Handbook of Clinical Neurology, Vol.

133 (3rd series)

Autoimmune Neurology
S.J. Pittock and A. Vincent, Editors
© 2016 Elsevier B.V. All rights reserved

Chapter 4

Overview of the immune system

KAY L. MEDINA*
Department of Immunology and Department of Medicine, Mayo Clinic, Rochester, MN, USA

Abstract
The immune system is designed to execute rapid, specific, and protective responses against foreign path-
ogens. To protect against the potentially harmful effects of autoreactive escapees that might arise during
the course of the immune response, multiple tolerance checkpoints exist in both the primary and second-
ary lymphoid organs. Regardless, autoantibodies targeting neural antigens exist in multiple neurologic
diseases. The goal of this introductory chapter is to provide a foundation of the major principles and
components of the immune system as a framework to understanding autoimmunity and autoimmune
neurologic disorders. A broad overview of: (1) innate mechanisms of immunity and their contribution
in demyelinating diseases; (2) B and T lymphocytes as effector arms of the adaptive immune response
and their contribution to the pathophysiology of neurologic diseases; and (3) emerging therapeutic modal-
ities for treatment of autoimmune disease is provided.

INTRODUCTION mechanisms are generally quite effective in resolution

of infection. However, this first antigenic encounter also
Fundamentally the immune system is designed to carry
initiates immunologic memory that affords protection
out rapid, specific, and protective responses against
against secondary challenge. Immunologic memory
harmful pathogens or their biologic products. The mech-
leads to rapid, highly specific clearance of the infectious
anisms of immunity function across a broad spectrum
agent by high-affinity antibody molecules and is the
of clinical conditions spanning from resolution of
basis of vaccine strategies.
infectious disease, recognition and rejection of tumors,
Autoimmune neurology is a rapidly emerging sub-
tolerance or rejection of transplanted tissues or organs,
specialty in the field of immunology (Chapter 1). Autoan-
autoimmunity, and allergy.
tibodies targeting neural antigens have been documented
The immune system is comprised of two arms, the
in multiple neurologic diseases. Target antigens include
innate (nonspecific) and adaptive (specific) arms, consist-
extracellular and intracellular proteins and their molecu-
ing of specialized cell types that carry out distinct effector
lar identification has provided insight into pathogenic
functions. The two arms of the immune system, however,
mechanisms of autoimmune neurologic diseases (Iorio
do not function completely independently of one another.
et al., 2015). The goal of this chapter is to provide a foun-
For example, the innate system recruits antigen-specific dation of the major principles and components of the
responses by attracting cells to the site of infection/injury immune system, with particular emphasis on
and by transporting antigen to lymphoid tissues, leading B lymphocytes, as a framework to understanding autoim-
to activation of adaptive effector cell types. munity and autoimmune neurologic disorders.
There are two types of adaptive immune responses,
primary and secondary. Primary immune responses
INNATE MECHANISMS OF IMMUNITY
are initiated when foreign antigen interacts with
antigen-specific lymphocytes leading to their activation. The innate immune system is comprised of a variety
Primary responses in combination with innate of diverse mechanisms that execute different functions

*Correspondence to: Kay L. Medina, Ph.D., Associate Professor, Department of Immunology, Department of Medicine, Mayo
Clinic, 200 First Street SW, Rochester MN 55905, USA. Tel: +1-507-266-4283, E-mail: Medina.Kay@mayo.edu
62 K.L. MEDINA
Innate immunity Adaptive immunity
(rapid response) (slow response)
Dendritic cell Mast cell

Macrophage B cell

γδ T cell
T cell

Natural
killer cell
Basophil

Complement
protein
Natural Antibodies
Eosinophil CD4+
kiler T cell CD8+
T cell T cell
Granulocytes

Neutrophil

Nature Reviews | Cancer

Fig. 4.1. The innate and adaptive immune systems. The innate immune response functions as the first line of defense against
infection. It consists of soluble factors, such as complement proteins, and diverse cellular components including granulocytes
(basophils, eosinophils, and neutrophils), mast cells, macrophages, dendritic cells, and natural killer cells. The adaptive immune
response is slower to develop, but manifests as increased antigenic specificity and memory. It consists of antibodies, B cells, and
CD4 + and CD8+ T lymphocytes. Natural killer T cells and gd T cells are cytotoxic lymphocytes that straddle the interface of innate
and adaptive immunity. (From Dranoff (2004), with permission from MacMillan Publishers.)

in host defense. These include, but are not limited to: neutrophils to the site of infection/tissue injury
(1) the phagocytic system; (2) the acute-phase response and triggers expression of acute-phase genes in
and complement; (3) natural killer (NK) cells; and (4) the liver. Many effector functions of macro-
dendritic cells (DCs). Recently, data have emerged that phages are strongly augmented by interferon-
the peripheral innate immune system plays significant gamma (INF-g) produced by NK cells. INF-g
roles in neuroinflammatory pathologies. Innate immune induces the antigen-presenting function of mac-
cells that participate in these pathologies include DCs, rophages by activating genes involved in antigen
NK cells, microglial cells, and astrocytes. Here we will processing and presentation. Macrophages also
provide a basic overview of select components of the function as professional scavenger cells. They
innate immune system that contribute to the pathophys- phagocytize apoptotic cells, cellular debris, and
iology of autoimmunity (summarized in Fig. 4.1). byproducts of normal physiology.
b. Neutrophils are very short-lived phagocytic
1. Phagocytic system – the phagocytic system consists
cells that reside in the circulation and are
of macrophages and neutrophils that perform spe-
recruited to the site of infection/tissue injury
cific defense functions that rely upon uptake of
by cytokines and chemokines produced by res-
pathogens, including extracellular, intracellular,
ident macrophages that have encountered path-
and fungal pathogens. They are equipped with anti-
ogens. At the site of tissue injury, neutrophils
microbial mechanisms that become activated upon
phagocytize and kill pathogens. Neutrophils
contact with pathogen. Opsonins, products of the
produce several types of antimicrobial proteins
acute phase and complements systems, greatly aid
and peptides stored in neutrophil granules.
the function of phagocytic cells.
Neutrophil granules are specialized for the stor-
a. Macrophages execute the most central and
age and secretion of antimicrobial products.
essential functions in innate immunity. Mature,
Neutrophils kill extracellular and intracellular
tissue-resident macrophages differentiate from
micro-organisms depending on the type of
circulating monocytes and localize to sites where
granules used.
they are most likely to encounter pathogens.
2. Acute-phase response and complement – acute-
Upon encounter with pathogens, macrophages
phase proteins and complement products opsonize
deploy antimicrobial effector mechanisms,
pathogens for phagocytic uptake, recruit phago-
including production of the inflammatory medi-
cytes to the site of infection/tissue injury, and have
ators interleukin-1 (IL-1) and IL-6. The localized
direct antimicrobial activities. The proteins that
inflammatory response results in recruitment of
 OVERVIEW OF THE IMMUNE SYSTEM 63
Macrophages
Dendritic
Mast cells cells
Monocytes B cells

Neutrophils T cells

Complement
system

Innate immunity Disposal system Adaptive immunity

Opsonization Clearance of Augmentation of
Lysis of pathogens immune complexes antibody response
Chemotaxis and apoptotic cells Promotion of

