Immunology

What is Immunity
• “Immunis” is a Latin word meaning free from
burden or taxes.
• Immunity is defined as resistance to disease,
specifically infectious disease.
• The collection of cells, tissues, and molecules that
mediate resistance to infections is called the
immune system
• The coordinated reaction of these cells and
molecules to infectious microbes is the immune
response.
 What is Immunology
• Immunology is the study of the immune system,
including its responses to microbial pathogens
and damaged tissues and its role in desease.
• The role of the Immune system is: defense
against infections, defense against tumors. The
immune system can injure cells and induce
pathogenic inflammation. The immune system
recognizes and responds to tissue grafts and
newly introduced proteins.
 The importance if immune system
• The immune system is clearly essential for survival.
• It constantly defends the body against bacteria, viruses,
and other foreign substances it encounters.
• It also detects and responds to abnormal cells and
molecules that periodically develop in the body so that
diseases such as cancers do not occur.
• An essential aspect of the immune response is the
ability to recognize almost limitless numbers of foreign
cells and non self substances, distinguishing them from
self molecules that are native to the body – it
distinguishes self from non self.
 Definitions
• The immune system consists of the central and
peripheral lymphoid organs and tissues.

• The individual components of the substance

that the immune system recognizes as foreign
are called antigens.

.
 The immune system
• The immune system
– Nonspecific or innate defense system
• Cellular
• Humoral
– Specific or acquired or adaptive immune system
• Cellular
• Humoral
 Innate and Adaptive Immunity
• Host defense are grouped under innate
immunity, which provides immediate
protection against microbial invasion
• Adaptive immunity, which develops more
slowly and provides more specialized defense
against infections
• Innate Immunity is phylogenetically older, and
the more specialized and powerful adaptive
immune response evolved later.
 Nonspecific or innate Immunity
(the Early Defense Against Infections)
• First line of defense system
• It distinguishes self from non-self but does not distinguish one
type of pathogen from another.

