so it leads to the there are false positives (18). Hence, once positive is confirmed,
emergence of pathological autoimmunity, which is accompanied by antibody tests are also performed, combined with clinical features to
a decrease in the survival rate and activation threshold of B cells, as obtain more accurate diagnostic information (19).
well as changes in T cell activation and proliferation, which also The reactivity of binding autoantibodies in serum of autoimmune
marks immune tolerance disorders (5, 10). The main feature of patients is a key step in diagnosis, and autoantibodies have been
AIDs is the presence of autoantibodies targeting the bulk tissue, initiated as to be used as a biomarker in the diagnosis of some

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diseases. For instance, autoantibodies against SSA and SSB in frequently connected with risk factors including smoking, obesity,
Sjogren’s syndrome (3), anti-PLA2R antibodies in primary family history of AIDs, immune deficiency, and low vitamin D
membranous nephropathy (20), and IgM anti-dsDNA antibodies status, so these aspects could be used to avoid it when considering
to prevent lupus nephritis (21). These predictive antibodies might be preventive measures for the disease to reduce the probability of the
able to recognize the presence of risk of AIDs and play a preventive disease (22).
role in risk factors (22). Meanwhile, citrullineated products, including Nevertheless, the occurrence of AIDs is caused by a
CPs and citrullineated proteins, began to be used as markers for the combination of genetic susceptibility and environmental factors
diagnosis of RA. CPs were detected by synovial samples from of to contribute an imbalanced response of the immune system
inflammatory joints in RA patients, while anti-citrullinated between self-defense and immune tolerance (2, 4). Environmental
peptides/protein antibodies (ACPAs), which could be converted to factors also play a crucial role, for example, cutaneous lupus might
citrulline by PADs enzymes, disrupting immune tolerance, could be be caused by excessive apoptosis due to ultraviolet radiation, which
detected by mass spectrometry (17). In addition, RA-related possibly results in the production of autoantigens to trigger an
autoantibodies rheumatoid factor (RF) are also an indicator of autoimmune response (26). Meanwhile, genetic and environmental
laboratory testing, but diagnosis must be made in conjunction with factors interact with each other, for example, smoking may
imaging (23). Therefore, the autoantibody immune reactivity in the contribute to the production of autoantibodies in autoimmune
patient is important diagnostic information, which has reference myositis, which is the result of interaction with HLA haplotypes
significance for some potential immune diseases. Autoantibody (11). Therefore, immune-related gene polymorphisms may lower
detection experiments should be carried out on the basis of some the threshold for autoreactive T cell activation, which combined
other test results and clinical features, and finally combined with a with environmental stimulation and improper regulation of
variety of test results to obtain diagnostic conclusions (3, 19). cytokines to lead to tissue damage ultimately.
In addition, inflammatory factors may play a role in the
diagnosis and treatment of diseases by acting as biomarkers of
inflammatory diseases to assess the degree of activity. For example, 3 Autoimmune diseases and
integrin is a key pathogenesis in the mechanism of juvenile autoinflammatory diseases
idiopathic arthritis, and elevated level of it is an important
marker for patients. Meanwhile, testing for CXCL9 may be a The most essential difference between autoimmunity and
useful test for this disease activity (24). Measurement for serum autoinflammation is that the type of immune system disorder is
levels of cytokines or soluble cytokine receptors may make a not the same (27). First of all, it is necessary to understand two
judgment about the efficacy of biologics in patients. Nishina et al. concepts, innate immunity and adaptive immunity, the former is the
found that baseline levels of IL-6R appear to predict clinical first barrier against injury and infection, mainly involving monocytes,
remission after tocilizumab treatment in RA patients, but are not macrophages, neutrophils, but less specificity, while the latter has a
associated with disease activity (25). Therefore, inflammatory stronger resistance but takes more time to appear, produced by innate
factors are not only important players in the pathogenesis of immune stimulation (28). Both activate the conduction of TNF, IL
AIDs, but also have an auxiliary role in diagnosis and treatment. and IFN signaling pathways, but overactivation carries a risk of
autoimmunity and autoinflammation (29). Autoimmunity is an
adaptive autoimmunity, the major body involved is lymphoid T
2.3 Causative factors and B cells, mainly after the autoimmune tolerance is disrupted and
the immune system dysfunction appears a sustained immune
The genetic susceptibility to AIDs may be related to the response to its own cells, which in turn leads to tissue damage and
incidence and risk of diseases. Studies have shown the prevalence clinical features (30).
of first-degree family members and monozygotic twins of patients, However, AIDs and autoinflammatory diseases are similar and
and the matching rate of monozygotic twins is higher than that of potentially linked. Both diseases can cause systemic injury, although
monozygotic twins. The reason is probably the genes of such people the pathways leading to tissue damage are different,
are too similar to the genes of infected people, and then the autoinflammatory diseases are inflammation and damage directly
probability of carrying disease genes would be higher. so the risk caused by the innate immune system, while AIDs lead to the
of disease would increase, indicating vulnerability to these diseases persistence of inflammation through the corresponding pathway
must be rooted at least in part in heredity (10). AIDs, on the other after the emergence of adaptive immunity caused by innate
hand, are often the result of multiple susceptibility genes leading to immunity (28). However, the emergence of adaptive immunity
an abnormal phenotype. At the same time, the presence of involves innate immunity, and long-term stimulation of
susceptibility genes makes gene polymorphisms promote congenital inflammation contributes to abnormal activation and
autoimmunity (10). According to genomic analysis, gene infiltration of T and B cells, which disrupts immune tolerance and
mutations and polymorphisms are strongly associated with the leads to the production of autoantibodies, resulting in
development of AIDs. For example, the correlation between HLA- autoimmunity to aggravate tissue damage and inflammation (28).
DR3, a class II HLA molecule, and autoantibodies, might affect In the meantime, both innate immunity and adaptive immunity are
subtypes of systemic lupus erythematosus, Sjogren’s syndrome, and affected by the cytokine IL-1b. The former manifests IL-1b, as a
autoimmune myositis (11). The emergence of susceptibility is driver of inflammation, might lead to innate immune abnormalities

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to result in the emergence of autoinflammation (31), while the latter injury, accompanied by a persistent inflammatory state (38). RA
is an increase in proliferation of lymphoid T and B cells due to the is usually caused by immune cells soaking the membrane joints. The
impact of IL-1b, which possibly increases adaptive immunity, and if occurrence of synovitis is induced by the infiltration of a large
this process is excessive, it might lead to the development of AIDs number of white blood cells into the synovial compartment, which
(32). Hence, the emergence of AIDs might be accompanied by the is related to immune activation. Under the combined action of
appearance of features of autoinflammation, and the demarcation innate and adaptive immune systems, heterogeneous changes in
between the two is not very well defined clinically. So there are three stromal cells (fibroblasts) in the synovium result in RA (39, 40).
situations in the pathogenesis of immune diseases, namely simple Macrophages polarize to the M1 pro-inflammatory phenotype and
autoimmune mechanism, complete autoinflammatory mechanism produce a large number of pro-inflammatory cytokines (such as
and autoinflammatory-autoimmune mechanism, and clarifying the TNF, IL-1 and IL-6) and pro-inflammatory molecules or mediators
specific pathogenesis is very critical for the treatment of the (such as inflammasomes, reactive oxygen species, MMPs) to
disease (27). promote the ongoing inflammatory process and activate
At present, the treatment strategies of AIDs focus on targeting neighboring T cells, dendritic cells, fibroblast-like synovial cells
lymphocytes, and anti-inflammatory strategies have good results in (FLS), ultimately leading to joint cartilage damage (39, 41); the M2
the treatment of autoinflammatory diseases. From the perspective of anti-inflammatory phenotype is far from sufficient to resist the
pathogenesis, these related cytokines and inflammatory complexes deterioration of inflammation (41). In the remission of RA, a cluster
also play an important role in AIDs. For example, a significant of macrophages, MerTKposCD206pos, has a recovery effect on
increase in IL-18 levels was found in the serum of patients with inflammation and induces the repair capacity of FLS, which
systemic lupus erythematosus, and its expression also correlated with probably helps maintain immune homeostasis in the joints (40),
the intensity of damage and renal activity in patients (33). The innate so the bidirectional action of macrophages works at different stages.
immune system of rheumatoid arthritis patients was activated, so the Adaptive immune cells (such as T-helper-1 and T-helper-17 cells, B
macrophages involved in it released the pro-inflammatory factors cells) begin diffuse infiltration into the synovium, and gradually
TNF, IL-1b, IL-8, and the inflammatory process indicated that the proliferate, differentiate and produce autoantibodies, which also
nlrp3 inflammasome was abnormally activated, which possibly drove produce inflammation-related effector factors (such as IL-10, IL-17)
the stimulation of adaptive immunity, potentially leading to and recruit inflammatory cells (37). This process is accompanied by
autoimmune production (34, 35). These suggest that inflammatory selective activation of aggressive synovial fibroblasts, which produce
processes play an important role in autoimmune responses, and that pro-inflammatory factors and induce the transition from joint
anti-inflammatory strategies might become another effective inflammation to chronic synovitis, while accelerating the
therapeutic measure for AIDs. migration of synovitis to other joints, driving synovial
inflammation and bone erosion (39, 42–44). Hence, the
inflammatory state has always been accompanied by the
4 The role of inflammation in the development of RA, and the degree changes with different stages,
pathogenesis of autoimmune diseases from the initial arthritis to chronic synovitis, and may continue
to worsen.
When the body is subjected to external adverse stimuli, it will ACPAs produced by B cells and rheumatoid factor (RF) are the
stimulate the body’s innate immunity and trigger inflammation, hallmark autoantibodies in RA patients, the former is significantly
followed by the emergence of adaptive immunity. Once the adaptive more specific in patients than the latter, and plays a key role in the
immune system is disordered, it may lead to AIDs. The autoimmune response (42, 45). Individuals with high expression of
microenvironment balance of pro-inflammatory and anti- ACPAs and RF develop acute arthritis for a short time but resolve
inflammatory cytokines in these processes is closely associated quickly, and yet, there is still a possibility of developing chronic
with AIDs, particularly rheumatoid arthritis, inflammatory bowel synovitis. Under the induction of ACPAs, osteoclasts secrete
disease, and systemic lupus erythematosus, which have a persistent CXCL8 to promote neutrophil differentiation and infiltration into
inflammatory response in the pathological features of AIDs (36, 37). the synovial compartment. ACPAs and the immune complex
Therefore, inflammatory dysfunction plays an important role in the between ACPA-IgG stimulates macrophages to produce pro-
pathogenesis of AIDs. Subsequently, inflammation may become the inflammatory factors to drive inflammation by binding to Toll-
treatment direction of the disease. However, there are many AIDs, like receptor 4 (TLR4) and Fc receptors (42). In addition,
and the role of inflammation in different diseases may be different. complement activation or microvascular damage may alter
The potential role of inflammation in the pathogenesis of different vascular permeability to accelerate the transfer of inflammatory
AIDs will be briefly introduced below. cells to the synovium, promoting the progression of RA (45). Thus,
ACPAs and RF-mediated events promote the activation of
inflammation-associated cytokines, increasing the damaging
4.1 Rheumatoid arthritis effects of inflammation and driving the development of chronic
synovitis (39). There are also studies that show in leukocyte-rich
Rheumatoid arthritis (RA) (Figure 1) is a chronic inflammatory RA, levels of inflammatory response genes (PTGS2, PTGER3, and
autoimmune disease characterized by synovitis that clinically ICAM1) in fibroblasts and monocytes are significantly elevated
presents with joint swelling and pain, cartilage erosion, and (46). The above shows that inflammation is an important player in

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FIGURE 1
The pathogenesis of RA. Antigen-presenting cells activate T cells and B cells to trigger adaptive immunity. B cells produce autoantibodies that
stimulate macrophages to secrete pro-inflammatory factors and promote transcription of inflammatory genes. T cell differentiation into TH17 cells
plays a pro-inflammatory role, and IL-4/IL-13 produced by TH2 cells triggers the activation of anti-inflammatory signaling pathways, and the
production of anti-inflammatory factors and anti-inflammatory lipids is conducive to disease reversal. PD1 PD15, anti-inflammatory lipids. APCs,
antigen-presenting cells. TCR, T cell receptor. TLR, Toll-like receptor.