Katie Ris-Vicari
Inflammation T-cell response
Cell activation Elimination of
self-reactive B cells
Enhancement of
immunologic memory
Fig. 4.2. The complement system. Although the complement system has traditionally been considered part of the innate immune
system, research in recent decades has revealed that complement is able to activate cells involved in both the adaptive and innate
immune response. Complement triggers and modulates a variety of immune activities and acts as a linker between the two branches
of the immune response. In addition, the complement system maintains cell homeostasis by eliminating cellular debris and immune
complexes. (From Ricklin and Lambris (2007), with permission from MacMillan Publishers.)

constitute the acute-phase response and comple- Mechanisms of recognition of infection by

ment (Fig. 4.2) are secreted by hepatocytes in the innate immune system
response to the inflammatory cytokines IL-1 and
The innate immune system has two basic strategies of
IL-6. The phagocytic system and acute-phase pro-
immune recognition: recognition of microbial nonself
teins are functionally linked through IL-1 and
and recognition of missing self. Recognition of micro-
IL-6, produced by phagocytes that stimulate the
bial nonself is based on recognition of molecular
acute-phase response. The acute-phase proteins then
structures unique to microorganisms, and recognition
function as opsonins to facilitate phagocytosis by
of these structures directly leads to activation of innate
macrophages and neutrophils.
immune effector cells. The products of metabolic path-
3. NK – NK cells play an essential role in the elimina-
ways intrinsic to microorganisms are referred to as
tion of infected host cells. They also aid in defense
pathogen-associated molecular patterns (PAMPs) and
against viral and intracellular infections through
are targets of innate immune recognition. The receptors
production of INF-g. Antibodies attached to patho-
of the innate immune system that recognize PAMPs are
gens are recognized by NK cells mediating antibody-
pattern recognition receptors (PRRs). The recognition of
dependent cellular cytotoxicity (ADCC).
PAMPs by cells displaying PRRs signals the presence
4. DCs – DCs are professional antigen-presenting cells
of infection. Collectively, TLRs, phagocytic receptors,
(APCs) and play a key role in the initiation of adap-
secreted pattern recognition molecules, and intracellular
tive immune responses. They reside in peripheral
recognition systems constitute categories of PAMPs
tissues and are active in micropinocytosis and
recognized by PRRs that trigger the innate immune
receptor-mediated endocytosis. DCs express phago-
response. The second strategy of innate immune
cytic receptors and Toll-like receptors (TLRs). Stim-
recognition, recognition of missing self, is based on
ulation of DCs with microbial products leads to the
the recognition of molecules expressed only on normal,
induction of antimicrobial effector responses,
uninfected cells of the host. These functional molecular
including nitric oxide production. DCs exist in mul-
flags are not expressed by microorganisms and their
tiple forms that can present antigen to B cells and
expression is lost on infected cells. Importantly, these
T-helper (TH) cells.
64 K.L. MEDINA
flags are recognized by inhibitory receptors expressed on debris. Microglial cells can have toxic effects on oligo-
NK cells or by proteins that inhibit activation of innate dendrocytes. On the other hand, microglia and macro-
immune effector mechanisms. phages support remyelination, promote neural
survival, and suppress adaptive immune responses
directed at the CNS. In demyelinating pathologies,
Summary of innate immunity and
microglial and monocytes perform both neurodestruc-
contribution of the innate immune system in
tive and neuroprotective roles (Mayo et al., 2012).
demyelinating diseases
Astrocyte activation is associated with human demy-
The innate immune system is the universal system of elinating disorders, including MS and neuromyelitis
host defense. Recognition of pathogenic microorgan- optica (NMO) (see Chapter 6 and 21). Astrocytes are
isms leads to the induction of antimicrobial effector the most abundant cells in the CNS, accounting for
mechanisms and provides the first line of host defense. nearly half of the cells in the brain in humans. They
The first line of defense includes the blood–brain bar- express a large array of PRRs. They secrete chemokines
rier, which is composed of endothelial cells, astrocytes, that attract immune cells to the inflamed CNS, as well as
pericytes, perivascular macrophages, and mast cells (see resident CNS cells to the site of lesions. Importantly, che-
Chapter 3). PRRs play a key role in regulation of demy- mokines produced by astrocytes mobilize cells and have
elinating pathologies when activated by disease- the ability to shape neuroinflammation. Astrocytes are
associated pathogens or to endogenous stimuli. Innate an integral component of the blood–brain barrier and
effector functions include nitric oxide production and play an important role in its formation. They stop entry
respiratory burst, which may lead to neuronal and oligo- of immune cells into the CNS by regulating endothelial
dendrocyte cell death, phagocytosis of dying cells and cells, mast cells, and the extracellular matrix of the
myelin, cytokine, and chemokine production, antigen blood–brain barrier. Importantly, they modulate the
presentation, secretion of trophic factors, or release of activity of multiple types of immune effector cells,
soluble proteins that affect the extracellular matrix including T cells, B cells, microglia/macrophages,
and the blood–brain barrier. DCs, NK cells, and mast cells. For more information
In demyelinating disorders, the entry of cells from the regarding the innate immune system in demyelinating
periphery to the central nervous system (CNS) plays a disorders, including the role of IL-17, see reviews by
pivotal role in disease pathology. The CNS has been con- Mayo et al. (2012) and Waisman et al. (2015).
sidered an immune-privileged site for many years. How-
ever, CNS neurons, microglia, and astrocytes regulate KEY PLAYERS AND THEIR ROLES IN
immune responses. Neurons maintain a quiescent immu- ADAPTIVE IMMUNITY
nologic profile of microglial cells and dysregulation of
B and T lymphocytes occupy the center stage because
this function as a result of neural stress triggers micro-
they dictate the specificity of the adaptive response
glial activation. The absence of serum proteins that acti-
and orchestrate the effector limbs of the response. Also
vate phagocytic cells, the presence of anti-inflammatory
very important in adaptive immunity are cells that inter-
cytokines, and expression of specific microRNAs, also
act with lymphocytes, including APCs and those that
contribute to innate immune regulation of the CNS.
mediate innate effector mechanisms that ultimately lead
Proinflammatory cytokines such as tumor necrosis
to the killing and clearance of agents that initiate patho-
factor-alpha (TNF-a) and IL-6, components of the histo-
genic states.
compatibility complex and complement cascade, also
have dual roles in influencing the development of the
B lymphocytes
CNS (Mayo et al., 2012).
Microglia are a resident CNS macrophage population A central feature of the adaptive immune system is pre-
that constitute 20% of the glial population that regu- existing diversity in the antigen receptor repertoire.
late local innate and adaptive immune responses. Alter- B lymphocytes recognize foreign antigen through their
ations in CNS homeostasis leads to rapid microglial B-cell receptor (BCR) and each B lymphocyte has a
activation causing release of proinflammatory cyto- unique BCR. The diversity of B cells expressing unique
kines, reactive oxygen intermediates, proteinases, and BCRs is the result of their highly regulated process of
complement proteins, recruitment of white blood cells, development in the bone marrow. B-cell differentiation
phagocytosis of debris, apoptotic cells and pathogens, in the bone marrow represents the antigen-independent
and antigen presentation to T cells. In multiple sclerosis phase of B-cell development. Briefly, B lymphocytes,
(MS) and experimental autoimmune encephalomyelitis, like all other blood cells, are derived from pluripotent
microglia/monocytic cells are involved in demyelination hematopoietic stem cells that reside in the marrow.
and phagocytosis of degraded myelin and neuronal Key events in bone marrow B-cell development include
 OVERVIEW OF THE IMMUNE SYSTEM 65
V(D)J recombination Class-switch recombination
(bone marrow) (peripheral lymphoid tissues)