• Components:
– skin and mucous membranes
– inflammatory response
– phagocytic and non phagocytic leukocytes cells
 Nonspecific or innate defense system
• 1. Mechanical factors
– The epithelial surfaces form a physical barrier that is very
impermeable to most infectious agents.
– The skin acts as our first line of defense against invading
organisms. The desquamation of skin epithelium also helps
remove bacteria and other infectious agents that have
adhered to the epithelial surfaces.
– Movement due to cilia or peristalsis helps to keep air
passages and the gastrointestinal tract free from
microorganisms.
– The flushing action of tears and saliva helps prevent
infection of the eyes and mouth.
– The trapping effect of mucus that lines the respiratory and
gastrointestinal tract helps protect the lungs and digestive
systems from infection.
 Nonspecific or innate defense system
• 2. Chemical factors
– Fatty acids in sweat inhibit the growth of bacteria.
– Lysozyme and phospholipase found in tears, saliva and nasal
secretions can breakdown the cell wall of bacteria and destabilize
bacterial membranes.
– The low pH of sweat and gastric secretions prevents growth of
bacteria.
– Defensins (low molecular weight proteins) found in the lung and
gastrointestinal tract have antimicrobial activity.
– Surfactants in the lung act as opsonins (substances that promote
phagocytosis of particles by phagocytic cells).
• 3. Biological factors
– The normal flora of the skin and in the gastrointestinal tract can
prevent the colonization of pathogenic bacteria by secreting toxic
substances or by competing with pathogenic bacteria for nutrients or
attachment to cell surfaces.
 Immune Cells
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 Nonspecific immune cells
• Phagocytes:
– Neutrophyles – bacteria
– Eosinophyles – enzymes that kills parasites
– Macrophages - "big eaters"
• Non phagocytic leukocytes:
– Basophiles – role in allergic response
– Mastocytes
– Natural killer lymphocytes – antiviral and anti-tumor
activity
 PHAGOCYTES: NEUTROPHILS
• The two types of circulating phagocytes, neutrophils
and monocytes, are blood cells that are recruited to
sites of infection, where they recognize and ingest
microbes for intracellular killing.
• Neutrophils, also called polymorphonuclear leukocytes
(PMNs), are the most abundant leukocytes in the
blood. Neutrophils are the first cell type to respond to
most infections, particularly bacterial and fungal
infections, and thus are the dominant cells of acute
inflammation.
Phagocytes: Monocytes/Macrophages
• Monocytes are less abundant in than neutrophils,
numbering 500 to 100 per μL. They also ingest
microbes in the blood and in tissues. During
inflammatory reactions, monocytes enter
extravascular tissues and differentiate into
macrophages.
• Macrophages serve several important roles in
host defense: they produce cytokines that induce
and regulate inflammation, they ingest and
destroy microbes, and they clear dead tissues and
initiate the process of tissue repair.
 Nonspecific immune cells
• Macrophages have important functions in both innate and antigen-specific
immune responses.
• As phagocytic cells with antigen nonspecific activity, they help to contain
infectious agents until specific immunity can be marshaled.
• In addition, early in the host response, the macrophage functions as an
accessory cell to ensure amplification of the inflammatory response and
initiation of specific immunity.
• Macrophages are activated by the presence of antigen to engulf and
digest foreign particles.
• Activated macrophages act as antigen presenting cells (APCs) that break
down complex antigens into peptide fragments that can associate with
class I or II Major Histocompatibility Complex (MHC) molecules.
Macrophages can then present these complexes to the helper T cell so
that nonself-self recognition and activation of the immune response can
occur.
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 DENDRITIC CELLS
• Dendritic cells respond to microbes by
producing cytokines that serve two m,ain
functions: they initiate inflammation and
initiate adaptive immune responses.
• Dendritic cells constitute an important bridge
between innate and adaptive immunity.
 Mast Cells
• Mast cells are bone marrow–derived cells with
abundant cytoplasmic granules that are present
in the skin and mucosal epithelium.
• Mast cell granules contain vasoactive amines
such as histamine that cause vasoincreased
capillary permeability, as well as proteolytic
enzymes that can kill bacteria or inactivate
microbial toxins. They synthesize and secrete lipid
mediators (e.g., prostaglandins) and cytokines
(e.g., tumor necrosis factor [TNF])
 Natural Killers (NK) cells
• Natural killer (NK) cells recognize infected and stressed cells and
respond by killing these cells and by secreting the macrophages
activating cytokine IFN-γ.
• NK cells contain abundant cytoplasmic granules and express some
unique surface proteins but don’t express immunoglobulins or T cell
receptors.
• The cytotoxic mechanisms of NK, which are the same as the
mechanisms used by cytotoxic T lymphocytes (discussed next),