RA, and what are the effects of inflammatory factors and Granulocyte-macrophage colony-stimulating factor (GM-CSF), a
inflammatory mediators produced by these cells on RA? hematopoietic growth factor produced primarily by T cells and
Up to now, there have been two pro-inflammatory factors in the stromal cells, acts as a soluble pro-inflammatory factor that can
pathogenesis of RA, TNF and IL-6, which are the most studied. Both lead to inflammation by stimulating innate immune cells, such as
of them play a multifaceted role in the pathogenesis of RA, which inducing the polarization of the macrophage M1 phenotype and
stimulate the activation of stromal cells to aggravate the inflammatory stimulating the activation of neutrophils (47, 50). Some research also
response. TNF activates NF-kB and induces transcription of indicates that MMPs, highly expressed in RA patients, are derived
downstream inflammatory target genes through binding to TNF1R, from a variety of cells, particularly cadherin-11-positive FLS, where
and also promotes the recruitment of immune cells to the site of proteases such as collagenase and matrix lysin cause severe damage to
inflammation to accelerate tissue damage, while binding to TNF2R cartilage (39). These pro-inflammatory factors activate FLS to release
mediates the function and differentiation of Treg cells to maintain more cytokines, resulting in the recruitment of a large number of pro-
immune homeostasis (47). IL-6, mainly derived from Subliming inflammatory factors in the synovial space, which extremely increases
fibroblasts and B cell (46), activates the intracellular JAK/STAT the number of such cytokines and stimulates the formation of
signaling pathway by binding to receptors, and STAT osteoclasts and the degradation of cartilage. The synergistic effect
phosphorylated by JAK translocates to the nucleus to mediate the between pro-inflammatory factors is required for the pathogenesis of
transcription of target genes, affecting cell proliferation and RA, such as the stimulating effect of TNF-a on IL-6 and the IL-6-
differentiation (47, 48). This signaling pathway exhibits constitutive STAT pathway on IL-17-induced inflammation (47).
phosphorylation activity in both T cells and monocytes. If this At the same time, some anti-inflammatory factors play a role in
signaling pathway is impaired, it could effectively alleviate and disease alleviation in RA, including IL-4, IL-13, IL-5, IL-9, and IL-
improve the progression of RA (49), so JAK inhibitors have good 33 (47). IL-4 and IL-13, mainly produced by helper T cells 2 (TH2)
therapeutic prospects in RA patients. IL-6 also stimulates CD4+ T cell and 2 groups of innate lymphoid cells (ILC2s), activate the
proliferation and differentiation of Treg, Th17, and Tfh cells (47). downstream STAT6 pathway by binding to the receptor to

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promote the polarization process of the macrophage M2 phenotype, reference indicator for SLE activity scores, including the level of
accelerating the release of other anti-inflammatory factors, and C-reactive protein (CRP), a standard marker of inflammation,
inhibit the infiltration of inflammatory cells into the synovium and decreased erythrocyte sedimentation rate (ESR) possibly triggered
the production of pro-inflammatory factors. These effects reduce by inflammation and anemia (57, 58).
the production of osteoclasts and the damage of chondrocytes, so Studies have shown that most patients with SLE have “type I
ultimately the tissue damage and inflammation of RA are alleviated interferon (IFN) characteristics”, and its content and induced gene
(47). The anti-inflammatory effect of IL-5 is mainly manifested in expression are elevated in vivo, which is highly related to the
the recruitment of eosinophils at the site of inflammation, and the pathogenesis of SLE. So IFN is an important pathogenic factor
cells help the resolution of inflammation by the production of IL-4 leading to the destruction of immune tolerance in SLE. Previous
and IL-13 to mediate the differentiation of the M2 phenotype and studies have shown that IFN has antiviral function, which is a key
the secretion of anti-inflammatory lipids (such as PD1, PD15) (47, linker of innate immune response and adaptive immune response.
51). The anti-inflammatory action of IL-9 occurs mainly during the Under abnormal external stimulation, a large number of IFN-a/b
regression phase of RA, which affects the proliferation of ILC2 to produced would affect the activation and proliferation of immune
make Treg cells be activated, and this regressive role on arthritis cells (macrophages, CD8-T cells, B cells) and induce apoptosis of
reduces cartilage damage to relieve inflammation and maintain infected cells (59, 60). But in SLE, the imbalance in the production
immune homeostasis (52). The function of IL-33 on RA varies with and clearance of apoptotic cells leads to an increase in autoantigens,
the stage of the disease. In the early stage, it plays a pro- which might be presented to autoreactive B cells to influence the
inflammatory role by promoting the migration of inflammatory body’s immune tolerance. These induce the emergence of pro-
cells and the release of related factors, while in the regression phase inflammatory factors and autoantibodies and an increase in
of RA, IL-33 affects the proliferation and differentiation of ILC2 and immune complexes to lead to massive deposition of their various
TH2 cells, as well as the tendency to regulatory M2 phenotypic organs and tissues, which might stimulate the response of the
production, especially the activation of Treg cell population, which autoimmune response to result in tissue damage and
are very beneficial for reversing RA (53). inflammation (61, 62). IFN-a, mainly derived from plasmacyte-
In summary, most anti-inflammatory cytokines indirectly or like dendritic cells (pDC), could affect B cells in many ways,
directly mediate the polarization process from macrophage M1 to including stimulating dendritic cells to produce B-cell activating
M2 phenotype, which ultimately influences tissue damage and factor (BAFF, also known as BLyS), increasing the response of B
inflammation. However, there are more than two phenotypes of cells to BAFF and promoting the transformation of B cells (63),
macrophages, and the distribution of polarized macrophage subsets which may increase the production of autoantibodies. Stimulation
varies in different diseases. Studies have shown higher expression of of Treg cell dysfunction by IFN-a may induce disruption of
CD163 in synovitis in spondylarthritis compared with RA, which immune tolerance, but the regulation of Treg cells by IL-2 may
might lead to different outcomes in chronic synovitis (54). In reverse this phenomenon. In addition, IFN stimulates multiple cells
addition to being an autoimmune disease, RA is also a chronic to produce pro-inflammatory and chemokines. It could be seen that
systemic inflammatory disease, in which inflammation is the main IFN plays an important role in the pathogenesis of SLE. Compared
pathological feature. Consequently, figuring out the role of to macrophages in RA, neutrophils are an important factor driving
inflammation in RA is very beneficial to the development of anti- early SLE inflammation and organ damage, which release proteases,
cytokine therapeutic agents. Anti-inflammatory therapy may ROS, and pro-inflammatory factors to stimulate immune disorders
become the first choice for this disease in the future, which has (64). Abnormal subsets have highly expressed NETosis, a cell death
two research ideas, namely inhibitors of pro-inflammatory factors mechanism, which presents neutrophil extracellular traps (NETs),
or agonists of anti-inflammatory factors, but which treatment of RA in which contain pro-inflammatory factors that promote the
is better needs further research. development of inflammation. At the same time, NETs as
autoantigens also stimulate the emergence of anti-neutrophil
cytosolic antibodies to form immune complexes, which promotes
4.2 Systemic lupus erythematosus more IFN production (62, 65). The immune complexes formed by
these processes are absorbed by phagocytes, DCs, and pDCs
systemic lupus erythematosus (SLE) (Figure 2), as a systemic through the Fc receptor to activate autoreactive T and B cells in
autoimmune disease, is also a chronic diffuse connective tissue the immune system (6, 57). Immune complexes may be deposited in
disease that invades the systemic system, which often occurs in various organs if they are not effectively cleared, leading to tissue
women, and clinically manifests skin lesions, arthritis, kidney damage and inflammation (6).
disease, hematologic changes, with a great risk of cardiovascular The expression of many cytokines in SLE is at an increased level,
morbidity (55). The main feature of SLE is that the process of which affects the destruction of susceptibility and tolerance of SLE
destruction of immune tolerance is accompanied by the emergence (65). These factors are dysfunctional before the appearance of
of autoantibodies and immune complexes, which lead to the clinical features of SLE, of which IL-18 and TNF are the two
dysfunction of T cells and B cells and the abnormal increasement most important pro-inflammatory factors. Both could be used as
in some cytokines (56). Such disease usually leaves most organs in inflammatory markers of SLE, are extremely elevated in patients,
an inflammatory state and tissue damage, and the degree of and their expression has a great correlation with the degree of SLE
inflammation of each organ is often used as an important activity (56). IL-18 and IFN-g are positively correlated, possibly

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FIGURE 2
The pathogenesis of SLE. The appearance of NETosis in neutrophils promotes the secretion of IFN-a/b by pDC cells to stimulate the body’s innate
immunity and adaptive immunity, while the frontal interaction between inflammatory cells and lymphoid T and B cells results in the production of a
large number of inflammatory factors. APCs, antigen-presenting cells. TCR, T cell receptor. BCR, B cell receptor. BAFFR, B-cell activating factor
receptor. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.

because IL-18 induces the production of IFN-g, while IFN-g in turn malignant consequences (71), suggesting that the effect of TNF-a
affects the expression of IL-18-binding proteins, so the synergy on lupus may vary depending on the state and tissue of the disease
between these two factors promotes the development of SLE (56, 66, (i.e., the former is the lupus susceptibility model and the latter is the
67). However, IL-18-binding proteins may produce a negative experimental SLE). These all show that the ambiguity of the effect of
feedback regulation to reduce the production of IL-18 and IFN-g, TNF-a on SLE, and how its interaction with the receptor would
which has been confirmed in some preclinical studies, and it may be have on SLE is not very clear. Subsequent experiments are needed to
a new idea in the treatment of SLE (67, 68). These proteins appear to explore, but the pro-inflammatory effect of TNF-a on inflammation
play the role of inhibitors in IL-18 and IFN-g. The role of TNF in in SLE is very clear (72). In addition, IL-17, as a pro-inflammatory
SLE is currently controversial, although TNF is involved in factor, recruits inflammatory factors, chemokines, and
autoimmune responses in a variety of pathways, including inflammatory cells to the tissue site to affect inflammation and
immunomodulatory effects through the effects on proliferation, damage (65). The IL-23/IL-17 axis formed by its combination with
differentiation and cytokine secretion of B-cells, T cells, and IL-23 may be positively correlated with the severity of SLE, mainly
dendritic cells, and the pro-inflammatory effects on the because Th17 cells acting on IL-23 could produce IL-17 and expand
aggregation of neutrophils and activation of monocytes, and the it to drive the development of inflammation (73). Meanwhile,
stimulation of IFN expression (69). Preclinical studies have shown studies found that the IL-12/IL-23 axis appeared to play a role in
that after administration of high doses of TNF-a, lupus-susceptible SLE, and targeting this mediator may inhibit the progression of the
mice delayed disease onset without preventing the onset of disease disease. It could be seen that the inflammation of SLE is produced
(70), while TNF-a in mice already suffering from lupus might have by the combined action of many factors.

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4.3 Systemic sclerosis response, microvascular damage and oxidative stress, which
trigger fibrosis (74, 77), in which oxidative stress plays an
Systemic sclerosis (SSc) (Figure 3), also known as scleroderma, important role. Abnormal oxidative stress has been found in SSc
is an autoimmune chronic fibrotic disease, clinically manifested as patients, that is, excessive production of ROS and an imbalance
skin hardening of the limbs and face, essentially caused by severe between oxidation and oxidation, and its effect with the
skin fibrosis. In the early stage of the disease there is no obvious inflammatory response (i.e., the effect of ROS on macrophage
specific clinical feature, making early diagnosis very difficult, so it polarization and activation of inflammasome NLRP3 (78)) may
can only be judged by the Raynaud’s phenomenon due to promote the development of vascular lesions, and its induction
endothelial dysfunction, autoantibodies and skin phenotype. In effect on autoimmune disorders, endothelial dysfunction, and
the terminal stage, the disease deterioration is more serious to be fibrosis is conducive to maintaining the pro-inflammatory state of
easily diagnosed, including ulceration of the fingers, joint SSc (79, 80).
contractures, sclerosis (74, 75). As a systemic disease, SSc is In the adaptive immune process, T cells undergo inflammatory
usually manifested in the kidneys, heart, gastrointestinal tract, infiltration and abnormal expression, and partially differentiate into
and musculoskeletal disease, especially the emergence of pathogenic T cells (such as Th17, Th1, TH2), which secrete pro-
interstitial lung diseases, which is the main cause of SSc’s death. inflammatory factors to aggravate early tissue inflammation.
Therefore, screening patients with SSc for organ involvement is Dysfunctional imbalances between pathogenic T cells and cells
critical (75). (Treg cells) which are beneficial to maintain immune homeostasis
The main pathological features in the pathogenesis of SSc are and abnormal differentiation of Treg cells might lead to SSc (77, 81).
vascular lesions, immune system disorders, and skin fibrosis, which At the same time, IL-4 and IL-13, secreted by TH2 cells, exert a
are closely related and accompanied by the emergence of early profibrotic role in SSc driving the deposition of ECM in fibroblasts,
inflammation, an important factor in inducing fibrosis (76, 77). which is different from the disease-reversal effect shown in RA (81).
Firstly, under endogenous or exogenous stimulation, vascular B-cells activated by BAFF are stimulated by DC-presented antigens
lesions occur, and abnormal expression of vasoactive molecules to produce autoantibodies that may have the ability to maintain and
changes vascular permeability, when endothelial cells are damaged stimulate fibrosis of SSc (82), for example, the induction of
or apoptosis and activated, recruiting inflammatory cells and persistent apoptosis of endothelial cells by endothelial
immune cells (such as monocytes/macrophages, pDC) to the autoantibodies (AECA) is beneficial to fibrotic lesions in SScs
lesion site to cause inflammatory infiltration, and activating the (83). B cells also secrete IL-6 to induce proliferative differentiation
innate immune response. These cells are activated to release pro- of autoreactive T cells and have pro-inflammatory effects, while
inflammatory and chemokines to induce tissue inflammatory direct or indirect contact between B cells and other cells is involved

FIGURE 3
The pathogenesis of SSc. Upregulation of vasoactive factors affects apoptosis of epithelial cells, followed by cytokines that stimulate the immune
response in the body, and the inflammatory response that occurs eventually triggers the transformation of fibroblasts, leading to the formation of
skin fibrosis. ECM, extracellular matrix. CXC, chemotaxis.

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in the induction of fibrosis, cell activation and apoptosis, vascular SSc have been discussed above. It can be seen that inflammation is
lesions, and immune dysregulation processes (82). Moreover, T and an important player in the pathogenesis of SSc.
B cells stimulate the proliferation, differentiation, and synthesis of
fibroblasts in SScs by secreting cytokines (e.g., TNF-a, IL-6, TGF-
b), promoting the progression of fibrosis (84, 85). This process leads 4.4 Sjogren syndrome
to persistent inflammatory infiltration of SSc, which is linked to
subsequent fibrosis and matrix deposition. Sjogren syndrome (SS) (Figure 4) is a chronic systemic
During the inflammatory phase, macrophages are activated to autoimmune disease, but it is more common in the lacrimal and
polarize into the M1 type, producing a large number of pro- salivary glands, and clinically manifests as keratoconjunctivitis
inflammatory and chemokines, especially TGF-b (mainly sicca, dry mouth (89). SS is divided into primary Sjogren
produced by macrophages), which leads to pathological fibrosis. syndrome (pSS) and secondary Sjogren syndrome (sSS), in which
Early studies clearly showed that TGF-b is the most important sSS appears on the basis of other immune diseases (such as RA,
effective inducer in fibrosis, stimulating the activation of fibroblasts SSc), so other AIDs have the possibility of sSS, and the symptom
and differentiation into myofibroblasts (the main effector cells for may overlap. The main pathological feature of SS is the dysfunction
fibrosis formation), which could also be obtained through of the exocrine glands (mainly lacrimal and salivary glands), which
endothelial-mesenchymal transformation of endothelial cells. is caused by the infiltration of the exocrine glands by immune
Myofibroblasts produce large amounts of collagen and express a- cells (90).
SAM, resulting in abnormal increase and excessive deposition of the Abnormal external stimuli triggers apoptosis or necrosis of cells
extracellular matrix (ECM), which causes fibrosis (86, 87). The in epithelial tissue and causes local inflammation of the gland, while
other effects of TGF-b on fibrosis have been described in other Serena et al. showed that the induction of tissue inflammation of the
literatures, so they would not be repeated here. The occurrence of gland to autophagy (anti-apoptotic pathway) of salivary gland
fibrosis and inflammation are inseparable, and chronic epithelial cells derived the activation of these cells in
inflammation is one of the pathological features of SSc, so inflammatory pSS (91). The activated epithelial cells secrete
inflammation must play an important role in the pathogenesis of cytokines (pro-inflammatory factors, chemokines, BAFF), and
SSc. In addition to being the cause of fibrosis, its related pro- upregulate the expression of adhesion factors to recruit immune
inflammatory factors and inflammatory mediators are also key cells (DC, lymphoid T and B cells) to the site of injury of the gland,
participants in the pathogenesis of SSc. These pro-inflammatory which makes them abnormally activated (92, 93). T cells are the
factors not only act as promoters of inflammation, but also are a core players in the pathogenesis of SS, of which CD4 T lymphocytes
mediator to induce pathological fibrosis. For example, in SSc lung account for the main (7). CD4 T cells are essentially immune
fibroblasts, inflammatory some NLRP3 mediated collagen synthesis regulation as a helper T cell. According to scRNA-Seq, studies have
by increasing miR-155 expression to promote fibrosis (88), while shown specific expansion of CD4 T cells in pSS patients, and the
the effects of inflammatory factors IL-6, TNF-a, IL-4, and IL-13 on pathogenic effects of their cell subsets TFH, TH17, TH2 on SS have

FIGURE 4
The pathogenesis of SS (take the lacrimal glands as an example). The cytokines produced by epithelial cells stimulate the secretion of inflammatory
factors by monocytes and macrophages and the joint response of inflammasomes, which combine with the interaction between bound immune
cells, ultimately leading to inflammation. NLRP3, inflammasomes. CXC, chemotaxis.