Plasma cell
Immature Mature
Pro-B cell B cell B cell

B-cell development Activation

Immunoglobulin
SHM

Heavy-chain-gene rearrangement
Light-chain-gene rearrangement
Receptor editing of light-chain gene Memory B cell

V(D)J recombination Class-switch recombination

V D J μ VDJ μ ε α
Immunoglobulin Immunoglobulin
gene heavy-chain gene

Looped out AID

DNA
RAG
VDJ ε α

VDJ μ VDJ ε

A B
Fig. 4.3. Generation of antibody diversity. (A) Recombination of variable (V), diversity (D), and joining (J) segments of immu-
noglobulin genes generates B-cell receptors during development in the bone marrow. If the immunoglobulin (antibody) on the
developing B cell reacts against “self” antigen, the cell undergoes further light-chain–gene recombination (receptor editing),
to generate a nonautoreactive immunoglobulin. (B) Class-switch recombination occurs after activation of mature B cells in periph-
eral lymphoid tissues (the spleen and lymph nodes). In class switching, the mexons are swapped with downstream exons to generate
a different antibody class. Activated B cells also undergo somatic hypermutation (SHM) as they develop into memory B cells.
Whereas the RAG proteins initiate V(D)J recombination (A), class-switch recombination and somatic hypermutation are triggered
by the AID enzyme (B). All processes are initiated by or involve DNA double-strand breaks. (From Diaz and Daly (2009), with
permission from MacMillan Publishers.)

activation of the lymphoid lineage developmental pro- category of mature B cells is the B1 B cell. B1 B cells,
gram within the multipotent progenitor pool followed naı̈ve FO B cells, and MZ B cells have unique cell surface
by commitment to the B-cell fate. Thereafter, the pro- phenotypes, tissue distributions, and ontogenies (Fig. 4.4).
gram of B-cell development and differentiation is cen- Furthermore, they respond characteristically to different
tered upon the rearrangement of genes that are sets of foreign antigens, exhibit differences in BCR
components of the BCR, assembly of the components repertoire and dependence on T-cell help in responding
into the BCR, followed by surface expression and testing to antigen.
of the BCR for self-reactivity (Fig. 4.3). The B-cell differ-
B1 B CELLS
entiation process in bone marrow is controlled by a series
of rigorous checkpoints that require successful comple- B1 B cells are phenotypically distinguished from FO and
tion of prior steps before allowing B-cell progenitors to MZ B cells by surface expression of CD5 (Fig. 4.4). They
move forward in development. The end product of this express high levels of IgM and low levels of IgD, CD21,
carefully controlled differentiation process is an imma- and CD23. B1 B cells are found in very small numbers in
ture nonself-reactive B cell, with a unique BCR, that spleen and lymph nodes and are enriched in the pleural
leaves the marrow and enters the periphery to begin the and peritoneal cavities. Unlike FO and MZ B cells that
antigen-dependent phase of B-cell differentiation derive from adult hematopoietic stem cells in the bone
(Fig. 4.3). marrow, B1 B cells arise largely from precursors in the
Upon exiting the bone marrow, immature B cells travel fetal liver and neonatal bone marrow. B1 B cells express
to the spleen, where they begin the peripheral B-cell mat- a unique BCR repertoire with restricted VH gene usage,
uration process. Newly arrived immature B cells in the no evidence of somatic hypermutation (SHM), and few
spleen are referred to as transitional B cells (TS). In nontemplated nucleotide additions. In mice, adoptively
humans, two TS subsets have been identified that differ transferred B1 B cells spontaneously secrete IgM and
based on surface expression of CD10. T1 TS B cells are IgG3 serum antibodies. These natural antibodies have
CD10+ and T2 TS B cells are CD10–. T2 B cells adopt extensive polyreactivity and self-reactivity, and bind
one of two fates: they either become a naı̈ve follicular pathogen-associated carbohydrates. B1 B cells are the
(FO) B cell or a marginal-zone (MZ) B cell. A third primary responders to type II thymus-independent
66 K.L. MEDINA

Immature Immature Naive MZ B GC B Memory B Plasmablast Long lived Breg B1 B

TS1 TS2 FO B CD19+ CD19+ CD19+ PB PC CD19+ CD19+
CD10+ CD19+ CD19+ CD1d+ CD24lo CD20+ CD19+ CD19+ CD1d+ CD11b+
CD19+ CD24hi CD24+ CD20+ CD20+ CD21+ CD38hi CD21lo CD5+ CD5+
CD24hi CD20+ CD20+ CD21hi CD21hi CD22+ CD27hi CD22lo CD24hi IgM+
CD20+ CD21-lo CD21+ CD22+ CD22hi CD38+/− CD138+ CD38hi CD27+
CD21-lo CD22+ CD22+ CD24+ CD23+ CD27+ BCMA+ CD27hi IL-10+
CD22 CD23+ CD23+ CD5+ CD38+ CD24hi CD319+ CD138+ IgM+
CD23- CD38+ CD38+ IgM+IgDlo IgM+IgD+ μ,δ,α,γ,ε IL-6R+ BCMA+
CD38hi IgM+IgD+ IgM+IgD+ CD27+ CD27+ CXCR4+ CD319+
IgM+IgD-/lo BAFF-R+ CXCR5+ BAFF-R+ CXCR5+ IL -6R+
BAFF-R+ CXCL4+ CXCR4+
CD77+
BAFF-R+
TACI+
IL-6R+
CD40+
Bcl-6+
AID+
Fig. 4.4. Phenotypic characterization of human peripheral B-cell subsets. (Data summarized from Levesque and St Clair, 2008;
Weill et al., 2009; Ries et al., 2014.)