result in the death of infected cells. The NK cells function to
eliminate cellular reservoirs of infection and eradicate infections by
obligate intracellular microbes, such as viruses.
• Programmed killing is inhibited if the NK cell membrane molecules
contact MHC self-molecules on normal host cells.
• The mechanism of NK cytotoxicity depends on production of pore-
forming proteins (i.e., NK perforins), enzymes, and toxic cytokines
 Cellular Receptors for Microbes and
Damaged Cells
• The receptors used by the Innate Immune system
to react against microbes and damaged cells are
expressed on phagocytes, dendritic cells, and
many other cell types, and are expressed in
different cellular compartments where microbes
may be located.
• These receptors are present on the cell surface, in
vesicles (endosomes) and in the cytosol.
 PAMPs and DAMPs
• The microbial molecules that stimulate innate
immunity are often called pathogen-associated
molecular patterns (PAMPs) to indicate that they
are present in infections agents (pathogens) and
shared by microbes of the same type.
• The Innate immunity system also recognizes
molecules that are released from damaged or
necrotic host cells, such molecules are called
damage-associated molecular patterns (DAMPs)
 Toll-Like Receptors (TLRs)
• TLRs are homologous to a Drosophila protein called
Toll. there are 10 distinct TLRs in humans all of which
act as sensors for PAMPs
• TLR ligands include peptidoglycan, lipoproteins, yeast
zymosan, mycobacterial lipoarabinomannan, flagellin,
microbial DNA, microbial RNAs, as well as other
pathogen‐derived ligands
• Although many TLRs are displayed on the cell surface,
some, such as TLR3 and TLR7/8/9 that are responsive
to intracellular viral RNA and unmethylated bacterial
DNA, are located in endosomes and become engaged
upon encounter with phagocytosed material
Ligands for Toll-like Receptors (TLRs)
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 NOD-Like Receptors (NLRs)
• The NLRs are a large family of cytosolic
receptors that sense DAMPs and PAMPs in
the cytoplasm.
• NLRs are soluble proteins that reside in the
cytoplasm, where they also act as receptors
for PAMPs.
• Three important NLRs are NOD-1, NOD-2, and
NLRP-3.
 Nonspecific defense system
• The anatomical barriers are very effective in
preventing colonization of tissues by
microorganisms.
• However, when there is damage to tissues the
anatomical barriers are breached and infection
may occur. Once infectious agents have
penetrated tissues, another innate defense
mechanism comes into play, namely acute
inflammation.
• Humoral factors play an important role in
inflammation, which is characterized by edema
and the recruitment of phagocytic cells.
 Nonspecific humoral immune system
• The complement system
– The complement system is a primary mediator of the humoral
immune response that enables the body to produce an
inflammatory response, lyse foreign cells, and increase
phagocytosis.
– The complement system, like the blood coagulation system,
consists of a group of proteins that normally are present in the
circulation as functionally inactive precursors. These proteins
make up 10% to 15% of the plasma protein fraction.
– For a complement reaction to occur, the complement
components must be activated in the proper sequence.
– Uncontrolled activation of the complement system is prevented
by inhibitor proteins.
 SUMMARY of INNATE IMMUNITY
• All multicellular organisms contain intrinsic mechanisms of
defense against infections, which constitute innate immunity.
• The mechanisms of innate immunity respond to microbes and
not to nonmicrobial substances, are specific for structures
present on various classes of microbes, are mediated by
receptors encoded in the germline, and are not enhanced by
repeat exposures to microbes.
• The principal components of innate immunity are epithelia,
phagocytes, dendritic cells, NK cells, cytokines, and plasma
proteins, Including the proteins of the complement system.
• In addition to providing the early defense against infections,
innate immune responses provide second signals for the
activation of B and T lymphocytes. The requirement for these
second signals ensures that adaptive immunity is elicited by
microbes (the natural inducers of innate immune reactions)
and not by nonmicrobial substances.
Immune Organs - organs of the
immune system and immune
cells
 TISSUES OF THE IMMUNE SYSTEM
• The tissues of the immune system consist of the generative lymphoid
organs, in which T and B lymphocytes mature and become competent to
respond to antigens, and the peripheral lymphoid organs, in which
adaptive immune responses to microbes are initiated
• All lymphocytes arise from stem cells in the bone marrow .B lymphocytes
mature in the bone marrow, and T lymphocytes mature in an organ called
the thymus.
• These sites in which mature lymphocytes are produced (generated) are
called the generative lymphoid organs. Mature lymphocytes leave the
generative lymphoid organs and enter the circulation and the peripheral
lymphoid organs, where they may encounter antigen for which they
express specific receptors.
 Organs of the immune system