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also been confirmed in multiple studies (94). In the lip salivary interaction between this cell and innate, adaptive response leads to
glands, high expression of TH2-related factors in infiltrating the occurrence of SS. In NZB/W F1 mice it has been verified that
lymphocytes stimulated the formation of ectopic GC, which may persistent inflammatory stimulation produced gland dysfunction,
be beneficial for infiltrating B cells to produce autoantibodies. which was a catalyst for the development of SS-like diseases (107).
Therefore, compared with its role in RA, TH2 may play a At the same time, inflammation may be presented as a pathological
pathogenic effect in SS (95). feature of SS, including conjunctivitis, the complication interstitial
Stimulated by DC, T cells, and BAFF, B cells are overactivated. pneumonia. Studies have shown that infiltration of inflammatory
The hallmark event is the presence of ectopic germinal centers cells (macrophages) is not much associated with the degree of MSG
(GCs) in the glands of SS patients, followed by the production of lesion in SS patients, but may be related to adverse prognostic
autoantibodies that interfere with the expression of muscarinic factors or later systemic features (108), which indirectly illustrates
receptors on the glands and the formation of immune complexes the expression of inflammation in the late stage of SS.
with ribonucleoproteins to worsen the infiltration process of
immune cells to circulate the cycle of immune activation,
eventually leading to tissue damage (89, 92, 96). At the same 4.5 Ankylosing spondylitis
time, immune cells secrete cytokines (such as IL, TNF, MMPs) to
damage the gland. IL and TNF, in addition to aggravating the local Ankylosing spondylitis (AS) (Figure 5), also known as
inflammation of the gland, destroy the release of acetylcholine to radiographic axial vertebral osteoarthritis (radiology axSpA), is a
affect its effect on gland receptors, while MMPs interfere with the chronic systemic inflammatory rheumatoid disease. The main
interaction between gland cells and cytoplasmic matrix, which leads pathological features of AS are inflammation of spinal attachment
to obstruction of gland secretion, thereby making gland dysfunction points and sacroiliac joints, accompanied by inflammation of
(92, 97). tendons and formation of ligamentous osteophytes, making it
The innate immune process of SS is accompanied by the have osteogenic changes and osteolytic bone destruction,
infiltration of monocytes, and the presence of a large number of eventually leading to abnormal bony rigidity. AS is clinically
macrophages is detected. The number of monocytes is positively manifested as arthritis, inflammatory back pain, spinal
correlated with the level of tissue inflammation, and the resulting dysfunction that obstructs movement and extra-articular
inflammation may drive the activation of epithelial cells, which complications (109–111).
affect the release of pro-inflammatory factors and the proliferation As an immune-mediated inflammatory disease, is AS classified
and differentiation of inflammatory cells, thereby maintaining the as autoinflammatory or autoimmune disease? This point is not
inflammatory state of the gland (98). Meanwhile, the activation of clearly defined. Both innate and adaptive immunity are involved in
inflammasome NLRP3 and the upregulation of downstream the pathogenesis of AS, among which human leukocyte antigen
caspase-1, IL-1b and IL-18 expression in infiltrating monocytes (HLA)-B27 has a strong correlation, with only about 20% genetic
and macrophages were observed in patients with pSS. NLRP3 correlation, but may be an important predisposing factor of AS.
appeared to be activated by purinergic P2X7 receptors (P2X7R) There are related “articular peptide theory” and misfolded protein
and DNA deposits produced by persistent inflammatory conditions, response hypothesis, the former is that HLA-B27 presented
and it ultimately mediated the pathogenesis of SS with the IFN antigenic peptides trigger lymphocyte cross-reaction, and the
pathway (99–101). Studies have also shown that in SS, angiogenesis abnormal adaptive immune response triggered is the basis for
was associated with gland inflammation. Neo angiogenesis autoimmunity. The latter refers to the accumulation of incorrect
accompanied by epithelial tissue lesion processes leaded to or partial folds of HLA-B27 in the cell results in an endoplasmic
increased infiltration of monocytes, and the presence of vascular reticulum (ER) stress response, which may lead to the activation of
endothelial growth factor was detected in the inflammatory cells of the unfolded protein response (UPR), subsequently triggering the
the gland, so the formation of micro vessels may reflect the degree of activation of NF-kB. This induces the release of pro-inflammatory
chronic inflammatory lesions of gland tissue (102). At the same factors in nuclear cells/macrophages and promotes the
time, in the inflammatory microenvironment of SS patients, pro- development of AS inflammation, which indicate the
inflammatory factors produced by inflammatory cells and immune inflammatory effects of HLA-B27 on AS (112, 113). The specific
cells form a complex cytokine network to intervene in the disease mechanisms of these two hypotheses have not been fully elucidated,
process. For instance, in AQP5-Cre mice, the upregulation of TNF- and have not been fully combined, and are still partially questioned.
a expression weakened the immune dysfunction of the salivary In addition to the importance of HLA-B27, the correlation
glands and induced inflammation, accompanied by atrophy of between the IL-23/IL-17 pathway and AS has gradually been
acinar cells to reduce saliva secretion (103); In mouse models, IL- revealed by more experiments. IL-23 itself could drive attachment
17 secreted by TH17 cells reduced saliva flow rate and aggravated inflammation in spondyloarthropathy by binding to receptors
glandular tissue damage (104); In SS, levels of IL-6 were associated affecting Rag-dependent cells (114), while ER stress induces
with the amount of monocyte infiltration, inflammation of the macrophage polarization stimulation to produce IL-23 to
salivary glands, and TH17 production (105). upregulate the expression of transcription factor Blimp-1 through
In the pathogenesis of SS, inflammation may be an important STAT3-dependence, inducing the differentiate of pathogenic helper
element of salivary gland epithelial cell activation, and the concept T17(TH17) cells to develop an inflammatory cascade (115). TH17
of “autoimmune epitheliitis” has been proposed (106), and the cells specifically express the transcription factor ROR-gt to induce

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FIGURE 5
The pathogenesis of AS. ER stress triggered by the HLA-B27 gene may be the trigger for AS, and the T cell cross-reactivity triggered by the formed
complex may also be one of the triggers. The IL-23/IL-17 pathway in the body plays an important role in the overall pathogenesis and is an
important player in leading to inflammation and cartilage damage. MIF, macrophage migration inhibitor. TCR, T cell receptor.

transcription of the IL-17 gene. Subsequently, the production of IL- the secretion of a large number of pro-inflammatory factors (TNF-
17 promotes the secretion of IL-1, IL-6, TNF-a by other cells. IL-17 a, IL-1b and IL-23) after polarization and the stimulation of
is synergistic with these factors to exert pro-inflammatory effects, lymphoid T cell activation by antigen presentation (119). In
ultimately inducing joint inflammation in AS (116). IL-17 could inflamed tissues, macrophage migration inhibitor (MIF), mainly
also stimulate the activation of osteoclasts to inhibit bone produced by neutrophils, acts as the upstream driver of pro-
regeneration, but the downstream cytokine IL-22 of IL-23 has the inflammatory factors and promotes the activation of TH17 cell-
effect of inducing osteoblast activation to stimulate bone like phenotypes, which accelerate the emergence of SpA-like clinical
proliferation (114, 117), so the IL-23/IL-17 pathway may explain features (120). Existing studies have shown that intestinal disorders
the existence of two contradictory phenomena of bone erosion and have a strong correlation with the inflammation of AS. ILC3 in AS
new bone formation in AS patients. However, in another study, patients with intestinal inflammation migrated to peripheral blood,
although it was confirmed that IL-23 and IL-17 expression were at synovial fluid and bone marrow (BM) to expand after intestinal
an increased level and positively correlated in AS, it was shown that polarization to participate in the development of AS, as well as
IL-23R-positive g/d T cells in peripheral blood secrete IL-17 to produce IL-17 and IL-22, in response to IL-23 to induce
mediate the progression of AS, rather than TH17 cells, which may inflammation (121); In AS patients with intestinal inflammation,
be related to the sample site of AS selected in the experiment (118), overexpression of NLRP3, NLRC4 and AIM2 were observed in
indicating that the sources of IL-17 are multifaceted, including inflammatory-infiltrating monocytes and epithelial cells, which
neutrophils, macrophages, and innate lymphocytes. might be driven by gut bacteria. And then, the inflammasome
Although both innate and adaptive immunity are involved in regulated IL-17, IL-22 and IL-1 expression through IL-23b
the pathogenesis of AS, according to the current research results, induction, indirectly affecting the IL-23/IL-17 pathway. Intestinal
the innate immune system occupies a dominant position, in which dysbiosis may induce activation of innate immunity, and the
innate immune cells (neutrophils, monocytes, macrophages, ILCs) resulting inflammasome activation may be involved in the
play a key role. The role of macrophages in AS is mainly reflected in formation of intestinal inflammation (122), so the effect of

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intestinal dysregulation on inflammation may be involved in the minimal in the pathogenesis of AS, and not many experiments have
development of AS, which possibly has strongly associated with the revealed it, but specific autoantibodies have been detected in serum
ILC3 population of intestinal origin. samples of AS patients (127). Immune complexes, B cell activation
In addition to being a pathological feature of AS, inflammation and immune tolerance disruption all seem to be verified (110),
is an important driver in the pathogenesis of AS. Early making AS seemly have some characteristics of autoimmunity and
inflammation leaded to the destruction of intervertebral discs, as AIDs possibly. Although more evidence suggests that AS is more
followed by focal bone erosion and cartilage damage. This likely to be a chronic autoinflammatory disease, autoimmunity and
sustained destruction eventually contributed to excessive tissue autoinflammation seem to be connected in the pathogenesis of AS,
formation and ectopic chondrocytes formation (123). The but a clear dominance of one may help the study of the treatment
dysfunction of the inflammasome on the activation of strategy of this disease. The autoimmune characteristics in AS
autoreactive T cells and the effect of pro-inflammatory factors on should be explored later, such as the role of autoantibodies, which
bone hyperplasia have been confirmed (124), indicating that is conducive to a clearer elucidating of the pathogenesis of AS.
inflammation is an important cause of AS. In the late stage of AS,
inflammation is more present as a pathological feature in various
organs of the patient, such as arthritis, enthesitis and uveitis. One 4.6 Autoimmune hepatitis
study showed that the occurrence of inflammation in the advanced
stage of SpA was greatly correlated with IL-17, but situ analysis of Autoimmune hepatitis (AIH) (Figure 6), one of the most
IL-17 in the patient’s bone tissue samples showed that it was mainly common autoimmune liver diseases (AILD), is a persistent
produced by granulocytes, not TH17 cells (125), in which mast cells inflammatory disease with women as the main affected
released stored exogenous IL-17A to amplify local tissue population. The main pathological features of AIH are interface
inflammation of peripheral SpA (126).Therefore, from the hepatitis, autoantibodies and lymphocyte infiltration, but there is no
cytokine sources, innate immunity seems to be more involved in significant specific clinical phenotype, making diagnosis very
the pathogenesis of AS than adaptive immunity, and has a greater difficult, and later inflammation, liver fibrosis and liver failure
correlation with it. would occur (128, 129).
In the adaptive immune response to AS, more research has The core key to the pathogenesis of AIH is the destruction of the
shown that TH17 cell responses trigger inflammation in AS. In liver’s immune tolerance, which triggers the imbalance between
mouse models of SpA, the presented antigen activated cytotoxic effector cells and Treg cells in the liver. This results in the liver’s
CD8+ T cells, and immunodeficiency appeared to increase these immune response to autoantigens, eventually leading to
immune responses, leading to the emergence of SpA-like diseases autoreactive liver damage and continuous occurrence (129), and
after combining genetic predisposition to dysfunction and the liver dysfunction leads to liver failure. Regulation of T cells plays
autoreactivity of Treg cells (110). The role of B cells seems to be a key role in the pathogenic process of AIH. After the resting

FIGURE 6
The pathogenesis of AIH. The activation of T cells by antigen-presenting cells prompts them to differentiate into multiple cells, which act in tandem
with B cells and innate immune cells by secreting different inflammatory factors to promote apoptosis and damage of liver cells, which eventually
leads to the appearance of chronic hepatitis. Treg cells, regulatory T cells; DAMP, damage-related molecular patterns. APCs, antigen-presenting
cells. CLT, Cytotoxic lymphoid T cells.