antigens and their innate sensing mechanisms allow differentiation that contributes to accelerated primary
rapid mobilization regardless of specificity. IgA plasma antibody responses. In humans, MZ B cells express
cells (PCs) found in mucosal and intestinal tissues are somatically diversified BCRs resembling IgM + memory
believed to stem from peritoneal B1 B cells and provide B cells.
important innate-like defense mechanisms at those sites.
B1 B cells can be subdivided into B1a and B1b types. NAÏVE FOLLICULAR B CELLS
Functionally, B1a cells are the precursors of PCs that
are the source of natural serum antibody, while B1b cells Naı̈ve FO B cells represent the largest subset of
are the primary responders to T-independent type B lymphocytes in the spleen and secondary lymphoid
I responses. organs. Phenotypically, FO B cells are distinguished
from MZ or B1 B cells by high levels of expression of
CD23, low levels of CD21, and lack of expression of
MARGINAL-ZONE B CELLS CD1 or CD5 (Fig. 4.4). FO B cells organize into primary
follicles of B cells that are focused around follicular den-
MZ B cells segregate into the MZ of the spleen, which is dritic cells (FDCs) in the splenic white pulp and the cor-
located at the perimeter of splenic white pulp beginning tical areas in lymph nodes. Unlike MZ B cells, FO B cells
with the marginal sinus and bordering the red pulp. This circulate freely within the spleen and lymph nodes. FO
region of the spleen is not fully developed until 1–2 years B cells exhibit a broad repertoire diversity compared
after birth in humans and contains, in addition to MZ to MZ or B1 B cells. Another important distinction
B cells, multiple subtypes of macrophages and dendritic between FO B cells and MZ or B1 B cells is that FO
cells with specialized functions. In mice, MZ B cells are B cells require T-cell help to promote effective primary
confined to the MZ of the spleen, whereas in humans responses, undergo isotype switching and SHM, and
MZ B cells can be found circulating in blood. MZ establish immunologic memory. Antigen-activated
B cells express high levels of IgM, CD21, CD1, and T-dependent antibody responses by FO B cells are the
CD9 and are low to negative for IgD, CD23, CD5, and primary source of adaptive antibody.
CD11b, which distinguishes them from FO and B1
B cells (Fig. 4.4). Functionally, MZ B cells are strategi-
ANTIGEN-DRIVEN B-CELL
cally positioned to respond quickly to blood-borne path-
DIFFERENTIATION AND ANTIBODY
ogens in the circulation that become trapped in the
PRODUCTION
spleen. Importantly, this subset of B cells can be rapidly
recruited into early adaptive responses in a Immediate antibody responses against many infectious
T-independent manner. They have a lower activation agents are due to rapid T-independent expansion of
threshold with heightened propensity for PC B cells, resulting in their differentiation into PCs. These
 OVERVIEW OF THE IMMUNE SYSTEM 67
rapid responses are largely carried out by B1 and MZ B-CELL ANTIGEN ENCOUNTER AND BCR
B cells that are the result of polyclonal activation or SIGNALING
BCR recognition of multivalent epitopes that activate
Immature FO B cells circulate in the blood and secondary
B cells without T-cell help. In contrast, antibody
lymphoid organs. The spleen and lymph nodes provide
responses to monovalent protein antigens are dependent
the necessary structural and chemical microenvironment
on linked recognition between antigen-activated B cells
for B cells to encounter antigens and become fully acti-
and their cognate antigen-specific helper T cells. Cog-
vated. B cells can encounter soluble or large particulate
nate interactions between antigen-specific B cells and
antigens that are attached to the surface of macro-
TH cells promote high-titer antibody production and
phages, FDCs, or DCs. Small soluble antigens gain
establishment of immunologic memory. In the context
access to secondary lymphoid organs through afferent
of T-dependent protein antigens, the BCR must recog-
lymph vessels and pass directly into the B-cell follicle.
nize and bind antigen, followed by internalization, pro-
It has been speculated that low-molecular-mass antigens
cessing, and presentation of peptides from the antigen in
gain access to the B-cell zone by small pores in the sub-
the context of major histocompatibility complex (MHC)
capsular sinus region of the lymph nodes or by simple
class II to receive TH cell help. We note that, if the
diffusion (Yuseff et al., 2013).
T-dependent antigen is B-cell-associated, and adequate
The BCR is composed of membrane immunoglobulin
co-stimulation is provided, the B-cell response can pro-
molecules and associated Iga/Igb (CD79a/CD79b) het-
ceed in a T-independent manner. However, the range
erodimers. The BCR binds antigen, resulting in receptor
of outcomes and extent of protective immunity are
aggregation. The associated Iga/Igb subunits transduce
strictly limited in this scenario.
signals to the cell interior. BCR aggregation rapidly acti-
In contrast to rapid antibody responses mediated by
vates the Src family kinases Lyn, Blk, and Fyn, as well as
B1 and MZ B cells, T-dependent antibody responses
the Syk and Btk tyrosine kinases. A “signalosome” com-
are delayed. However, they display a spectrum of
posed of the BCR, various tyrosine kinases, adaptor pro-
B-cell affinities and isotypes that allow the B cell to
teins such as CD19 and BLNK, and signaling enzymes
engage multiple strategies for antigen clearance.
such as PLCg2, PI3K, and Vav, is formed. The signalo-
Antigen-experienced professional APCs are key players
some activates signaling cascades involving kinases,
in the initiation of adaptive antibody responses by shap-
GTPases, and transcription factors, causing changes in
ing the quality and quantity of peptide-MHC class II
cell metabolism, gene expression, and cytoskeletal orga-
(pMHCII+) specific TH responses. DCs are essential
nization. The outcome of BCR signaling is determined
APCs in initiating adaptive immune responses. Multiple
by the maturation state of the cell, the nature of the anti-
subsets of DCs exist and reside at various levels in all
gen, the magnitude and duration of signaling, and sig-
secondary lymphoid tissues. DCs are readily available
nals from other receptors such as CD40, the IL-21
to differentially process and present antigen to adaptive
receptor, and B-cell-activating factor receptor (BAFF-
immune effector cells. Following infection, antigen-
R). Other transmembrane proteins modulate BCR sig-
experienced pMHCII+-bearing DCs appear in the lymph
naling, including CD45, CD19, CD22, PIR-B, and
nodes that drain the site of antigen insult and their
FcgRIIB1. Finally, negative-feedback loops (Lyn/CD22/
numbers depend on the quality of the immune stimu-
SHP-1, Cbp/Csk, SHIP, Cbl, Dok-1, Dok-3, FcgRIIB1,
lus. pMHCII+ DCs survey the naı̈ve TH compartment
PIR-B) restrict BCR signaling (Dal Porto et al., 2004;
localized in T-cell zones for clones that express a
Harwood and Batista, 2008, 2010; Goodnow et al.,
pMHCII+-restricted T-cell receptor (TCR). Successful
2010; Kurosaki et al., 2010; Szydlowski et al., 2014).
cognate interactions between the DC and TH cells lead
to the formation of an immunologic synapse. The
result of DC-TH immunologic synapse formation is
THE GERMINAL CENTER REACTION
TCR-driven activation, expansion, and development of
effector TH precursors, including TFH precursors. The GC pathway for B-cell differentiation involves
Antigen-specific TFH cells migrate to T-B borders, which clonal expansion, BCR diversification, and antigen-
allows them to come in contact with antigen-primed driven selection for high-affinity variants. After making
pMHCII+ B cells and promote their further expansion. TFH cell contact, antigen-primed B cells (pre-GC) move
pMHCII+-primed B cells can adopt one of two cell fates: into the follicular region of the lymphoid organs. Pre-
they can follow an extra-FO pathway, switch antibody GC B cells expand rapidly within the follicles, forming
isotype, and become a short-lived plasmablast (PB), or secondary follicles. Secondary follicles of antigen-
they can enter the germinal center (GC) pathway to specific B cells polarize into T-cell proximal dark zones
long-lived PC differentiation or memory B-cell of rapidly proliferating B cells and opposing light zones
development. of noncycling B cells that are interspersed among FDCs
68 K.L. MEDINA

Fig. 4.5. B-cell tolerance models. If immature B cells bind to self-antigens, they can undergo secondary rearrangement of L-chain
loci to generate new specificities with lower affinity to self-antigens. Strongly binding cells will die in the bone marrow; all other
cells emigrate to the spleen, where B-cell receptors bind to self-antigens with various affinities. Strong binding can lead to exclu-
sion from B-cell follicles (FO), and intermediate binding can lead to enhanced IgM internalization and functional anergy. Binding
of (foreign) antigens to IgD combined with T-cell help rescues anergic B cells and allows activation and entry into the germinal
center (GC) reaction. Cells exposed to self-antigens in the GCs are not selected into the pool of long-lived switched memory B cells
and plasma cells (PC). B cells expressing B-cell receptors reactive against self-antigens located outside the GCs are selected into
the memory B-lymphocyte and plasma cell pool. This mechanism might account for the generation of autoreactive B cells in
patients with autoimmune diseases. BAFF-R, B-cell-activating factor receptor; CSR, class switch recombination. (Reproduced
with permission from Pieper et al., 2013.)