• "Primary organs” - These are immune organs concerned with production

and maturation of lymphoid cells and including bone marrow and thymus
gland.
• “Secondary organs” - these immune organs are spots or sites in which the
lymphocytes localize, identify unfamiliar antigens and triggers reaction in
opposition to it. It Contains tonsils , lymph nodes, Spleen, Peyer’s patches (
in the small intestines), appendix and liver.
• B lymphocytes mature in the bone marrow, and T lymphocytes mature in
an organ called the thymus These sites in which mature lymphocytes are
produced (generated) are called the generative lymphoid organs. Mature
lymphocytes leave the generative lymphoid organs and enter the
circulation and the peripheral lymphoid organs, where they may
encounter antigen for which they express specific receptors
 Bone marrow

• Bone marrow is a sponge-like tissue situated inside of the bones.

Most defense cells are produced and then also multiply here. They
then migrate from the bone marrow into the bloodstream and reach
other organs and tissues where the defense cells mature and
specialize. At birth, many bones contain red bone marrow, which
actively builds defense cells. During the course of life, more and more
red bone marrow turns into fat tissue. Adults only have red bone
marrow in a few bones, for example in the ribs, in thebreast bone and
in the pelvic bone
 Thymus

• Thymus- also called the thymus gland, is only fully developed in children. From adolescence onwards, it is
slowly turned into fat tissue. The gland-like organ is situated behind the breast bone above the heart.
Certain defense cells are differentiated in the thymus: the so-called T lymphocytes, or T cells for short,
among other things, are responsible for coordinating the innate and the adaptive immune system.
• The T in T lymphocytes stands for thymus, the place where they mature. T cells move through the body and
constantly watch the surfaces of all cells for changes. To be able to do this job, they learn in the thymus
which structures on cell surfaces are self and which are non-self.
• Immature thymocytes, also called prothymocytes, abandon bone marrow to move in to the thymus. By way
of an extraordinary maturation process at times called thymic education, T cells which are good for the
body's defense mechanisms are spared, but other T cells which may stimulate a harmful autoimmune
reaction are eliminated. The Release of Mature T cells into the bloodstream takes place next.
• When coming into contact with a non-self body, T cells turn into so-called T effector cells, which trigger and
regulate different defense reactions. This type of cells includes T killer cells, which can destroy cells infected
with a pathogen T helper cells are another kind of effector cells, which support other immune cells in doing
their work.
• In childhood, the Thymus tissue also produces two hormones – thymosin and thymopoietin – which regulate
the maturation of defense cells in the Lymph nodes.
 Negative and positive selection
• Lymphocytes are selected at multiple steps during their maturation to
preserve the useful specificities. Selection is based on the expression of
intact antigen receptor components and what they recognize. Pre
lymphocytes and immature lymphocytes that fail to express antigen
receptors die by apoptosis. In order to preserve the T cells that will be
functional, immature T cells are selected to survive only if they recognize
MHC molecules in the thymus. This process, called positive selection,
ensures that cells that complete maturation will be capable of recognizing
antigens displayed by the same MHC molecules on APC.
• Other antigen receptors may recognize peptides of self proteins. Therefore,
another selection process is needed to eliminate these potentially
dangerous lymphocytes and prevent the development of autoimmune
responses. The mechanisms that eliminate strongly self-reactive B and T
lymphocytes constitute negative selection.
 Peripheral Lymphoid Organs
• The peripheral lymphoid organs, which consist of the lymph nodes,
the spleen, and the mucosal and cutaneous immune systems, are
organized in a way that promotes the development of adaptive
immune responses.
 Lymph nodes
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• Lymph nodes are encapsulated nodular aggregates of lymphoid tissues located along lymphatic
channels throughout the body . Fluid constantly leaks out of blood vessels in all epithelia and
connective tissues and most parenchymal organs.
• The lymphatic system of lymph nodes and vessels is important for continually exchanging
substances between the blood and the tissue in the body. Fluid constantly leaves the blood, and
defense cells and proteins migrate into the surrounding tissue. Most of the fluid is later taken
back into the blood vessels. This fluid, called lymph, is drained by lymphatic vessels from the
tissues to the lymph nodes and eventually back into the blood circulation
• The rest of it is removed by the drainage system of the lymph vessels which forms a fine net of
thin-walled vessels in the body. The lymph nodes filter and clean the lymph fluid (lymph) on its
way to the larger lymph vessels. The lymph finally travels to a vein called the superior vena cava,
where it enters the blood stream.
• lymph nodes work like biological filter stations. They contain different defense cells, which
trap pathogens and activate the production of specific antibodies in the blood. If lymph nodes
become swollen, painful or hard, it can be a sign of an active defense reaction, for example in
an infection or, in rare cases, in malignant changes of the body’s own cells.
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 Spleen