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antigen-presenting cells (APCs) are activated, the autoantigen cells to make it malfunction, eventually inducing persistent chronic
peptide is presented to the naïve T cells (TH0) through the T cell inflammatory states (139); Toll-like receptors on CD14 monocytes
receptor (TCR), so that TH0 is differentiated into TH1, TH2 and were stimulated by damage-related molecular patterns (DAMP) to
TH17, and recruited to the site of liver injury (130, 131). In the liver, activate inflammasome NLRP3 and its signaling pathway, so that
a variety of cells could act as APCs, including dendritic cells, Kupfey the secretion of IL-12, IL-1b and IL-18 was enhanced. Under the
cells, hepatic sinus endothelial cells, hepatic stellate cells (132). TH1, action of inflammatory factors, Treg cells transformed to a pro-
TH2 and TH17 exert pathogenic effects, TH2 secretes IL-4, IL-10, inflammatory phenotype to cause dysfunction, thereby promoting
1L-13 to promote the maturation of B cells, thereby promoting the autoimmunity, while monocytes also stimulated apoptosis of
production of autoantibodies (130, 131), such as ANA, anti-smooth hepatocytes to aggravate hepatitis (140). Therefore, the regulation
muscle antibodies (SMA), anti-liver and kidney microsomal type 1 of Treg cells by the pro-inflammatory environment may be a key
(anti-LKM1) antibodies, anti-LKM3 antibodies and anti-hepatic factor in the pathogenesis of emerging AIH. In the ConA-induced
cytoplasmic type 1 (anti-LC1) antibodies, these autoantibodies bind AIH mouse model, it has shown that pathogenic NLRP3 had a
to hepatocytes to cause toxic reactions (130); IL-2 produced by TH1 promoting effect on liver injury and hepatitis, which might be
induces the expression of HLA class I molecules on cytotoxic T activated by ROS produced by inflammatory cells in the inflamed
cells, while the resulting IFN-g provokes the expression of HLA site. Subsequently it stimulated caspase-1-mediated pyroptosis and
molecules on hepatocytes, and ultimately stimulates effector T cells IL-1b production to aggravate damage and inflammation in AIH
to trigger adaptive autoimmunity. TH17 secretes IL-17 and IL-22 to (141). In addition, the infiltration of inflammatory cells in AIH
affect hepatocyte damage and tissue inflammation (130, 131), and patients is observed, which play an important role in maintaining
the above process eventually leads to liver parenchymal damage and the state of hepatitis through a large amount of pro-inflammatory
worsening of inflammation. factors. Macrophages can be stimulated by IFN-g secreted by TH2
In AIH, Treg cell defects are advantageous for the maintenance to produce IL-1, TNF-a (130), while monocytes are activated to
of autoimmune responses and loss of immune tolerance. Stimulated spontaneously migrate to the site of liver injury to aggravate the
by TGF-b, TH0 differentiates Treg cells to produce anti- degree of inflammation. The over-activation of monocytes seems to
inflammatory factors that play a role in maintaining immune be enhanced by conventional Treg cells (142). Therefore, in
homeostasis (130). Treg cells themselves are functionally repaired addition to directly accelerating liver injury and inflammation,
in immunoregulation, and although previous experiments have inflammatory mediators could mediate the action of T cells in
confirmed that the number and proliferation of CD4+CD25+Treg autoimmunity to influence the pathogenesis of AIH.
cells are reduced in active disease (133, 134). More studies have
shown that the number and expansion of functional CD4+CD25
+FOXP3+Treg cells are increasing in AIH patients. The frequency 4.7 Inflammatory bowel diseases
of Treg cells increases with the degree of inflammation in patients,
and they migrate and accumulate to inflamed parts of the liver, Inflammatory bowel diseases (IBDs) (Figure 7) are an
which appears to be associated with stimulation of the inflammatory autoimmune disease characterized by chronic
inflammatory factors TGF-b, IL-2, and the chemokine CXCR3/ intestinal inflammation, mainly including Crohn’s disease (CD)
CXCL9 (135–137). This contradictory result seems to have and ulcerative colitis (UC). The clinical manifestations of IBDs
population differences with a phenomenon of patient involve abdominal pain, diarrhea, blood in the stool, and weight
heterogeneity, that is, the number of Treg cells decrease in loss. UC usually occurs only in the colon and rectal mucosa, while
pediatric patients but enrich in the adult’s liver. This is possible CD possibly occurs in all parts of the gastrointestinal tract (143,
because the child’s development is not mature enough, so Treg cells 144). The appearance of IBDs may have the following causes:
are not very resistant to the effects of external adverse stimuli. The impaired mucosal barrier, intestinal flora infection, immune
difference in the selection criteria for Treg cells in the previous and dysregulation, intestinal dysbiosis (145). The root cause of IBDs
later studies might make the final conclusion different, which needs may be a disorder of the mucosal immune system, which may be
to be confirmed by further experiments. However, immune system triggered by damaged intestinal epithelial cells or abnormal
disorders in the AIH have greatly increased apoptosis in Treg cells intestinal flora. The dysregulated mucosal immune system
(138), although whether this affects Treg cells’ control of the disease produces an excessive immune response to the normal microbial
has not been experimentally explained. composition of the intestine to lead to the destruction of intestinal
However, Treg cells may undergo pathogenic transitions in immune tolerance, thereby inducing intestinal inflammation (146).
AIH. Arterbery et al. found that newly onset AIH patients had the The pro-inflammatory factors and chemokines secreted by
transformation of FOXP3 Treg cells to a pro-inflammatory intestinal epithelial cells after injury promote the infiltration of
phenotype, that was, an increase in the frequency of TH1-like innate immune cells to the inflammatory site (147), while the
Treg cells and TH17-like Treg cells. Subsequently, secretion of antimicrobial peptides produced by epithelial cells that have a
effector factors IL-17 and IFN-g were important participants in the protective effect on the body are reduced in IBDs patients. This
pathogenesis of AIH. This transition seemed to be related to the increases the enrichment of immune cells and the translocation of
negative impact of the inflammatory microenvironment on Treg intestinal flora, thereby inducing inflammation, in which defensins
cells. Inflammatory factors secreted by monocytes (such as IL-12 have antibacterial properties. However, in UC patients, under the
and IL-6) might promote the pro-inflammatory phenotype of Treg inducement of the pro-inflammatory factor TNF-a, IL-6, the

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FIGURE 7
The pathogenesis of IBDs. The occurrence of IBD is often accompanied by immune disorders, intestinal flora disorders, and metabolic disorders,
which are related to the imbalance regulation between inflammatory cells, immune cells, and intestinal groups. The damage of this intestinal
epithelial cell triggers a cascading response by the immune system, and the various cytokines produced can trigger the destruction of the intestinal
mucosal barrier, leading to the appearance of intestinal inflammation.CLT, Cytotoxic lymphoid T cells. CXC, chemotaxis.

abnormal increasement of HBD-2 of Defensin-b may exacerbate adversely affect IBDs (147). So, these innate immune cells are key
the inflammatory response (148). Under normal conditions, M2 initiators or continuators of IBD.
macrophages secrete anti-inflammatory factors to maintain The pathogenic TH17 immune response appears to dominate the
immune homeostasis, but once overstimulated, there would be a pathogenesis of IBD, performing key pro-inflammatory processes.
tendency to polarize to M1 type (147). Local inflammatory TH17-related cytokines seemingly have increased expression at the
microenvironment of the intestine might stimulate the site of inflammation in IBD patients, in which IL-17 expression in the
transformation of macrophages to pro-inflammatory phenotypes. inflamed mucosa of active CD and UC patients was significantly
Studies have shown that there is a unique subset of intestinal increased, mainly derived from monocytes/macrophages and T cells
macrophages CD14 in the inflamed mucosa of IBDs patients, (148). IL-17 would aggravate the induction and persistence of
which are obtained by abnormal differentiation of macrophages inflammation by increasing the expression and production of pro-
induced by IFN-g. Under the action of coexisting bacteria, excess inflammatory factors. The differentiation of IL-17-producing T cells
IL-23, TNF-a, and IL-6 produced by macrophages may induce can be induced by TGF-b stimulated by IL-6, while the inhibitory
effector T cells to produce IFN-g in response to TH17/TH1 cell effect of TGF-b on TH1 and TH2 differentiation indicates its anti-
responses. The forming IL-23/IFN-g axis affects local inflammation inflammatory potential, and this difference appears to be related to
in the gut, while the role of IL-23/IL-17 axis may be more systemic or local expression (150). However, studies have shown that
manifested in systemic inflammation (149). In addition, TH17 cells induced by TGF-b and IL-6 appear to be non-pathogenic,
macrophages can also stimulate TH17/TH1 differentiation as while IL-23/IL-6/IL-1b stimulation produces inflammatory TH17 cell
antigen-presenting cells. DC cells undergo antigen presentation to phenotype (151), which indirectly explains the disease-promoting
activate the immune response of T cells. Next, IL-23 secreted by effect of the IL-23/IL-17 axis. Th17 cells also indirectly promote the
these two cells after activation not only participates T cell migration and recruitment of neutrophils by secreting IL-17 to
differentiation, but also stimulates ILCs to produce IL-22 to induce other factors, while neutrophils in turn present antigens to
promote epithelial cells to produce antimicrobial peptides to stimulate T cells (152), thereby maintaining the occurrence of
maintain intestinal homeostasis, but dysfunction of ILCs may still intestinal inflammation.

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A healthy gut microbiota is an important factor in maintaining countries for monotherapy or combined administration, and is
homeostasis, but the presence of ecological disturbance in the co- widely used to treat moderate and severe RA, active AS, and
existing flora could have an adverse effect and increase the burden psoriasis (161), which might have better relief when used early in
of chronic inflammation. In IBDs patients, the number of anti- the disease. However, IFX undergoes loss of response over time and
inflammatory properties (eg, Bifidobacteria) decreases, while serious adverse effects, such as infection, infusion reactions,
pathogenic adherent Escherichia coli has an abnormal increase hypersensitivity reactions (160), which lead to greatly reduced
(153), which adheres to and invade intestinal epithelial cells patient compliance, so when treating these immune-mediated
(154). Its continuation of intestinal inflammation may be inflammatory diseases, active therapeutic drug monitoring (TDM)
achieved by mediating the differentiation of TH17 cells, the of IFX leads to better outcomes (162).
development of Treg cells, promotes the differentiation and Biosimilars of IFX are currently approved by the FDA and EMA
recruitment of inflammatory cells, and stimulates the release of for the treatment of IBD, including PF-66438179, CT-P13, SB-2,
their pro-inflammatory factors, ultimately resulting in the presence ABP 710 (163). CT-P13 (Remsima) is the first developed IFX
of more pathogenic T cells in the gut (155, 156). At the same time, biosimilar, produced in the same cell line (an SP2/0 murine cell
deficiencies of inflammasome NLRP6 in gut may alter the ecological line), with the same amino acid sequence, and the efficacy, safety,
regulation of the fecal microbiome to drive the onset and worsening and immunogenicity in most clinical trials are comparable to IFX
of intestinal inflammation (157). Studies have also shown a (163). While CT-P13 is commonly administered intravenously,
correlation between malnutrition, intestinal flora and intestinal subcutaneous CT-P13 has been developed and shown to have a
inflammation. A stronger response to inflammation was observed similar safety and durability to intravenous treatment for IBD
in nutrient-deficient individuals, which might aggravate the (NCT02148640), resulting in higher patient satisfaction and
inflammatory response to produce more pro-inflammatory acceptance (164). This route of administration shift not only
factors, ultimately leading to systemic chronic inflammation. improves patient compliance but may also help reduce the risk of
Intestinal inflammation and impaired mucosal barriers might lead infection. Moreover, a 13-year global study of CT-P13 after its
to bacterial translocations to alter gut microbial composition, which launch is ongoing (NCT02557295) (165). SB-2 differs from
influenced the metabolism and absorption of nutrients (158). In the Infliximab in that the murine cells used (a Chinese hamster ovary
meantime, inflammatory factors reduced the synthesis of metabolic (CHO) cell line) are different, which may lead to differences in C-
hormones by activating NF-kB, and affected appetite, which was terminal Lys residues, changing the proportion of their different
not conducive to the body’s absorption of nutrients, aggravating the charge isomers, but this does not affect the site recognition and
body’s malnutrition (159). This whole process is the result of a antigen fragment binding of SB-2, which has a high degree of
vicious circle, which also explains the clinical characteristics of biological similarity with IFX. SB-2 is currently approved by the
weight loss in IBDs patients. European Union in 2015 for the treatment of IFX indications (163,
166). PF-06438179 (GP1111) is another IFX biosimilar produced
after SB-2, developed in accordance with regulatory
5 Targeted therapy related to recommendations from the FDA and EMA. PF-06438179 has
inflammation differences in N-glycosylation and charge heterogeneity caused by
C-terminal Lys compared to IFX, but these have no clinical
At present, the treatment of AIDs focuses on the use of relevance. It has been approved for the treatment of the
immunosuppressants, and the application of anti-inflammatory indications used for IFX, and all evidence indicates the
strategies in AIDs is gradually increasing. The following will focus biosimilarity between PF-06438179 and IFX (167). ABP 710
on the role of key inflammatory factors or mediators in the (AVSOLA) is developed as an IFX reference product using the
pathogenesis, and briefly introduce the inhibitors of many same CHO cell line as SB-2 and has been approved for clinical
popular targets such as TNF-a, IL-6, IL-1 in inflammation, treatment in the United States and Canada (168). Therefore, a large
mainly including antibodies (Table 1), small molecule compounds body of evidence suggests that there is no clinically significant
(Figure 8), and natural products related to the corresponding difference between IFX and its biosimilars, and that drug translation
targets, and antibodies are the main ones, in which antibodies are does not increase the risk of disease in patients, indicating the safety
classified based on targets. and efficacy of biosimilars.