and a few GC TH cells. During the GC reaction, antigen- generation of memory B cells that are the precursors for
specific B cells downregulate their germline BCR and a memory response to subsequent antigen challenge.
diversify variable region genes through SHM. The A second outcome is the generation of PBs that repre-
enzyme AID is the central component of SHM. AID sent terminally differentiated cells that produce high-
deaminates cytidine to uracil in single-stranded DNA affinity antibody molecules. A third outcome is that
that can be processed by a mutagenic repair pathway. B-cell clones that lose reactivity to antigen acquire
Processing of single-stranded DNA breaks by the muta- self-reactivity. However, tolerance mechanisms in the
genic repair pathway leads to double-stranded DNA late phase of the antibody response are believed to limit
breaks that are required for class switch recombination autoreactive B-cell clones. Loss or relaxation of
(CSR) and provide the substrate for SHM (Fig. 4.3). tolerance checkpoints could lead to the generation of
Positive selection of GC B cells expressing high- high-affinity, isotyped switched, autoreactive memory
affinity variant BCRs constitutes affinity maturation. B cells.
Trapping of immune complexes on FDCs is believed Memory B cells are IgM + or isotype-switched
to provide a mechanism for newly generated variant affinity-matured post-GC B cells competent to respond
BCRs to receive a survival signal. Selection of high- to low-dose soluble antigen in a TH-dependent manner.
affinity BCR variants is believed to take place in the light They survive independently of BCR specificity and are
zone. There are few TH cells in the light zone, thus com- not dependent on persistent antigen. Upon recall antigen
petition for cognate GC TH interaction provides a selec- exposure, memory B cells quickly expand and produce
tion mechanism. The result of GC B cell–TFH interaction large numbers of high-affinity PCs as the primary out-
is successive rounds of expansion, diversification, and come. GC reactions also occur as part of the memory
affinity variant selection. There are several potential out- B-cell response to antigen challenge, but are a minor out-
comes of the GC reaction (Fig. 4.5). One outcome is the come, compared to PC differentiation.
 OVERVIEW OF THE IMMUNE SYSTEM 69
PCs are antibody-secreting, terminally differentiated In addition to the bone marrow and secondary lymphoid
B lymphocytes. Several theories have been put forth to organs, inflamed kidneys have been shown to provide
explain the continued presence of antigen-specific anti- survival niches for PCs (Cassese et al., 2001). In
bodies (Radbruch et al., 2006). First, persisting antigen (NZBxNZW)F1 mice, numbers of PC survival niches in
drives continued production of PBs from memory inflamed kidneys are high. Thus, in this mouse model,
B cells. Second, signals provided by cytokine receptors chronic inflammation contributes to PC niches and the
and TLRs might drive continued production of long-lived ensuing immunopathology.
PCs (LLPCs) from memory B cells. Third, a pool of
memory PCs arises as a result of unconditional survival
ANTIBODY ISOTYPES
of PCs in bone marrow niches. Short-lived PCs, or PBs,
have half-lives of 3–5 days compared to LLPCs that can Epitopes specific for the constant region of the immuno-
persist for years. Newly formed PBs can be visualized globulin molecule are termed isotypes and allow group-
in T-cell zones of lymphoid organs within a few days of ing of Igs into five major classes: IgM, IgD, IgA, IgG,
antigen exposure. PBs are antigen-primed B cells that and IgE. IgA and IgG are further resolved into distinct
have committed to the PC fate but have not undergone subclasses: IgA1, IgA2, IgG1, IgG2a, IgG2b, IgG3, and
the GC reaction. Signals provided by TH cells facilitate IgG4. CSR is the molecular process that facilitates iso-
isotype switching of PBs. Unlike LLPCs, short-lived PBs type switching, is not dependent on the GC reaction,
retain the capacity to proliferate. Antibody production and also occurs in antigen-primed B cells that remain
by PBs is critically important for immediate antigen clear- in the T-cell zone and differentiate into short-lived
ance. Alternately, some PBs migrate to discrete niches in PBs. Signaling through CD40 on the antigen-primed
the bone marrow wherein they receive signals from the B cell via CD40 ligand produced by TH cells is required
microenvironment and become an LLPC. PC survival is for CSR. In the absence of CD40/CD40L, CSR can be
conditional. PCs rapidly die as a result of endoplasmic induced via TACI/BAFF-R signaling. How do TFH cells
reticulum stress caused by massive production of anti- control CSR? Directed delivery of cytokines by TFH cells
body unless an unfolded protein response is induced by at the immune synapse directs isotype switching and is
externally delivered survival signals (Iwakoshi et al., summarized in Figure 4.3. Each class and subclass of
2003). Survival signals provided by bone marrow niches Ig has unique roles in humoral immunity that are sum-
allow PCs to become long-lived and antibody production marized in Table 4.1.
by LLPCs affords long-term adaptive antibody-mediated
humoral protection. Survival niches in the bone marrow
OVERVIEW OF TH CELLS IN
are finite, limiting numbers of LLPCs. Importantly, if
PERIPHERAL B-CELL MATURATION
the PC niche is destroyed or the PC is dislodged from
its niche, the PC will die. Thus, much research effort Peripheral B-cell maturation to a high-affinity memory
has been directed at defining the bone marrow PC niche B cell or terminally differentiated PC is orchestrated
to design effective experimental strategies to target PCs through three developmental checkpoints that are
that produce pathogenic allo- or autoreactive antibodies. largely dictated through direct interactions with TH cells:

Table 4.1
Immunoglobulins have different functions and properties

Function or property IgM IgD IgG1 IgG2 IgG3 IgG4 IgA IgE

Neutralization + – ++ ++ ++ ++ ++ –
Opsonization – – +++ + ++ + + –
Sensitization for natural killer cells – – ++ – ++ – – –
Sensitization for mast cells – – + – + – – +++
Activation of complement system +++ – ++ + +++ – + –
Transport across epithelium + – – – – – +++ –
Transport across placenta – – +++ + ++ +/– + –
Diffusion into extravascular sites +/– – +++ +++ +++ +++ ++ +

There are five immunoglobulin classes (isotypes) of antibody molecules found in serum: IgG, IgM, IgA, IgE, and IgD. They are distinguished by the
type of heavy chain they contain. IgG molecules possess heavy chains known as g-chains; IgM have m-chains; IgA have a-chains; IgE have E-chains;
and IgD have d-chains. The variation in heavy-chain polypeptides allows each immunoglobulin class to function in a different type of immune
response or during a different stage of the body’s defense. The amino acid sequences that confer these functional differences are located mainly
within the Fc domain.
70 K.L. MEDINA
1. Checkpoint 1: Initial contact between the antigen- B cells exert regulatory and pathogenic roles that can
primed DC bearing pMCHII and a naı̈ve TH cell influence inflammation and autoimmunity. Based on
expressing a TCR competent to recognize the their cytokine secretion, B cells can be categorized into
pMCHII displayed on the DC results in TH clonal regulatory (Breg) or effector (Beff) subsets (Hamze et al.,
selection and directs TH differentiation, which will 2013). Bregs produce IL-10 or transforming growth
ultimately impact the cognate B-cell fate. factor-beta (TGF-b), whereas Beff produce either BTH1
2. Checkpoint 2: TH cognate control of antigen-primed or BTH2 cytokines. Cognate interactions between Beff
B cells directs CSR, PB development, or entry into and TH cells impact their respective differentiation
the GC reaction, and thus the developmental fate outcomes. INF-g production by Beff promotes TH1 dif-
of the B cell. ferentiation while IL-4 promotes TH2 differentiation.
3. Checkpoint 3: BCR–antigen interactions followed Expression of co-stimulatory molecules by B cells pro-
by cognate interactions between GC B cells and motes T-cell activation. Production of IL-6, IL-10, and
GC TH cells direct the memory versus PC cell fate TNF-a by B cells indirectly regulates T-cell responses
of high-affinity GC B cells. by modulating DCs or macrophage activation or func-
tion. Importantly, altered cytokine production by
B cells has been implicated as a contributor to the path-
B CELLS AS ORCHESTRATORS OF ophysiology of chronic inflammatory responses and
IMMUNITY diseases.
B lymphocytes play a key role in immunity beyond anti-
CD4+ T CELLS IN AUTOIMMUNE DISEASE
body production (Fig. 4.6). They serve as APCs and pro-
duce cytokines that alter adaptive and innate cell Cytokines produced by antigen-primed B cells control
effector functions. Through production of cytokines, T-cell polarization, including CD4 + Teff cells (Th2,