• The spleen is situated in the left upper abdomen, beneath the diaphragm. It has a variety of tasks
in the defense system. In the unborn child, the spleen mainly produces blood and defense cells.
After birth this organ is mainly responsible for removing blood cells and for specific defense
functions. As part of the immune defense, the functions of the spleen include the following:
• It stores different defense cells that are released into the blood to get to the organs, if
needed: macrophages, also called scavenger cells, can attack non-self substances
and pathogens directly. T lymphocytes inspect cell surfaces, help in controlling defense and can
also directly destroy cells that have been recognized as non-self or as pathogens. B lymphocytes
produce antibodies, if needed.
• It is responsible for removing red blood cells (erythrocytes).
• Blood platelets (thrombocytes), which are responsible for blood clotting together, are stored and
removed in the spleen.
• So there is always a lot of blood flowing through the spleen tissue. At the same time this tissue is
very soft. In heavy injuries, in an accident, for example, the spleen can therefore rupture easily.
The spleen then needs to be operated on, because otherwise there is a danger of bleeding to
death. If the bleeding cannot be stopped, and the spleen has to be removed, other
defense organs take on most of its tasks.
Lymphatic tissue in the bowel and in other mucous
membranes in the body
• The bowel plays a central role in defending the body against pathogens: More
than half of all cells that produce antibodies are found in the bowel wall,
especially in the last part of the small bowel and in the appendix. These cells
recognize pathogens and other non-self substances, and mark and destroy them.
They also store information on these non-self substances to be able to react
faster the next time. The large bowel also always contains bacteria that belong to
the body, the so-called gut flora. These bacteria in the large bowel make it
difficult for other pathogens to settle and to enter the body. The immune system
of the bowel tolerates the bacteria of the gut flora.
• Other parts of the body where pathogens may enter also contain lymphatic
tissue in the mucous membranes. All this tissue together is also called mucosa-
associated lymphoid tissue (MALT). Pathogens might enter the body through the
airways or the urinary tract, for example. Lymphatic tissue can be found in
the bronchi and in the mucous membranes of the nose, the urinary bladder and
the vagina with the defense cells being directly beneath the mucous
membrane where they prevent bacteria and viruse from attaching.
Lymphocyte Recirculation and Migration into
Tissues
• Naive lymphocytes constantly recirculate between the blood and
peripheral lymphoid organs, where they may be activated by antigens to
become effector cells, and the effector lymphocytes migrate from
lymphoid tissues to sites of infection, where microbes are eliminated .
lymphocytes at distinct stages of their lives migrate to the different sites
where they are needed for their functions. Migration of effector
lymphocytes to sites of infection is most relevant for T cells, because
effector T cells have to locate and eliminate microbes at these sites. By
contrast, plasma cells do not need to migrate to sites of infection; instead,
they secrete antibodies, and the antibodies enter the blood, where they
may bind blood-borne pathogens or toxins. Plasma cells in mucosal organs
secrete antibodies that enter the lumens of these organs, where they bind
to and combat ingested and inhaled microbes.
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Immune cells
• B lymphocytes mature in the bone marrow, and T lymphocytes
mature in an organ called the thymus. These sites in which mature
lymphocytes are produced (generated) are called the generative
lymphoid organs. Mature lymphocytes leave the generative lymphoid
organs and enter the circulation and the peripheral lymphoid organs.
• When naive lymphocytes recognize microbial antigens and also
receive additional signals induced by microbes, the antigen-specific
lymphocytes proliferate and differentiate into effector cells and
memory cells
Principal cells of the immune system
Cell type Principal function(s)