5.1.1.2 Etanercept and its biosimilars (2)

5.1 Antibodies Etanercept is a dimeric fusion protein produced by recombinant
DNA consisting of the extracellular fraction of human p75 TNFR
5.1.1 TNF-a with the Fc fraction of IgG1, the presence of the latter fraction
5.1.1.1 Infliximab and its biosimilars (1) giving it a half-life of up to 4.8 days. As an inhibitor, Etanercept
Infliximab(IFX; Remicade™), a chimeric IgG1-infused human competitively binds to soluble and membrane-bound TNF to
monoclonal antibody (mAb) that selectively blocks TNF-a activity, inhibit its activity, exhibiting high binding capacity (Ki = 10-10M),
was developed early and was the first biologic agent approved for which has effective relief of inflammation, and now is used to treat
the treatment of CD and UC (160). IFX is now approved in various severely active AS, psoriasis, juvenile idiopathic arthritis, especially

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TABLE 1 The antibodies that could be used to treat AIDs.

Research
Class Name Type Target Major indication
stage
Infliximab mAb TNF-a RA,CD,UC,AS,pasoriasis marketed

AS, psoriasis, juvenile idiopathic

Etanercept fusion protein TNF marketed
arthritis, RA

Adalimumab mAb TNF RA, AS, CD, UC, psoriasis marketed

TNF inhibitor
Certolizumab
mAb TNF CD, RA, AS marketed
pegol

Golimumab mAb TNF RA, psoriatic arthritis, AS, UC marketed

Ozoralizumab nanobody TNF-a RA marketed

RA, juvenile idiopathic arthritis, CD,

Tocilizumab mAb IL-6R marketed
SLE, SSc

Sarilumab mAb IL-6R RA marketed

Sirukumab mAb IL-6 RA, SLE phase III

IL-6 inhibitor
Clazakizumab mAb IL-6 RA phase III

Olokizumab mAb IL-6 RA phase III

ALX-0061 nanobody IL-6R, HAS RA phase II

Anakinra recombinant IL-1Ra IL-1R RA, NOMID marketed

Canakinumab mAb IL-1b CAPSs, sJIA marketed

IL-1 inhibitor
Rilonacept fusion protein IL-1b recurrent pericarditis, CAPSs, sJIA marketed

Gevokizumab mAb IL-1b autoinflammatory diseases marketed

Secukinumab mAb IL-17A PsA, AS, psoriasis, PSO, axSpA marketed

IL-17A or IL-
Ixekizumab mAb PsA, AS, psoriasis, PSO, axSpA marketed
17A/F

Brodaluma mAb IL-17R Psoriasis, PsA marketed

Bimekizuma mAb IL-17A, IL-17F PSO, PsA, AS, axSpA marketed

Sonelokimab nanobody IL-17A/F PsA, PSO phase II

IL-17 inhibitor Netakimab mAb IL-17A PSO, AS phase III

Vunakizumab mAb IL-17A PSO phase II

CNTO6785 mAb IL-17A RA phase II

COVA322 FynomAb TNF, IL-17A PsA phase I

mutant immunoglobulin (DVD-Ig™)

ABT-122 TNF, IL-17A RA, PsA phase II
molecule

CJM112 mAb IL-17A PSO phase I

Ustekinumab mAb IL-12/23 p40 CD, UC, PsA, PSO marketed

Guselkumab mAb IL-23 p19 PsA, PSO, IBD marketed

IL-12/23
Tildrakizumab mAb IL-23 p19 PSO, PsA marketed
inhibitor
Risankizumab mAb IL-23 PSO, PsA, CD marketed

Mirikizumab mAb IL-23 p19 UC marketed

moderately or severely active RA (169). Because Etanercept is ISR and shows better clinical efficacy in the treatment of RA (170).
administered subcutaneously, the most common adverse reactions Due to the high production cost of Etanercept, leading to only a
are injection site reaction (ISR) and serious infection, but it small number of people have the affordable availability, the
combined with methotrexate (MTX) may reduce the incidence of emergence of biosimilars is very necessary. Some biosimilars of

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FIGURE 8
The structure of small molecule inhibitors.

Etanercept have been developed, including SB4, GP2015, high degree of similar clinical efficacy to Adalimumab with no
LBEC0101, DWP422, HD203, CHS-0214, TuNEX/ENIA11 ® . significant difference, and the immunogenicity of it is also
These antibodies have been incorporated into clinical use and comparable, which have generally been used in the treatment of
have shown better efficacy in the treatment of RA patients who related indications (173, 174).
do not respond to MTX, even better than Etanercept, but there is a
lack of real-world research data to confirm (171). 5.1.1.4 Certolizumab pegol (4)
Certolizumab pegol (Cimzia) is a humanized mAb of
5.1.1.3 Adalimumab and its biosimilars (3) recombinant and polydiethanolated Fab’ fragments, in which the
Adalimumab (Humira®, AbbVie) is a fully human IgG1 mAb fragments of Fab are synthesized by microbial fermentation in
obtained by bacteriophage display technology, consisting of two k Escherichia® coli through DNA recombinant technology. It has the
light chains and one heavy chain, with a total molecular weight of advantages of low cost, short cycle, good returns and sufficient
148 kDa, which only binds specifically to soluble TNF (Kd = 6×10-10 sources (175). From the structural point, Certolizumab lacks the Fc
M) (172, 173). Adalimumab was approved for clinical use by the part of IgG1 in previous anti-TNF drugs, resulting in different
EMA in 2003, initially primarily for the treatment of RA, and is now performance in in vitro experiments. The structural modification of
also used for the treatment of AS, CD, UC and psoriasis, and the polydiethanolation may be beneficial to its half-life, penetration and
indications are increasing all the time (173). Compared to other staying power in vivo, ultimately resulting in Certolizumab
TNFi, Adalimumab appears to have the broadest range of specifically binds to TNF-a, which is used to treat CD, RA, AS
therapeutic indications. However, the cost of using Adalimumab (176). Certolizumab, whether alone or in combination with MTX,
is relatively high, imposes a significant financial burden on patients, has been shown to be good at alleviating clinical signs and reducing
which may limit its use. With the time of administration, the joint damage in patients with RA. The efficacy of Certolizumab
proportion of patients with anti-drug antibodies increases, so appears to be comparable to other TNF-a inhibitors, due to its
biosimilars are gradually being developed. There are currently structural differences may have lower immunogenicity (6.9%),
more than ten biosimilars, including ABP 501, SB5, FKS327, which helps reduce the risk of infusion reactions and allergic
BI695501, MSB11022, GP2017, PF-061410293, CTP17, AV702. reactions in patients (177). However, Certolizumab appears to
Most of these antibodies are composed of two heavy chains and have a greater risk of serious infection and a higher frequency of
two light chains of the k subclass, with molecular weights adverse events (NCT01491815), but lack of clinical data related to
comparable to Adalimumab. According to a large number of safety in long-term use (178), so the duration of treatment needs to
preclinical studies and clinical trial results, these antibodies have a be confirmed when choosing Certolizumab.

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5.1.1.5 Golimumab (5) 186). In recent years, TCZ has been increasingly studied for the
Golimumab (Simponi™) is a mAb of human immunoglobulin treatment of COVID-19 and appears to be effective in reducing
G1k produced by knocking human immunoglobulin genes into the mortality, and other indications (giant cell arteritis, polymyalgia
mouse genome, with subcutaneous and intravenous injection, only rheumatica) are increasing.
once a month, which is now used to treat multiple inflammatory
AIDs, such as RA, psoriatic arthritis, AS, UC (179). The main 5.1.2.2 Sarilumab (8)
feature of Golimumab is that it has high binding to TNF-a and low Sarilumab (REGN88; Kevzara®), a human IgG1 mAb, was
immunogenicity, and its binding force to soluble TNF-a is 19 pM approved by the FDA in 2017 for the treatment of RA. Compared
measured by surface plasmon resonance, which seems to be with TCZ, it appears to have a higher affinity for the target, with Kd
comparable to Etanercept, but significantly higher than other of 61.9 pM and 12.8 pM for recombinant monomer and dimer hIL-
antibodies. The immunogenicity is the lowest (3.8%) (compared 6Ra, respectively, and has higher inhibitory efficacy against IL-6,
with the above inhibitors), which indicates that the proportion of but no significant difference in safety has been observed in clinical
patients with anti-drug antibodies is the smallest, so it is not likely trials (NCT01768572) (187, 188). Whether alone or in combination
to occur hypersensitivity reactions, infusion response and has easier therapy, Sarilumab seems to have a good therapeutic effect on RA
drug efficacy (180). Although these adverse effects are a few, the and improvement of physical function, and its efficacy is higher
frequency of infection is increased in patients with Golimumab, than Adalimumab. In patients with insufficient response to
particularly the risk of tuberculosis, so screening or potential viral antirheumatic drugs, inflammatory symptoms and cartilage
testing is necessary before patients receive treatment to reduce the damage in patients treated with Sarilumab are significantly
frequency of infection (179, 180). relieved. ADA in a small number of patients seems to have no
effect on its efficacy and adverse effects, and might have greater
5.1.1.6 Ozoralizumab (6) advantages for the treatment of RA. However, when choosing
Ozoralizumab is a 38-kd trivalent anti-TNFa NANOBODY combination therapy, Sarilumab is more likely to be used in
compound consisting of two humanized anti-human TNF VHH combination with conventionally synthesized DMARDs, and it
antibodies and one humanized anti-human serum albumin (HSA) binding to biological DMARDs appears to increase the risk of
VHH antibody. The presence of the latter part gives it a long half- immunosuppression and infection (189). Overall, Sarilumab has
life, namely, there is t1/2 for 30 days after subcutaneous injection of good therapeutic prospects as the second IL-6 inhibitor on the
30mg, which has been approved by Japan for the treatment of RA in market, which is now also beginning to be used as a treatment for
2022 (181). Ozoralizumab had the potent inhibition to arthritis and COVID-19.
showed low immunogenicity and long-term efficacy, which were
demonstrated in transgenic mouse models, possibly due to the 5.1.2.3 Sirukumab (9)
special structural composition of Ozoralizumab. It seemed to tend Sirukumab(SRK; CNTO 136) is a human IgG1k mAb against
to form small immune complexes (ICs) with TNF-a trimers that IL-6 that specifically targets soluble IL-6 to block signaling of
were not easily recognized by Fcg receptors on immune cells to STAT3 (190). Based on phase I and II trials, phase III clinical
trigger additional immune responses. Therefore, in animal models, trials (NCT01604343, NCT01606761, NCT02019472,
ICs were not easy to induce neutrophil recruitment at the injection NCT01689532, NCT01856309) for inflammatory diseases (RA,
site to stimulate acute inflammation, so the frequency of ISR was SLE) have been completed, and SRK produces therapeutic effects
low, which indirectly indicated that Ozoralizumab was an effective and adverse reactions that are comparable to other IL-6 blockers,
candidate for alleviating inflammation (182, 183). In a phase II/III showing a longer half-life (>15 days) and decreased levels of CRP (a
trial (NCT01007175) of Ozoralizumab in combination with MTX nonspecific marker of inflammation activation), and a few ADA
in the treatment of RA, patients experienced improvements in signs occurred. However, it was not known whether it was associated with
and symptoms with acceptable safety and tolerability (184). a reduction in CRP due to higher mortality from severe infection
Therefore, Ozoralizumab is expected to be subsequently marketed and cardiovascular disease in later follow-up (191). In the latest
in other countries for the treatment of RA. clinical trial (NCT01856309), SRK maintained the safety and
efficacy consistent with previous trials, namely the reduction in
5.1.2 IL-6 symptom of RA and improvement in physical function (192).
5.1.2.1 Tocilizumab (7) Therefore, more clinical trials are needed to confirm whether SRK
Tocilizumab (TCZ; MRA) is the first humanized mAb that is truly incorporated into clinical use.
blocks IL-6 by transplanting the complementarity determining
region of the anti-human IL-6 receptor of mice into human IgG1 5.1.2.4 Clazakizumab (10)
using genetically engineered recombinant technology. TCZ Clazakizumab (CLZ; BMS945429; ALD518) is a humanized
competitively binds specifically to IL-6R to inhibit IL-6 activity, mAb that specifically targets IL-6 using rabbit antibodies, with a
and is used to treat active RA, juvenile idiopathic arthritis, CD, SLE, high affinity of about 4 pM for human IL-6, which produced in
and SSc. As a drug for RA, TCZ has the advantages of low Pichia pastoris yeast, and has entered clinical stage (193). In
immunogenicity, long-term and short-term efficacy, and good multiple phase II trials (NCT01373151, NCT00867516) with
monotherapy, but the risk of infection is still relatively high (185, moderate or severe RA or inadequate response to MTX, CLZ had