Fig. 4.6. Intersection between humoral and cellular immune responses. B lymphocytes play a key role in immunity beyond anti-
body production. They serve as antigen-presenting cells and produce cytokines that alter adaptive and innate cell effector functions.
Through production of cytokines, B cells exert regulatory and pathogenic roles that can influence inflammation and autoimmunity.
Cognate interactions between B cells and T-helper cells impact their respective differentiation outcomes. Production of cytokines
by B cells also indirectly regulates T-cell responses by modulating dendritic cells or macrophage activation or function. BCR,
B-cell receptor; ADCC, antibody-dependent cellular cytotoxicity; IFNg, interferon-g; TCR, T-cell receptor; MHCII, major his-
tocompatibility complex II; PRR, pattern recognition receptor; IL-4, interleukin-4. Used with permission of Mayo Foundation for
Medical Education and Research. All rights reserved.
 OVERVIEW OF THE IMMUNE SYSTEM 71
Th1, and Th17), regulatory T cells (Treg), and NK cells been shown to play a direct role in cell-mediated, tissue-
(Fig. 4.6). As APCs, B cells modulate CD4 + T-cell specific autoimmune disease development, including
activity through pMHCII/CD40 and NK cells via MS, experimental autoimmune encephalomyelitis, and
CD1d. Each category of CD4 + Teff cell provides spe- type 1 diabetes. In type 1 diabetes, CD8 + T cells are
cialized functions. Th1 cells secrete INF-g and activate the most abundant pancreas-infiltrating cells during
macrophages, NK cells, and CD8 + T cells and play a insulitis, and autoreactive clones identified in peripheral
key role in defense against intracellular pathogens. blood have the same antigenic specificity as the cells that
Th2 cells secrete IL-4, IL-13, and IL-25, provide an infiltrate the pancreas and cause disease (Singh et al.,
important barrier defense at mucosal and epithelial 2007). Myelin basic protein-specific CD8 + T cells can
surfaces, and mobilize and activate eosinophils, baso- induce experimental autoimmune encephalomyelitis
phils, mast cells, and alternatively activated macro- (Huseby et al., 2001). Depletion of CD8 + T cells has been
phages. Th17 cells secrete IL-17, IL-6, and TNF-a, highly beneficial in reducing the severity of multiple
regulating acute inflammation and work in concert autoimmune disorders, including experimental autoim-
with neutrophils in defense against extracellular bacte- mune glomerulonephritis, experimental autoimmune
ria. Pathogenic Th17 cells play a crucial role in the myasthenia gravis, and rheumatoid arthritis (Larsson
induction of autoimmune tissue injury while FoxP3+ et al., 1989; Zhang et al., 1995; Reynolds et al., 2002;
regulatory T cells inhibit autoimmune tissue injury Raposo et al., 2010). CD8 + T cells promote autoim-
(Bettelli et al., 2006). At least two categories of Tregs munity in multiple ways, including through dysregulated
have been described. Adaptive Tregs express FoxP3 secretion of inflammatory cytokines, altered differenti-
and are the progeny of conventional naı̈ve T cells acti- ation, and killing of target cells. On the other hand, CD8
vated by antigen plus TGF-b or low doses of antigen + T cells can block autoimmune disease by eliminating
(Chen et al., 2003). IL-10-producing Tregs do not express self-reactive cells, removing excess antigen, minimizing
FoxP3 but have comparable regulatory function to inflammatory signals, or by functioning as Tregs.
adaptive Tregs (Vieira et al., 2004).

THE IMMUNE SYSTEM GONE AWRY,

CD8+ T CELLS IN AUTOIMMUNE DISEASE LEADING TO AUTOIMMUNE DISEASE
The role of TH cells in autoimmunity is well established. B lymphocytes are multifunctional. They bind, internal-
However, the contribution of CD8 + T cells has been ize, and present antigen to T cells. B cells are intricately
less clear. Importantly, recent studies have shown that involved in the generation and maintenance of neo-
CD8 + T cells contribute to the induction, progression, organogenesis at sites of disease, leading to the forma-
pathogenesis as well as protection from autoimmune tion of ectopic lymphoid structures. Antigen-activated
disease (Fig. 4.7). CD8 + effector T cells have been B lymphocytes directly regulate immune outcomes
found within tissue sites of disease and mediate differ- through production of immunostimulatory and immu-
ent effects depending on their antigenic specificity nomodulatory cytokines, and they are the source of nat-
(Gravano and Hoyer, 2013). CD8 + effector T cells have ural, adaptive, and autoreactive antibodies. Clinically,

Tolerance Autoimmune Disease

Anergy

De • Selection defects
leti
on • Pathogen induction Altered Fas. GrzB. Perforin
Naïve • Inflammation • Abnormal killing of targets
Auto-reactive CD8+ • Decreased ability to
CD8+ Effector eliminate diseased cells
n
tio

Altered Cytokine Production

tia

n?
en

ion

tio
r

tia
ffe

ss

n
Di

re

re
fe
pp

dif
Su

Dysregulated Treg Function

g”
IL-10 re • Loss of suppression
CD8+ -T CD8+
PD-1
Treg “Ex Treg
• Reduced Treg: Effector
etc. ratio