Lymphocytes: B lymphocytes; T lymphocytes Specific recognition of antigens
• B lymphocytes: mediators of humoral immunity
• T lymphocytes: mediators of cell-mediated immunity
Antigen-presenting cells: Capture of antigens for display to lymphocytes:
dendritic cells; macrophages; • Dendritic cells: initiation of T cell responses
B cells; follicular dendritic cells • Macrophages: effector phase of cell-mediated
immunity
• Follicular dendritic cells: display of antigens to B
lymphocytes in humoral immune responses
Effector cells: Elimination of antigens:
T lymphocytes; • T lymphocytes: activation of phagocytes, killing
macrophages; infected cells
granulocytes • Macrophages: phagocytosis and killing of microbes
• Granulocytes: killing microbes
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Naive and effector lymphocytes and Memory
cells
• Naive lymphocytes express receptors for antigens but do not perform the
functions that are required to eliminate antigens. These cells reside in and
circulate between peripheral lymphoid organs and survive for several
weeks or months, waiting to find and respond to antigen. If they are not
activated by antigen, naive lymphocytes die by the process of apoptosis .
• Effector lymphocytes are the differentiated progeny of naive cells that
have the ability to produce molecules that function to eliminate antigens.
The effector cells in the B lymphocyte lineage are antibody-secreting cells,
called plasma cells. Effector CD4+ T cells (helper T cells) produce proteins
called cytokines that activate B cells, macrophages, and other cell types,
thereby mediating the helper function of this lineage. Effector CD8+ T cells
(CTLs) have the machinery to kill infected host cells.
• Memory cells, also generated from the progeny of antigen-stimulated
lymphocytes, do survive for long periods in the absence of antigen.
 T cells
• T cells are maturated in the thymus.
• There, they learn how to distinguish self from non-self. Only the T
cells that ignore self antigen molecules are allowed to mature and
leave the thymus. Without this training process, T cells could attack
the body's cells and tissues.
• Mature T cells are stored in secondary lymphoid organs (lymph
nodes, spleen, tonsils, appendix, and Peyer's patches in the small
intestine).
• These cells circulate in the bloodstream and the lymphatic system.
After they first encounter a foreign or abnormal cell, they are
activated and search for those particular cells.
 Types of T cells
• Helper T (CD4) cells help other immune cells. Some helper T cells help B cells produce antibodies against
foreign antigens. Others help activate killer T cells to kill foreign or abnormal cells or help activate
macrophages enabling them to ingest foreign or abnormal cells more efficiently.
• The Th1 response is characterized by the production of interferon - gamma, which activates the
bactericidal activities of macrophages, and induces B-cells to make opsonizing (coating) antibodies, and
leads to cell mediated immunity.
• The Th2 response is characterized by the release of interleukin 4, which results in the activation of B-
cells to make neutralizing (killing) antibodies, leading to humoral immunity.
• Generally, Th1 responses are more effective against intracellular pathogens (viruses and bacteria that
are inside host cells), while Th2 responses are more effective against extracellular bacteria, parasites
and toxins.
 Types of T cells
• Th1 cells:
• secrete IL-2, IL-12, IFN gamma, TNF-beta;
• activate macrophages, amplifying their cytokine secretion capacity and potential for
presentation of antigens;
• activate synthesis of IgG but not IgE;
• are involved in delayed hypersensitivity reactions;
• are activated by signals from intracellular bacteria and viruses;
• Th2 cells:
• secrete IL-4, IL-5, IL-6, IL-10;
• activate the synthesis of IgE;
• stimulate proliferation and activation of eosinophils;
• are stimulated by allergens or parasite components.
Types of T cells
• Cytotoxic (Killer) T cells (CD8) attach to particular foreign or abnormal (for
example infected) cells because they have encountered them before. Killer
T cells may kill these cells by making holes in their cell membrane and
injecting enzymes into the cells or by binding with certain sites on their
surface called death receptors.