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a long half-life, was well tolerated, had rapid improvements in competitively binding to IL-1R and has been approved by the
patient mobility and HRQoL, and changes in laboratory indicators FDA for the treatment of RA, early-onset multisystem
(eg, increased aminotransferases, slight injection responses, inflammatory disease (NOMID) in children and adults (202, 203).
neutrophil reductions) were within the range of IL-6 inhibitors. Compared with other drugs for RA, ANA shows a lower efficacy, in
Its combination therapy with MTX has shown better efficacy than which injection site reactions, high-dose infection, and
monotherapy (194, 195) and has also demonstrated good immunogenicity are the most common adverse reactions, so the
tolerability and safety of CLA in a phase IIb trial (NCT01490450) overall frequency of use for RA is not very high (202). Clinical trials
with active psoriatic arthritis (196), and a clinical trial on CLZ (NCT01399281, NCT03932344) demonstrated the safety of ANA in
therapy in patients who do not respond adequately to TNF the long-term treatment of JIA, with a higher incidence of serious
inhibitors (NCT02015520) has been completed, but results have adverse events in the first six months but a decrease thereafter.
not yet been disclosed. Clinical trials of CLZ for other indications Existing studies have shown therapeutic promise in refractory brain
for non-AID are ongoing, suggesting that CLZ has great potential autoinflammatory-autoimmune diseases, with improved benign
for inclusion in clinical use. responses to symptoms (204). Therefore, the indications for ANA
increase, but its adverse effects and safety for long-term use in
5.1.2.5 Olokizumab (11) different diseases have yet to be confirmed.
Olokizumab)OKZ; CDP 6038), an anti-IL-6 mAb obtained after
humanization of antibody 132E09 produced in immune rats, exerts 5.1.3.2 Canakinumab (14)
inhibitory activity by binding to IL-6 at site3 (Kd = 10 pM) to block Canakinumab (CAM; ACZ885; Ilaris®), a human IgG1 mAb
the gp130 signaling that forms hexamers, showing significant anti- that specifically targets IL-1b (binding dissociation constant 40
inflammatory effects in arthritis models (197), which is currently in pmol/L) with no cross-reactivity to IL-1a or IL-1Ra, is currently
the clinical stage of the treatment of RA. According to previous used as an orphan drug for cryopyrin-associated periodic
studies, OKZ has a half-life of up to 31 days, so it is administered less syndromes (CAPSs) and systemic-onset juvenile idiopathic
frequently There is a significant reduction in the levels of IL-6 and arthritis (sJIA) (>2 years) (205, 206). During treatment with sJIA,
CRP, and it has similar therapeutic results to the two IL-6 inhibitors CAM rapidly reduced disease activity to delay onset and effectively
already on the market (198). In a phase III trial (NCT02760407) in allowed a gradual decrease in glucocorticoids, and maintained
RA, OKZ showed efficacy no less than Adalimumab (199). However, efficacy over a 49-week follow-up period. When reducing the dose
the frequency of TEAEs appears to be dependent on OKZ dose, or increasing the dosing interval, CAM appears to maintain the
which may have implications for long-term treatment (198), so more clinical remission of CAM in patients with long-term inhibition
trials are needed to further explore OKZ dose and long-term efficacy (206, 207). In terms of safety, patients have mild or moderate
once to evaluate the level of RA in treatment. adverse reactions in most cases, and the proportion of infections
and infestations is the highest, so screening or detection of potential
5.1.2.6 ALX-0061 (12) virus should be performed prior to CAM and avoiding combination
ALX-0061 is a 26 kDa bispecific Nanobody targeting IL-6R and with TNF inhibitors to reduce the possibility of infection. CAM is
HAS, consisting of two sequence-optimized variable domains of not recommended for severely active patients (206). In addition,
VHH antibodies, much smaller than mAbs to facilitate specific CAM appears to be effective in the treatment of autoinflammatory
binding to IL-6R, so it shows a high binding capacity (Kd of 0.19 ± diseases (such as familial Mediterranean fever, mevalonate kinase
0.08 pM for hsIL-6R), whose interaction with HAS effectively deficiency) (NCT02059291). It has a good prevention control and
prolongs the half-life. ALX-0061 is a novel IL-6 inhibitor that has mitigating effects of flares (based on the PGA score, a
shown dose-dependent anti-inflammatory effects in IL-6-induced comprehensive clinical measure of severity, and the CRP level)
inflammatory models in cynomolgus monkeys (200). In the Phase I/ and fever to reduce the incidence of disease (208), suggesting that
II RA trial, ALX-0061 showed the desired therapeutic outcome, the inhibitory effect of CAM on IL-1 seems to exert a good anti-
namely well tolerated, no found serious infection and ADA (201), inflammatory effect, so it is very effective in inflammatory diseases.
and more trials are needed to confirm its efficacy and safety in the
treatment of AIDs. 5.1.3.3 Rilonacept (15)
Rilonacept (Arcalyst) is a dimeric fusion protein with a
5.1.3 IL-1 molecular weight of 251 kDa composed of the domain of IL-1R
5.1.3.1 Anakinra (13) and its essential protein and the Fc fraction of human IgG1, which
Anakinra (ANA; Kineret) is an exogenous recombinant IL-1Ra has a high affinity by targeting IL-1b to block IL-1a signaling by
obtained by mimicking the natural presence of IL-1R antagonist, acting as a soluble decoy receptor. Rilonacept seems to be used more
which is produced by recombinant DNA technology using in the treatment of inflammatory diseases, and has been approved
Eschericlzia coli fermentation. ANA lacks glycosylation and for recurrent pericarditis, CAPSs (209). Studies have shown that
additional amino acid residues in structure, but it does not affect Rilonacept has the therapeutic potential of sJIA, but it has not been
its affinity with IL-1R (binding is comparable to IL-1Ra). ANA approved for the treatment of this indication, and it may be that the
restores IL-1/IL-1Ra balance by inhibiting IL-1 activity by therapeutic effect is not as good as the previous two IL-1 inhibitors.

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5.1.3.4 Gevokizumab (16) 5.1.4.3 Brodalumab (19)

Gevokizumab (XOMA 052) is a humanized anti-IL-1b mAb Brodalumab (AMG827; KHK4827) is a fully human IgG2 mAb
containing the Fc fraction of IgG1 (high affinity of 300 fM for IL-1b) that works by blocking the IL-17RA chain of the IL-17 receptor on
designed by computer and obtained by ergonomic technology. The the cell surface compared to the first two antibodies, and is the first
inhibitory effect of it on IL-1b-induced IL-6 expression was anti-IL-17RA inhibitor to treat psoriasis. The improvement in PsA
measured in human lung fibroblasts with an IC50 of 4.9 pM, conditions, safety and good tolerability of AMG827 have been
significantly higher than that of Anakinra (210). The advantage of validated in multiple trials (NCT02029495, NCT02024646), which
XOMA 052 is that it has a long half-life, allowing it to only need to could be used in a larger population (222). However, in the early
be administered once a month and improving patient acceptability. clinical stages, patient became suicidal after taking AMG827, so it
XOMA 052 effectively reduces inflammation and improves blood was discontinued and subsequently developed. In the treatment of
glucose in type 2 diabetes, but has no clear improvement effect on PSO, AMG827 quickly controls the disease, has a good efficacy,
C-peptide levels and b cell function in type 1 diabetes (211, 212). It better than ustekinumab, and may be higher than SEC and IXE,
seems that XOMA 052 is more inclined to the treatment of which may be because it blocks IL-17 signal more thoroughly. The
autoinflammatory diseases, and whether it would have clinical adverse reactions appear to be consistent with the first two
value for AIDs in the future remains to be studied. antibodies, such as nasopharyngitis, upper respiratory tract
infections, headache and joint pain. However, the FDA issued a
5.1.4 IL-17 black box warning after six patients committed suicide in four
5.1.4.1 Secukinumab (17) clinical trials. So, when using AMG827, it is necessary to pay close
Secukinumab(SEC; AIN457; Cosentyx) is a fully human IgG1k attention to the patient’s depressive tendencies and suicide
mAb that specifically targets IL-17A, which has been approved for attempts, and this drug cannot be used for patients with such
the treatment of PsA, AS, psoriasis, moderate to severe plaque symptoms (223, 224). The existing trial (NCT02985983) also
psoriasis (PSO), and axSpA (213). SEC reduces immune-mediated revealed the potential therapeutic effect of AMG827 on axSpA,
inflammatory response by inhibiting the activity of IL-17A and with long-term safety and efficacy, so its indications may increase
lowers disease activity, which is effective in improving clinical signs subsequently (225).
and conditions with or without MTX, exhibiting tolerable
characteristics consistent with other indications. The most 5.1.4.4 Bimekizumab (20)
common adverse reactions are nasopharyngitis, headache, Bimekizumab (UCB4940; Bimzelx) is a humanized IgG1/k
diarrhea, and upper respiratory tract infections, with the mAb produced from CHO cells based on recombinant DNA
incidence of severe infections ranging from 1.2/100 to 1.8/100 PY, technology, which selectively inhibits IL-17A and IL-17F to block
but it does not appear to increase the risk of viral infection, so the interaction with IL-17RA/IL-17RC receptor complexes. The
SEC has a long-term safety and therapeutic effect (214, 215). In a binding to IL-17A is higher than that of IL-17F, and the Kd of
phase III comparative trial (NCT02745080) for PsA, SEC did not Human IL-17A, IL-17F and IL-17A/F are 3.2 pM, 23 pM, and 26
show a better treatment effect than adalimumab, but had higher pM, respectively. Its inhibitory effect on the pro-inflammatory
treatment retention. Other trials confirmed no significant difference factor IL-17 allows inflammation to be reversed to improve signs
in treatment endpoints (216, 217), which may be that the inhibitory of disease in patients (226, 227). Compared to ustekinumab or
effect on IL-17 and TNF-a did not produce a therapeutic difference adalimumab, Bimekizumab appears to have a faster onset of action
in PsA. and better efficacy in short-term treatment of PSO, better than SEC
as well. Its most common adverse reactions are infections, such as
5.1.4.2 Ixekizumab (18) upper respiratory tract infections, Candida infections, so preclinical
Ixekizumab)IXE; LY2439821; Taltz) is an anti-IL-17A hinge- testing, patient screening, and preventive measures are necessary
modified humanized IgG4 mAb with high binding power to human (228, 229). At present, Bimekizumab has been approved to treat
IL-17A or IL-17A/F(Kd<3 pM) to block the binding of IL-17A to moderate to severe PSO, and the treatment of PsA, AS, and axSpA is
IL-17AR. IXE has been approved for PsA, AS, psoriasis, moderate to in clinical trials.
severe PSO, and axSpA (218). IEX appears to slow disease activity
and radiographic disease progression in these diseases, but there is 5.1.4.5 Sonelokimab (21)
an increased risk of infection. The most common adverse effect is Sonelokimab (M1095; ALX-0761) is a novel trivalent anti-IL-
injection site reactions, particularly in the treatment of PsA, which 17A/F bispecific nanobody with a molecular weight of 40 kDa,
occurs at a significantly higher rate than adalimumab (219); In including three sequence-optimized monovalent camel nanobodies,
terms of efficacy, IEX showed superior results over AIN457 and and specifically targets human IL-17A, IL-17F, and HAS. In a phase
TNF inhibitors in short-term treatment of plaque psoriasis, I trial of moderate to severe PsA (NCT02156466), M1095 resulted
comparable to brodalumab, risankizumab and guselkumab (220); in a significant reduction in inflammatory markers of psoriasis with
The efficacy of IEX for AS is similar to that of TNFi and SEC, which a favorable safety profile at doses up to 240 mg, and a dose-
could be an alternative for AS patients with an inadequate response dependent improvement in the patient’s skin condition was also
to TNFi, but does not appear to be applicable to AS patients with observed (230). In the Phase II trial for PSO (NCT03384745),
IBD (221). M1095 showed significant and rapid clinical efficacy, tolerability

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and safety similar to SEC. Although its efficacy was confirmed, Phase II trials (NCT02433340, NCT02349451) for patients with
more clinical data are needed to support subsequent clinical use RA or PsA, but with little variation, resulting in no further clinical
(231, 232). development (239).

5.1.4.6Netakimab (22) 5.1.4.11 CJM112 (27)

Netakimab(NTK; BCD-085) is a novel recombinant IL-17- CJM112 is a novel fully human anti-IL-17A IgG1/k mAb.
resistant humanized IgG1 mAb composed of modified Fc Compared with SEC, CJM112 has a higher affinity for human IL-
fragments (Fc fragment crystallizable region) and CDR 17A, but this does not seem to have a substantial increase in the
(complementary determinant region), with a strong affinity with efficacy of PSO. It shows a clinical effect on the disease, and the
IL-17A (Kd 10-12mol/L). Due to its structural characteristics, NTK efficacy seems to be prolonged with the increase of dose, but it may
has the characteristics of low immunogenicity, low toxicity and be accompanied by an increased risk of infection, and it have not
good tolerance. In phase II trials (NCT03390101, NCT02763111), shown a therapeutic effect on inflammatory lesions of acne
NTK has good efficacy on PSO and AS with a high clinical response (NCT01828086, NCT0299867) (240, 241), so the clinical use of
rate, reduces AS activity, improves psoriasis and inflammatory CJM112 for skin inflammation needs follow-up discussion.
symptoms, and maintains a good safety profile, while a phase III In addition to the above, there are a number of IL-17 antibodies
trial of NTK on active AS (NCT03447704) is ongoing (233, 234). that are still being studied but data have not yet been disclosed,
including SCH-90017 in phase I clinical trials and ANB004 (a non-
5.1.4.7 Vunakizumab (23) fucosylated ADCC-enhanced anti-human IL17A antibody) has
Vunakizumab (SHR-1314), a humanized IgG1/k mAb targeting been discovered.
IL-17A, has demonstrated good tolerability and safety in the
completed Phase I trials of PSO. In the latest short-term phase II 5.1.5 IL-12/IL-23
trial (NCT03463187), SHR-1314 has a significantly higher efficacy 5.1.5.1 Ustekinumab (28)
than placebo, effectively improves the skin of PSO patients with Ustekinumab (CNTO 1275; Stelara®) is a fully human IgG1/k
psoriasis area and severity index improvement of at least 75%. mAb obtained through hu-Ig mice technology, which inhibits
Adverse reactions of it are in the known range of (235), providing signaling of the two factors by binding to the IL-12/23 p40
data support for subsequent clinical trials of larger groups, so SHR- subunit to block its interaction with the cell surface IL-12R b1
1314 is a potential candidate for the treatment of PSO. receptor. The Kd of single-stranded and heterodimeric human IL-
23 is 106 ± 98 pM and 232 ± 23 pM, respectively (242, 243). CNTO
5.1.4.8 CNTO6785 (24) 1275 was approved in 2009, and is now used to treat CD, UC, PsA,
CNTO6785 is a fully human IgG1l mAb specifically targeting and PSO, whose safety and efficacy have been evaluated in multiple
IL-17A, showing high affinity and selectivity for IL-17A in vitro. In a clinical trials. In a long-term CD clinical trial (NCT01369355),
phase II clinical trial for RA with insufficient response to MTX, CNTO 1275 kept good safety and tolerability, maintained clinical
CNTO6785 has not shown significant clinical efficacy, but it has efficacy for five years, and did not observe an increased risk of
good tolerability and safety in patients (236), so whether it has a adverse effects, which was beneficial for refractory CD with dose
therapeutic effect on immune-mediated diseases needs to be escalation. In the treatment of other diseases, CNTO 1275 has also
studied later. shown long-term efficacy and safety, indicating that it can be used
for long-term clinical use (244), but CNTO 1275 is seemly not as
5.1.4.9 COVA322 (25) effective as Infliximab. CNTO 1275 has also been found to have
COVA322 is a bispecific FynomAb obtained by fusing a small clinical benefit for SLE.
anti-IL-17A Fynomer (7 kDa) with adalimumab, which can
significantly inhibit TNF and IL-17A (IC50 value of 169 pM) in 5.1.5.2 Guselkumab (29)
vivo and in vitro to exert anti-inflammatory effects, and is a Guselkumab (CNTO 1959) is a fully human IgG1/l mAb
potential drug for the treatment of inflammatory diseases, and is obtained by MorphoSys HuCAL phage display technology, which
currently in the phase 1b/2a trial of PsA (NCT02243787) (237). binds to the p19 subunit of IL-23 to inhibit the action with the IL-
23Ra receptor subunit (Kd 3.3 pM for IL-23 p19) with a higher
5.1.4.10 ABT-122 (26) affinity than CNTO 1275 (242). At present, CNTO 1959 has been
ABT-122 (AbbVie) is a novel dual mutant immunoglobulin used for the treatment of active PsA and moderate to severe PSO. It
(DVD-Ig™) molecule targeting both TNF and IL-17A, obtained by effectively improves enthesitis, dactylitis, body function, HRQoL in
combining existing IL-17 antibody with TNF antibody, and the Kd patients with PsA, inhibits imaging progression, and has effective
and IC50 are in the low pM range. ABT-122 showed good affinity, and long-term efficacy, higher than SEC and CNTO 1275, which
potency and long half-life in the mouse model of arthritis, and it may be the result of a larger reduction of IL-23/Th17 axis effect
binding inhibition of the two targets reduced the production of IL-6 factor IL-17 by CNTO 1959 (245). Multiple trials have shown that
by fibroblast-like synovial cells (238). Based on demonstrated CNTO 1959 has clinical benefit against CD, having completed
acceptable safety in healthy subjects, ABT-122 demonstrated Phase II (NCT03466411) (246), and its combination therapy with
clinical efficacy and safety similar to adalimumab in multiple golimumab (NCT03662542) appears to be more effective in treating