Fig. 4.7. Potential influence of CD8 + T cells on autoimmune disease. Self-reactive CD8+ T cells are normally controlled
by mechanisms of central and peripheral tolerance, but when these controls are dysregulated CD8 + T cells can promote the
development of autoimmune disease. Changes in cytolytic or death receptor signals, skewed differentiation of effectors, or loss
of regulatory function in the CD8 + T-cell population may promote autoimmune pathogenesis. (Reproduced with permission from
Gravano and Hoyer, 2013.)
72 K.L. MEDINA
autoimmune disease is a disease in which tissue damage The corresponding neural antigens are expressed on or
is mediated by self-reactive antibodies and/or effector in neurons, glia, or muscle, but the antibodies to cytoplas-
T cells. In systemic autoimmune disease, both the innate mic or nuclear antigens are not the direct effectors of
and adaptive systems are involved. Antibodies, activated immune attack. Instead, peptides derived from cytoplas-
T cells, or both, are present in damaged tissue. However, mic or nuclear antigens are displayed on MHC class I in a
as stated above, innate immune cells contribute to the proinflammatory cytokine environment and recognized
antigen-specific autoreactivity and their effector mech- by CD8+ cytotoxic T cells. On the one side, tumor spread
anisms contribute to tissue damage, including priming is contained by cytotoxic CD8+ T cells. On the other side,
of CD8 + cytotoxic T cells. the same effector CD8+ cells mediate tissue damage to
There are multiple mechanisms in place to limit B-cell neurons, glia, or other CNS tissues that normally express
self-reactivity: receptor editing, clonal deletion, and the target antigen. Tissue-specific CD8+ T cells can be
anergy (Fig. 4.5). During development in the bone mar- activated as a consequence of molecular mimicry or viral
row, self-reactive B cells are directed towards apoptosis infection of the targeted tissue leading to tissue-specific
and undergo clonal deletion or are rendered anergic. destruction. Tissue destruction causes the release of
Anergic B cells are unable to respond to BCR engage- self-antigen which is subsequently presented by activated
ment by antigen. However, these cells may be triggered antigen-presenting tissue DCs leading to autoantigen tar-
under conditions that contribute to autoimmunity, where geting (Gravano and Hoyer, 2013). Cross-presentation of
the fidelity of the selection process is compromised, such apoptotic cells by DCs leads to a potent CD8+ T-cell
as elevated levels of BAFF or elevated TLR signaling/ response in draining lymph nodes. For example, tumor
expression. Affinity maturation in the GC represents immunity to breast and ovarian cancer was linked to para-
another stage wherein autoreactive B cells can arise neoplastic cerebellar degeneration (Albert et al., 1998).
(Fig. 4.5). As a consequence of mutations induced by Peripheral activation of antigen-specific cytotoxic CD8
AID, BCR affinity for antigen is up- or downregulated. + T cells due to cross-presentation of apoptotic cells by
As stated above, selection checkpoints at the GC stage DCs was shown to contribute to the development of para-
are put in place to select against self-reactive clones neoplastic cerebellar degeneration (Albert et al., 1998).
before the B cell enters the PC or memory compart- Paraneoplastic autoantibodies arise when antibodies to
ments. Autoreactive B cells that escape GC selection tumor antigens cross-react with neural self-proteins.
mechanisms can differentiate into autoantibody- These autoantibodies against onconeural antigens are
producing PCs that drive autoimmunity through produc- detected in serum or spinal fluid of patients with paraneo-
tion of autoantibody, immune complex formation, pre- plastic neurologic disorders and are not found in healthy
sentation of autoantigen to T cells in the context of subjects or patients with neurodegenerative or inflamma-
co-stimulation, and production of cytokines. tory neurologic disorders.
How and why do specific antibodies to neural Guillain–Barre syndrome is a postbacterial infection
self-proteins arise? Where do antibodies to neural self- neural autoimmune disease with varying phenotypes that
proteins arise? Once the immune response is initiated, are associated with specific types of preceding infection
what mechanisms drive the response within the CNS? (Islam et al., 2010). Viral infections have been implicated
Autoantibodies to neural antigens arise idiopathically, in the onset and promotion of autoimmunity. Epstein–
paraneoplastically, or as a result of bacterial or viral Barr virus has been associated with MS and distinct pat-
infections (Islam et al., 2010; Iorio et al., 2015). Idio- terns of antibodies to herpesviruses have been documented
pathic autoantibodies arise as a result of breaches in cen- in aquaporin-4 antibody-positive CNS autoimmunity and
tral or peripheral tolerance selection checkpoints that relapsing-remitting MS (Sellner et al., 2010). Where do
occur as a consequence of normal B-cell differentiation antibodies to neural self-proteins arise? Two recent studies
and/or antigen-driven maturation. Patients with rheuma- focused on MS concluded that memory B cells actively
toid arthritis, systemic lupus erythematosus, and type 1 traffic between peripheral lymphoid tissue and the CNS.
diabetes have defects in central and peripheral tolerance, Stern et al. (2014) proposed a model wherein B-cell matu-
leading to the accumulation of self-reactive B cells ration initiates in the draining lymph nodes followed by
in blood, which are thought to provide a reservoir migration of the B cells to the CNS. The findings of
for the generation of disease-associated autoantibodies Palanichamy et al. (2014) suggested that class-switched
(Meffre and Wardemann, 2008). B cells form an antigen-experienced immune axis between
Paraneoplastic autoimmune neurologic disorders are the periphery and the CNS and that intrathecal tissues may
the consequence of immune responses to tumors initiated have the capability to support affinity maturation of
by antigens derived from a new or recurrent systemic can- antigen-specific B cells. PBs are the immediate antibody-
cer (Fig. 4.8). Immune responses are directed at the tumor secreting progeny of the GC reaction. PBs upregulate
target onconeural proteins expressed on the plasma mem- the chemokine receptor CXCR4 and home to the bone
brane or in the cytoplasm or nucleus of certain cancers. marrow, where they mature into long-lived PCs. In
 OVERVIEW OF THE IMMUNE SYSTEM 73

Fig. 4.8. Hypothetic mechanisms of paraneoplastic neurologic syndromes. Cancer cells share the antigens with neurons or
muscle cells; the antigens are exposed to the immune system and sensitize T cells and B cells. The sensitized cytotoxic T cells
may directly attack the neuronal cells, or the sensitized helper T cells and B cells may induce autoantibodies which cause dysfunc-
tion in the neurons or the muscle cells. NK, natural killer. (From Darnel and Posner, 2003. Copyright © Massachusetts Medical Soci-
ety. Reprinted with permission from Massachusetts Medical Society.)

NMO, Chihara et al. (2013) found that relapsed NMO cascade and/or Fc receptor-mediated activation of
patients had increased peripheral blood PBs that selectively FcR-expressing myeloid and lymphoid cells (Fig. 4.6).
upregulated CXCR3, the receptor for CXCL10, which is B cells can also contribute to autoimmunity by present-
elevated in the cerebrospinal fluid. Importantly, they went ing antigen and providing co-stimulation to T cells, rein-
on to show that CXCR3 + -activated PBs in the blood pref- forcing priming and activation of antigen-specific
erentially migrated to the cerebrospinal fluid during NMO T cells. Through production of cytokines, autoreactive
and take part in the inflammatory pathology. B cells can modulate the immune system. Secretion of
Autoantibodies are not intrinsically pathogenic, IL-4 and INF-g polarizes CD4+ T cells. IL-10-secreting
although a subset mediates direct cytopathology in Bregs (also known as B10 cells) attenuate autoimmune dis-
human disease, including myasthenia gravis, Graves dis- ease in mouse models of experimental allergic encephali-
ease, pemphigus vulgaris, autoimmune immune hemo- tis and lupus. B cells also have the ability to initiate
lytic anemia, NMO, and autoimmune encephalopathies formation of tertiary lymphoid structures at sites of
(Townsend et al., 2010; Hinson et al., 2007; Leypoldt end-organ autoimmune disease. Indeed, lymphoid struc-
et al., 2015; Wingerchuk, 2015). Binding of autoanti- tures with organized zones of B, T, and FDCs have been
bodies to self-antigens can lead to the formation of found in synovium, salivary glands, kidneys, and in the
immune complexes that activate innate effector func- ventricular-meningeal compartment in various autoim-
tions via Fc-receptor activation of the complement mune diseases. Finally, the dogma has been that PCs
74 K.L. MEDINA
Caused by
flares, then at lower dose to maintain remission. New
vitamin D
Genes HLA-DQ, DR, therapies have been designed in recognition that many
deficiency
and
and other Genes autoimmune diseases share common pathogenic mecha-
Disrupted nisms (Fig. 4.10). Here we highlight a few of the upcom-
by Leaky Gluten, grains, nutritional
Gut deficiencies, virus, ing therapeutic modalities undergoing consideration for
bacteria, etc
treatment of autoimmune disease.
1. TNF-a blockade – TNF-inhibitor drugs (infliximab,
T Autoimmune adalimumab, etanercept) have transformed the
disease
B
treatment of immune-mediated inflammatory
diseases.
DC Environment
2. CTLA-4Ig – CTLA4Ig is a fusion protein of the
Immune extracellular domain of CTLA4 and IgG1 that binds
regulation
to both CD80 and CD86 and prevents interaction of
these proteins with their counterreceptors CD28
Fig. 4.9. Requirements for the development of an auto- and CTLA4 expressed on T cells.
immune disease. The immune response of a genetically pre- 3. Tacrolimus – In T cells, activation of the TCR
disposed individual to an environmental pathogen, in normally increases intracellular calcium, which
association with defects in immunoregulatory mechanisms,
acts via calmodulin to activate calcineurin. Cal-
can lead to the development of an autoimmune disease. The
importance of the single components represented in this Venn
cineurin dephosphorylates the transcription fac-
diagram may vary between individuals and diseases. However, tor nuclear factor of activated T-cells (NF-AT),
the appearance of an autoimmune disease requires the conver- which regulates the genes coding for IL-2 and
gence of all three components. T, T cell; B, B cell; DC, related cytokines. Tacrolimus prevents the
dendritic cell. (Modified from Ermann and Fathman (2001), dephosphorylation of NF-AT. Tacrolimus re-
with permission from MacMillan Publishers.) duces peptidyl-prolyl isomerase activity by
binding to the immunophilin FKBP12 (FK506-
and/or PBs function exclusively as antibody factories. binding protein), which interacts with and
However, recent studies in mice have shown that PCs/PBs inhibits calcineurin, thus inhibiting both T-
are also a major source of the cytokines IL-10, IL-35, lymphocyte signal transduction and IL-2
TNF-a, IL-17, and granulocyte–macrophage colony- transcription.
stimulating factor (Dang et al., 2014). 4. B-cell depletion targeting the B-cell surface marker
The induction and perpetuation of autoimmune dis- CD20 (rituximab, ocrelizumab, ofatumumab)
ease are complex and strongly influenced by genetic which is broadly expressed on B cells, with the
predisposition, environmental factors, and immune exception of PCs and PBs.
regulation (Fig. 4.9) (Ermann and Fathman, 2001). Auto- 5. B-cell depletion targeting the B-cell surface marker
immune disease commonly appears in families, suggest- CD19 (SAR3419, MEDI-551, Combotox, MOR-
ing an underlying genetic susceptibility. Compelling 208/XmAb-5574, MDX-1342, SGN-CD19A,
associations between exposure to environmental anti- AFM11, GBR401, CD19xCD3 DART, Anti-CD19-
gens and autoimmune disease strongly support the exis- CAR, CART19), which is broadly expressed on
tence of an initiating external event such as exposure B cells, including PCs and PBs.
to an environmental pathogen. Finally, although numer- 6. B-cell depletion targeting the B-cell surface marker
ous tolerance mechanisms exist to limit potentially dan- CD22 (epratuzumab) – CD22, also known as
gerous autoreactive cells, it is clear from mouse models Siglec-2, is expressed on mature B cells and is
that disruption of immunoregulatory pathways leads to involved in B-cell activation and proliferation.
autoimmune manifestations. 7. B-cell depletion targeting BAFF/BLys (belimu-
mab) – BAFF is required for the development
EMERGING THERAPEUTIC MODALITIES
and survival of B cells. Belimumab binds to BAFF,
FOR TREATMENT OF AUTOIMMUNE
preventing BAFF from binding to B cells, leading to
DISEASE
apoptosis.
Early treatment strategies to treat systemic autoimmune 8. TACI-Fc immunoadhesin – inhibits antibody pro-
disease relied on global immunosuppression – cortico- duction, affinity maturation and GC formation
steroids are toxic to PCs and suppress many effector in mice.
mechanisms of inflammation. Cytotoxic agents directly 9. Eculizumab – blocks complement binding and acti-
kill immune cells and are used during major disease vation of the complement cascade. An open-label
 OVERVIEW OF THE IMMUNE SYSTEM 75

IL-21

T cell TCR MHC II

Anti-CD19 CD40L
DC
CD40
CTLA-4
CD19
Epratuzumab
Abatacept
CD22 CD80
and CD86
Rituximab BAFF-R BAFF
CD20
Belimumab
Ocrelizumab B cell
TACI
Tabalumab
CD52
Atacicept
Alemtuzumab BCMA
APRIL
FcγRIIb

Immune
Plasma cell Autoantibodies complexes
Fig. 4.10. Direct and indirect B-cell targeting. Direct targets of anti-B-cell therapy comprise surface molecules expressed by
B cells or their subsets, such as type I CD20 (target of rituximab and ofatumumab), CD22 (target of epratuzumab, which is
not in development for rheumatoid arthritis), CD19, CD52 (targeted by alemtuzumab, which also co-targets T cells), and recep-
tor–ligand pairs in co-stimulatory pathways, such as CD40–CD40L, CD80/CD86–CTLA-4 (inhibited by abatacept) and inducible
T-cell co-stimulator (ICOS)–ICOS ligand. FcgRIIb is thought to be an inhibitory receptor that controls B-cell activation. Inhibiting
cytokines involved in B-cell differentiation and maintenance is an indirect anti-B-cell principle. These molecules include BAFF
(specifically targeted by belimumab and tabalumab), APRIL (atacicept simultaneously blocks BAFF and APRIL), IL-21, IL-6–IL-
6R, IL-1 and others, which fuel the inflammatory response via activation of other immune cells (T cells, macrophages, neutrophils),
resulting into co-activation of B cells and effector functions. APRIL, a proliferation-inducing ligand (TNF ligand superfamily
member 13); BAFF, B-cell-activating factor (TNF ligand superfamily member 13B); BAFF-R, BAFF receptor (TNF receptor
superfamily member 13C); BCMA, B-cell maturation protein (TNF receptor superfamily member 17); CTLA-4; cytotoxic
T-lymphocyte protein 4; DC, dendritic cell; FcgRIIb, Fcg receptor IIb; TACI, transmembrane activator and CAML interactor
(TNF receptor superfamily member 13B); TCR, T-cell receptor; TNF, tumor necrosis factor. (Adapted from Gregersen and
Jayne (2012), with permission from MacMillan Publishers.)

study is investigating the effects of eculizumab in Cassese G, Lindenau S, De boer B et al. (2001). Inflamed kid-
patients with NMO, a complement-mediated neys of NZB/W mice are a major site for the homeostasis of
inflammatory disease of the brain tissues that plasma cells. Eur J Immunol 31: 2726–2732.
can potentiate immune attack on the brain, optic Chen W, Jin W, Hardegen N et al. (2003). Conversion of
peripheral CD4 + CD25- naive T cells to CD4 + CD25 +
nerves, spinal cord.
regulatory T cells by TGF-beta induction of transcription
10. Natalizumab – a humanized monoclonal antibody
factor Foxp3. J Exp Med 198: 1875–1886.
targeting the adhesion molecule alpha 4-integrin. Chihara N, Aranami T, Oki S et al. (2013). Plasmablasts as
The drug is believed to work by reducing the ability migratory IgG-producing cells in the pathogenesis of neu-
of inflammatory immune cells to attach to and pass romyelitis optica. PLoS One 8e83036.
through cell layers lining the intestines and blood– Dal Porto JM, Gauld SB, Merrell KT et al. (2004).
brain barrier. B cell antigen receptor signaling 101. Mol Immunol 41:
599–613.
Dang VD, Hilgenberg E, Ries S et al. (2014). From the regulatory
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