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UC (247), indicating the potential clinical benefit of CNTO 1959 in which is promising as a drug for the treatment of CD. At the
the treatment of IBD. same time, there are many phase III trials of UC (NCT03518086,
NCT04844606, NCT05509777) in progress (254).
5.1.5.3 Tildrakizumab (30)
Tildrakizumab(MK-3222; SCH 900222) is a humanized IgG1/k
mAb approved in 2018 that specifically targets the p19 subunit of 5.2 Small molecule inhibitors
IL-23 and has a binding capacity comparable to CNTO 1275.
Tildrakizumab has been used to treat moderate to severe PSO, 5.2.1 TIM1 (37)
which has a long-term clinical benefit and is less effective than other SPD304 (33) is the first batch of small molecule inhibitors of TNF-
IL-12/IL-23 inhibitors, possibly because of its lower affinity with the a, developed by He et al. SPD304 inhibits the signaling pathway by
target but higher than etanercept. In terms of safety, it seems that inducing the subunit decomposition of trimeric TNF-a, but its affinity
only MK-3222 has a higher incidence of nasopharyngitis (248). In a is general, the physicochemical properties are poor, and not much
real-world study (NCT03718299), Tildrakizumab showed an research has been carried out; JNJ525 (34) induces changes in the
improvement in HRQoL in PsA patients, and the overall clinical quaternary structure of TNF to affect the interaction between proteins
outcome was consistent with other trials (249), so Tildrakizumab (256); UCB-9260 (35) is a highly bound inhibitor (Kd=13nM) that
could be an alternative option for doctors to treat this disorder. binds to TNF by structural modification after screening by surface
plasmon resonance (SPR) measurement. It stabilizes the asymmetric
form of soluble TNF trimer to impair its signal conduction, which
5.1.5.4 Risankizumab (31)
Risankizumab(BI 655066; ABBV-06) is a high-affinity appears to improve arthritis in the CAIA model (257). Xiao et al.
developed the 1, 5-naphthydine compound - compound 42 (36),
humanized IgG1/k mAb with Kd of 21 ± 16 pM and 43 ± 7 pM
for single-stranded and heterodimeric human IL-23, respectively. which has shown biological efficacy in the CAIA model (258). It
could be seen that the research of TNF-a small molecule inhibitors is
The mechanism and affinity of it appear to be similar to CNTO
1959, and the antibody efficacy in vitro and inhibitory effect on skin being carried out one after another, and may be developed for clinical
use in the future, and TIM1 is a potential small molecule.
inflammatory models was also similar, higher than the other two
(242). Risankizumab was approved in 2019 for moderate to severe TIM1,N-(3-(2-(((3-ethynylphenyl)amino)-1,3-thiazol-4-yl)-
2,5-dimethyl 1H-pyrrol-1-yl)-3-methyl-4-oxo-3,4-
PSO, and its efficacy on PSO is higher than that of CNTO 1275, with
better skin clearance than adalimumab. Meanwhile, Risankizumab dihydrophthalazine-1-carboxamide, is a small molecule TNF
inhibitor screened based on existing compound libraries and
is in the process of evaluating PsA. A phase III trial (NCT03675308)
has shown that CNTO 1275 has significant improvements in joint ligand models of SPD304 and JNJ525, which may bind to the
central hydrophobic cavity of TNF dimers to block the formation of
symptoms, enthesitis, and dactylitis in active PsA, with good
efficacy and safety in both single and combination therapies, functional homotrimers (Kd 1.55 ± 0.32 mM with human rhTNF)
and low cytotoxicity (LD50> 200mM). In the mouse CIA model (a
indicating its therapeutic potential for PsA (250). Other phase III
trials (NCT03105102, NCT03105128, NCT03104413) confirmed preclinical model of RA), its derivative TIM1c, administered in oral
form, showed a similar effect to Etanercept, alleviating RA signs and
the clinical efficacy of BI 655066 on CD, which relieved
symptoms in patients, with a decrease in inflammatory markers arthritis, as well as a reduction in inflammatory factors IL-1ß and
IL-6, with better anti-inflammatory activity (259). Therefore, the
and IL-23 downstream factor IL-22. The overall safety profile of BI
655066 was consistent with previous studies, indicating its potential compounds of the TIM1 series have good development prospects.
as a drug for the treatment of CD (251, 252). Therefore, the
indications for Risankizumab will increase in the future. 5.2.2 Madindoline A derivatives (38 39)
IL-6 signaling relies on IL-6 binds to the D2/D3 domains of IL6-
5.1.5.5 Mirikizumab (32) Ra and GP130 to form IL-6/IL-6Ra/GP130 heterotrimeric
Mirikizumab (LY3074828; Omvoh®), a humanized IgG4 mAb, complexes. The natural product Madindoline A (MDL-A) (38) is
specifically targets the p19 subunit of IL-23 to inhibit its binding to the first selective IL-6 small molecule inhibitor identified, which
receptors (21 pmol/L Kd with human IL-23) with an IC50 of 82 inhibits the formation of complexes by binding to GP130-D1, but
pmol/L to human IL-23, but it does not affect IL-23 binding to IL- the activity of MDL-A is poor and difficult to obtain, so based on
12Rb1 receptors, which is approved in Japan in 2023 for moderate fragments of this structure, Aqel et al. obtained a derivative of
to severe UC with responding inadequately to conventional therapy MDL-A: MDL-101 (39), which inhibited the growth of Th17 cells,
(253, 254). In the completed phase III trial of UC, LY3074828 the proliferation and function of CD17 T cells and the production of
exerted a good clinical response and was significantly more effective IL-4 in vitro, and promoted the development of Treg cells, having
than placebo, but randomized discontinuation may lead to disease the potential to treat multiple sclerosis, but its pharmacokinetic
relapse (254). LY3074828 also completed the evaluation of the characteristics are poor. Daniel C. et al. used conformational
phase II trial (NCT02891226) for CD, effectively induced a adaptive monosaccharides as an alternative design strategy to
durable endoscopic response in patients after 12 weeks, and obtain a series of carbohydrate-contained compounds, which
achieved a relatively high endoscopic response rate of (255). improved the activity of the compounds and could be used as
LY3074828 has entered the phase III evaluation stage of CD, selective inhibitors of IL-6, requiring further research (260, 261).

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5.2.3 LMT-28 (40) to be revealed. There have been relevant reviews of natural products
LMT-28, an oxazolidinone derivative, was screened by HepG2 that have a curative effect on autoimmune arthritis have been
cells transfected with IL-6 stimulation of p-STAT3-Luc, and summarized. Most of the natural products seem to exert anti-
inhibited the action of IL-6 by targeting gp130 homodimers, with inflammatory activity, inhibit the expression of inflammatory
high activity (IC50 = 5.9 mM, Kd = 7.4 mM) and low cytotoxicity, and factors to alleviate the disease, and some have entered the
had good pharmacokinetic characteristics (262, 263). In CIA and evaluation of clinical trials, among which curcumin, resveratrol,
acute pancreatitis models, LMT-28 exerted a therapeutic effect on triptolian inner fat, green tea is highlighted. These substances have
arthritis and pancreatitis, decreased arthritis scores, and reduced therapeutic effects in a variety of AIDs, with immunomodulatory
expression of pro-inflammatory factors to exert anti-inflammatory activity, effectively improve autoimmune inflammation (270–272),
activity (263). Multiple studies confirmed that LMT-28 reduced and other natural products have been discovered, the following will
gp130 in the IL-6 pathway, phosphorylation of STAT3 with ERK to introduce some new natural products with the potential to
block signaling, and inhibited of Th17 differentiation, thereby treat AIDs.
improving arthritis symptoms in CIA, and had a combined effect Aureane-type sesquiterpene tetraketides, isolating from a
with metformin (264–266). Therefore, LMT-28 may have potential wetland mud-derived fungus, Myrothecium gramineum
therapeutic and preventive effects on inflammatory diseases (such (ZLW0801-19), exhibited IL-17A inhibitory activity to regulate
as RA, colitis), and may become the first orally available synthetic immunopathological injury in animal models of experimental
IL-6 inhibitor. autoimmune encephalomyelitis (EAE) and pulmonary
hypertension, reducing disease severity, having therapeutic
potential for MS and EAE (273).
5.2.4 PF-06650833 (41)
Prunella vulgaris L. (PV) is a dried fruit spike of the plant
PF-06650833, a highly selective IL-1 receptor-associated kinase
Prunella vulgaris L. in the family Lamiaceae, whose inhibition of the
4 (IRAK4) small molecule inhibitor (IC50 = 0.2 nM), could be orally
HMGB1/TLR9 pathway reduces the proliferation of Th1, Th2, and
absorbed, has good ADME characteristics, and inhibits the
Th17 cells and the levels of pro-inflammatory factors, thereby
production of inflammatory factors (such as TNF, IFN, IL-1, IL-
improving thyroiditis, and has now been used in China to treat
6, IL-12) and macrophage activation in RA, CIA and SLE animal
autoimmune thyroiditis (274).
models to reduce inflammatory symptoms (267). Based on good
The low-toxicity compound MYMD-1 is a synthetic derivative
preclinical data, PF-06650833 has completed a phase I trial
of tobacco alkaloids, which have been shown to act as an
(NCT02485769, NCT02224651), showing good tolerability and
immunomodulator to improve the disease degree and incidence
safety (268). It recently has completed a phase II trial
of thyroiditis in autoimmune models, possibly by inhibiting the
(NCT02996500) in RA patients who do not respond adequately
number of pathogenic Th1 cells and reducing TNF-a production,
to MTX, but the results of which have not yet been disclosed. In
which seems to have been validated in EAE models while inhibiting
addition, two IRAK4 inhibitors, BAY 1834845 (IC50 = 3.4 nM) and
the development of EAE. Therefore, MYMD-1 has great potential
BAY1830839 (IC50 = 3 nM), have completed multiple clinical trials,
for the treatment of AIDs (275, 276).
the former evaluated in a phase I/II trial (NCT03493269) in
Avocado and soybean unsaponifiables (ASU) are vegetable
psoriasis patients, and the latter completed a multi-dose trial
extracts prepared from fruits and seeds of avocado and soybean
(NCT03540615, NCT03965728).
oil in a ratio of 1:2. The active ingredients are complex (such as
In addition to the above, there are some small molecule
phytosterols, isoflavones), and have a powerful anti-inflammatory
compounds still under development, but the results are not clear.
effects, so they are effective against scleroderma and IBDs, reduce
For example, 2, 5-diaminobenzoxazole derivatives show good anti-
collagen content and skin fibrosis in scleroderma, and maintain the
inflammatory activity in the RA model, in which compound 3e has
intestinal barrier in enteritis (277).
an inhibition rate of 71.5% on IL-6/STAT3 pathway, and
Artemisinoids were first discovered as antimalarial drugs, and
compound 3a has an inhibition rate of IL-1b of 92.1%, and
more experiments have now found that they have a good
inhibition of these factors improves RA, so such compounds are
therapeutic effect on AIDs in preclinical models. Artemisinin
expected to become drugs for the treatment of RA (269). S011806 is
derivatives include artemisinin, artesunate, artemether,
an oral small molecule antagonist of IL-17 developed for the
dihydroartemisinin, and semi-synthetic derivatives (DC32, SM
treatment of psoriasis and has entered the phase I clinical stage to
903, and SM934), which inhibit inflammation in RA to alleviate
explore its safety and pharmacokinetic characteristics, but
symptoms, reverse signaling disorders in SLE, and improve clinical
preclinical data have not yet been disclosed. LEO 153339, as an
signs of IBD, and have therapeutic potential in multiple AIDs (278).
inhibitor of IL-17, has completed a phase I trial (NCT04883333),
but results have not yet been shown.
5.4 Others

5.3 Natural products In addition to the above hot targets, there are also some
cytokines closely associated with inflammation, including GM-
In addition to antibodies and small molecule inhibitors, the CSF, IL-33, TSLP, and related inhibitors have been gradually
therapeutic effect of natural products on AIDs has gradually begun developed in AIDs.

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Granulocyte-macrophage colony-stimulating factor (GM-CSF), of joint inflammation and cartilage damage, maintaining bone
a member of the b common cytokine family, appears to have a homeostasis, which indicates that bispecific antibodies have
pleiotropic modulation of inflammation. During the phase of better efficacy.
inflammation resolution, GM-CSF stimulates the proliferation of Given the benefits of multi-target inhibitors, more research is
immunosuppressive bone marrow cells to aid wound healing and increasingly biased towards the development of bispecific
tissue repair, while GM-CSF plays a pathogenic role in chronic antibodies (BsAbs). Kang et al. (286) developed a BsAb targeting
inflammation. GM-CSF promotes the development of TNF-a/CXCL10, obtained by combining a single-stranded variable
inflammation by acting on innate immune cells (monocytes, fragment (scFv) resistant to CXCL10 mAb and an Fc region of
neutrophils, macrophages), which are found in RA, IBD, and MS adalimumab. Compared with adalimumab, BsAb showed similar
(279, 280). Therefore, a number of GM-CSF inhibitors have been TNF inhibitory efficacy and anti-arthritis efficacy, but better
developed for the treatment of AIDs. For example, Tylor et al. inhibited the production of inflammatory factors. Whether BsAb
demonstrated that IgG1 mAb Namilumab (AMG203), targeting is more effective requires further experimental confirmation.
GM-CSF, effectively inhibited macrophage activity in RA patients,
exerting beneficial therapeutic effects (281).
IL-33, a member of the IL-1 superfamily, is highly expressed in 6.2 Combined immunotherapy
TH2 cells and mast cells to participate in T cell-mediated immune
responses. IL-33 is activated by the orphan receptor ST2 by affecting Nowadays, the therapeutic mechanism of AIDs includes
multiple pathways such as MAPK and NF-kB to increase the release interference with the cell cycle, control of cytokines, inhibition of
of inflammatory factors, thereby accelerating the pathogenesis of transport and activation of autoreactive cells and other pathways to
chronic AIDs. Studies have shown that IL-33 and ST2 were inhibit the development of diseases. In most cases, general
abnormally expressed in RA, SLE, SSc, and IBD, and the use of immunosuppressants are selected for the treatment of AIDs, but
anti-ST2 antibodies reduced the production of IFN-g, IL-17 and due to the lack of antigen specificity, therapeutic effects are not very
arthritis damage in mice, which indicated the potential role of IL-33 good, so combination immunotherapy is beginning to be included.
in AIDs (282). Although there is not much research on the use of The use of antigen-specific immunotherapy (ASIT) in combination
IL-33 inhibitors, clinical trials conducted by Nnane et al. have with immunomodulators appears to be a good therapeutic strategy,
demonstrated that IL-33R mAb CNTO 7160 had good PK, PD, and achieved through co-administration or co-delivery (287). Kang
safety in healthy, asthmatic, or atopic dermatitis patients, which et al. demonstrated that the combination of immunosuppressant
supports further clinical studies (283), suggesting that IL-33 FK506 and DNA vaccine stimulated regulatory DC, induced
inhibitors may be a treatment strategy for subsequent diseases. antigen-specific Treg, and inhibited the Th17 response, thus
Thymic stromal lymphopoietin (TSLP) activates intracellular preventing EAE (288).
JAK/STAT, PI3K pathways by binding to receptor TSLPR and In addition to being used as an alternative to other therapies
mediates the production of inflammatory factors IL-23, IL-17, and when other treatments respond inadequately, anti-inflammatory
IL-4, which may be involved in the pathogenesis of inflammatory factor inhibitors are commonly used in combination therapies.
AIDs. Although TSLP inhibitors are currently more used in the Numerous studies have shown that compared to biological
treatment of allergic diseases, the role of TSLP as a pro- monotherapy, the combination of it and MTX has a more
inflammatory mediator in RA has been discovered, and it is also favorable outcome for AIDs. A phase III clinical trial by Feist et al.
involved in the autoimmune response of some diseases, so the role (NCT02760433) demonstrated that combination therapy with OKZ
of TSLP on AIDs would gradually be revealed (284). and MTX was effective in improving signs and symptoms in RA
patients who did not respond adequately to TNFRi (289). While
autologous polyclonal Tregs cell therapy has been shown to restore
6 Other inflammatory tolerability in T1D patients, the latest experiments have shown that
therapeutic methods combined it with low-dose IL-2 (ld-IL-2) therapy effectively increased
the number of endogenous Tregs, resulting in amplification of Tregs
6.1 multi-target inhibitors with activation and memory phenotypes, which may be meaningful
for adoptive Treg transfer therapy for T1D treatment (290).
At present, the development of anti-inflammatory factor
inhibitors has focused on single-targeted mAb, but such
inhibitors are sometimes not very effective. The pathogenic 6.3 Gene therapy
process of AIDs is often accompanied by the action of multiple
inflammatory factors. Studies have shown that simultaneous With the gradual deepening of the molecular basis of AIDs,
selection of multiple cytokines for targeted therapy may be faster gene therapy has begun to become a potential curative method,
and better to inhibit disease progression. Fischer et al. (285) achieved by the inactivation or replacement of target genes. At
confirmed that the combined inhibition of TNF-a and IL-17 present, there are studies on siRNA treatment of AIDs, indicating
would have a synergistic effect on arthritis, which was more that gene therapy has great therapeutic prospects.
effective in reducing the production of cytokines and chemokines. siRNA is a novel drug that uses RNA interference to achieve
Meanwhile, combined inhibition was more prominent in inhibition targeted regulation of gene expression, which can effectively silence

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the gene of interest to treat diseases. Now some siRNAs have been With the increasing research on inflammation of AIDs, it is
found to be feasible in the treatment of RA. Lee et al. designed a beginning to realize that inflammation plays an important role in
nanocomplex of polymerized siRNA (poly-siRNA), which the pathogenesis of AIDs. For example, TNF and IL families play an
successfully reduced the production of these factors by targeting important pro-inflammatory activity in AIDs, so many treatment
the inflammatory genes TNF-a, IL-1, thereby improving arthritis. strategies for AIDs involve anti-inflammatory therapy,
However, siRNA has many problems such as short half-life, corticosteroids reduce inflammation. The use of cytokine
inaccurate positioning, and difficulty in penetrating cell inhibitors (such as TNF, IL-6) and JAK inhibitors for treatment
membranes, so it is necessary to achieve the targeting of siRNA reduces inflammation and pain, and shows better therapeutic
with the help of delivery systems. Aldayel et al. developed a TNF-a efficacy, which is typically used for the treatment of patients who
siRNA nanoparticle formulation that achieved a high encapsulation do not respond to basic drugs (39). According to the analysis for
rate (>90%) to siRNA to increase delivery in inflammatory tissues. biologics in a large number of literature (294, 295), compared with
In mouse models of arthritis, this formulation demonstrated a traditional antirheumatic drugs (MTX), glucocorticoids,
potential therapeutic effect of RA with ineffective against MTX corticosteroids, biologic disease-modifying antirheumatic drugs
(291). Song et al. got a lipid-polymer hybrid nanoparticle FS14-NP/ (such as TNF-a inhibitors) seem to improve the symptoms and
siRNA that packaged siRNA targeting IL-1 to successful delivery to signs of RA patients more quickly, without producing very serious
macrophages, showing high gene silencing efficiency. At the same adverse effects, so these drugs have a relative safety profile for RA in
time, its effective accumulation in tissues successfully reduced the the short term. Meanwhile, treatment with biologics and MTX may
expression of inflammatory factors in mice and the bone erosion lead to more effective treatment outcomes. For AS, TNFi has better
and cartilage destruction of inflammatory joints (292). These efficacy and safety than IL and JAK inhibitors, while IL-6 inhibitors
siRNA-nanoparticles show that siRNA interference with have less efficacy and a higher risk of adverse effects, which are not
inflammatory target genes has an effective therapeutic effect on RA. recommended for AS (296). TNFi is also the most effective
In addition, viruses often act as gene delivery vectors. Ebina treatment for CD, among which infliximab leads to better
et al. used adenovirus vectors to transfer APN that exerts anti- outcomes than adalimumab and certolizumab (297). In the
inflammatory effects to CIA mice, which subsequently inhibited the treatment of UC, the small molecule inhibitor Upadacitinib may
development of arthritis. Next, a recombinant AAV vector bring better clinical efficacy than biologics, but it has a high
containing a human TNF-immunoglobulin Fc fusion gene frequency of adverse events. In terms of safety, the anti-integrinin
(rAAV2-TNFR: Fc; tgAAC94) has been shown to be effective in inhibitor Vedolizumab performed best. In biologic-naïve UC,
inhibiting the development of arthritis in preclinical study, and infliximab has the best clinical response rate than adalimumab
subsequent clinical trials confirmed good tolerability and safety in and golimumab, and it may be the first-line drug of choice for UC
patients with RA (293). These all indicate that gene therapy has (298). Among these anti-inflammatory agents, TNFi is the most
good potential and may become an important treatment for RA in widely used, due to both efficacy and safety advantages, but it has
the future. not yet had a significant benefit in the treatment of SLE.
However, according to the above analysis of TNFi, most drugs
have high immunogenicity, which leads to poor final efficacy. Drugs
7 Discussion with lower immunogenicity may have a higher frequency of
infection, and the risk of causing other diseases is greatly
The treatment of autoimmune diseases aims to restore increased, which may not be conducive to long-term
homeostasis of the immune system and maintain immune administration. For patients with insufficient response to TNF-a
balance by controlling the degree of deviation of the autoimmune inhibitors, IL inhibitors are selected for treatment. Studies have
response. The treatment strategy has four aspects: changing the shown that IL inhibitors have better efficacy in the treatment of POS
immune activation threshold, modulating antigen-specific than TNF-a inhibitors, while some IL-17 inhibitors are more
responses, rebuilding the immune system with autologous or effective in blocking the IL-17 signaling pathway, IL-23 may only
allogeneic stem cells, and preserving the target organ. Antigen- be partially inhibited, which may be the reason for the difference in
specific therapy aims to induce tolerance to specific antigens. For the therapeutic effect of inhibitors (229).
different AIDs, the choice of drug treatment will be different.
Antimalarial drugs, corticosteroids are the preferred treatment
strategy for SLE, the first choice for RA treatment is 8 Prospect
antirheumatoid drugs (such as MTX), and azathioprine is
preferred for treatment of AIH. Most of the initial treatment is to Most of the above anti-inflammatory agents are antibodies, but
choose immunosuppressants, directly targeting B cells and T cell for the currently developed anti-inflammatory inhibitors, most
therapy, but these drugs are prone to intolerance, and the patient’s drugs seem to be injected intravenously, and not all patients
response to it is gradually reduced. Now the drugs for the treatment achieve a good expected effect. This may be that the pathogenic
of AIDs have poor efficacy, too toxic and other problems, so new effect brought by a single action on inflammatory factors is still
immunomodulators need to be developed for the treatment weak. Meanwhile, some antibodies have the potential for
of AIDs. immunogenicity and high production costs. Subsequently,

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Xiang et al. 10.3389/fimmu.2023.1267091

nanobodies begin to enter the market, with small molecular weight, Author contributions
strong specificity, good stability and other characteristics, have great
advantages in targeted therapy. However, no such small molecule JS: Writing – review & editing. YX: Writing – original draft. MZ:
inhibitors have been used, which is the defect of current anti- Writing – original draft. QS: Writing – review & editing. DJ:
inflammatory agent development. Therefore, there are still many Writing – original draft.
unanswered questions in the process of exploring targeting
inflammatory pathways to treat AIDs.
In AIDs, the development of inhibitors on inflammatory targets
is more focused on biologics, so targeted biological therapies have Funding
begun to become a hot treatment strategy. This review describes
antibodies (mAbs, BsAbs) in biologics, but in addition to them, This work is funded by the National Natural Science
antibody-drug conjugates (ADCs) are gradually being developed. Foundation of China (No. 82073311), The Natural Science
For example, Buttgereit et al. (299) demonstrated the ADC ABBV- Foundation of Sichuan Province (No. 2022JDTD0025), The
3373, composed of TNFi adalimumab and a glucocorticoid receptor Science and Technology Projection Chengdu of Sichuan Province
modulator (GRM), is effective in RA patients (NCT03823391). of China (No. 2022-YF05-01620-SN), The Key Research and
Compared with single-agent adalimumab, ABBV-3373 improved Development Program of Science and Technology Department of
patients’ symptoms. Therefore, new biologics (BsAb, ADC) are the Sichuan Province (No. 2019YFS0514), The Open Research Fund of
key research directions of the next generation of biologics, and also State Key Laboratory of Southwestern Chinese Medicine Resources
provide a new direction for the treatment of AIDs. These targeted (No. SCMR202105), The Open Fund of the State Key Laboratory of
inhibitors need to be selected according to the specific disease Traditional Chinese Medicine Resources in Southwest China (No.
characteristics of the patient, and the key cytokines for disease 2021HX026), The Open Research Fund of Cheng du University of
pathogenesis are identified, so that specific inhibitors are selected to Traditional Chinese Medicine Key Laboratory of Systematic
treat patients more effectively. Research of Distinctive Chinese Medicine Resources in South
For AIDs, other treatment strategies have emerged in addition west China (No. 2018GZ2011005), The State Administration of
to drug therapy. Car-T therapy is chimeric antigen receptor T cell Traditional Chinese Medicine (No. JDZX2015210), The Clinical
immunotherapy, which is currently mainly used as a targeted Research and Transformation Fund of Sichuan Provincial People’s
therapy for tumors, and has good advantages. It has been found Hospital (No. 2021LZ03), Health Care Scientific and Technology
that Car-T therapy has therapeutic prospects for AIDs. CARs Project of Sichuan Province (2022-219).
induce the regulatory role of effector and regulatory T cells in
autoimmunity, while CAR-modified T cells effectively kill abnormal
immune cells, such as autoantibody-related B cells and plasma cells
in AIDs. For example, Jyothi et al. used anti-CD19 CAR-T cells to
Conflict of interest
complete the continuous and effective consumption of B cells in SLE
The authors declare that the research was conducted in the
mouse models, and the duration was higher than that of antibodies,
absence of any commercial or financial relationships that could be
and improved the disease of SLE, delayed its occurrence, which
construed as a potential conflict of interest.
played a good preventive role, and showed the potential clinical
efficacy of CAR-T therapy on SLE (300). It has subsequently
confirmed the feasibility of Car-T therapy in SLE patients,
weakening the B-cell-mediated autoimmune response. This Publisher's note
relieves the patient’s clinical signs and is highly effective and
tolerated (301). This new treatment strategy increases the All claims expressed in this article are solely those of the authors
treatment options for patients with AIDs and may complement and do not necessarily represent those of their affiliated
immunosuppressants and anti-inflammatory agents. The most organizations, or those of the publisher, the editors and the
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