• Suppressor(regulatory) T cells produce substances that help end the

immune response or sometimes prevent certain harmful responses from
occurring.

• Sometimes T cells—for reasons that are not completely understood - do

not distinguish self from nonself. This malfunction can result in an
autoimmune disorder, in which the body attacks its own tissues.
Types of T cells
• Γδ T cells (gamma delta T cells) represent a small subset of T cells,
which possess a different receptor on the surface (TCR). Most T cells
receptor consists of two chains α-and β-gp. Unlike T cells, γδ cells
have a TCR composed of gamma and a delta chains. This group is
more poorly represented than beta alpha cells. They are abundant in
the intestinal mucosa.
• Natural killer T cells (NKT) are a heterogeneous group of T cells, which
have properties of both NK cells and T cells and represents only 0.2%
of all circulating T lymphocytes in the blood.
 B cells

• B cells are formed in the bone marrow. B cells have particular sites
(receptors) on their surface where antigens can attach.
• B cells are the major cells involved in the creation of antibodies that
circulate in blood plasma and lymph, known as humoral immunity.
• In mammals there are five types of antibody IgA, IgD, IgE, IgG, and IgM,
differing in biological properties.
• Each has evolved to handle different kinds of antigens.
• Upon activation, B cells produce antibodies, each of which recognizes a
unique antigen, and neutralize specific pathogens.
 B cell
• B lymphocytes are the only cells capable of producing antibodies;
therefore, they are the cells that mediate humoral immunity. B cells
express membrane forms of antibodies that serve as the receptors
that recognize antigens and initiate the process of activation of the
cells.
• Basic Immunology P.p.16-23
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 Antigen
• Any substance that is specifically recognized by
lymphocytes or antibodies is called an antigen. Antigen is a
molecule capable of inducing an immune response on the
part of the host organism, though sometimes antigens
can be part of the host itself.
• An antigen is a molecule that binds to Ag-specific receptors,
but cannot necessarily induce an immune response in the
body by itself. Antigens are usually proteins,
peptides, polysaccharides or lipids. In general, molecules
other than peptides (saccharides and lipids) qualify as
antigens but not as immunogens since they cannot elicit an
immune response on their own. (Least molecular mass of
Antigen is 1000 to 6000 Dalton).Antigen consists of many
antigenic determinants.
 Antigen
• The adaptive immune system is capable of
distinguishing among millions of different
antigens or portions of antigens
• In active immunity, an individual exposed to the
antigens of a microbe mounts an active response
to eradicate the infection and develops resistance
to later infection by that microbe. Such an
individual is said to be immune to that microbe,
in contrast with a naive individual, not previously
exposed to that microbe’s antigens
 Antigens

• Antigens, which in general are large and complex, are biologically

degraded into smaller chemical units or peptides.
• These discrete, immunologically active sites on antigens are called
antigenic determinants or epitopes.
• It is the unique molecular shape of an epitope that is recognized by a
specific receptor found on the surface of the lymphocyte or by the
antigen-binding site of an antibody.
• A single antigen may contain several antigenic determinants; each can
stimulate a distinct clone of lymphocytes to respond.
• Smaller substances (molecular masses <10,000 daltons) usually are unable
to stimulate an adequate immune response.
• Low–molecular-weight compounds, known as haptens, combine with
larger protein molecules they function as antigens.
 Immunogen
• An immunogen is a substance (or adduct) that
is able to trigger a humoral (innate) and/or
cell-mediated immune response. It first
initiates an innate immune response, which
then causes the activation of the adaptive
immune response. An antigen binds the highly
variable immunoreceptor products (B-cell
receptor or T-cell receptor) once these have
been generated. All immunogen molecules are
also antigens, although the reverse is not true.
 Epitope
• An epitope, also known as antigenic
determinant, is the part of an antigen that is
recognized by the immune system, specifically
by antibodies, B cells, or T cells. Antigenic
molecules, normally "large" biological polymers,
usually present surface features that can act as
points of interaction for specific antibodies. Any
such feature constitutes an epitope. Using the
"lock and key" metaphor, the antigen can be seen
as a string of keys (epitopes) each of which
matches a different lock (antibody paratopes),
 Antigens Epllapes
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 Hapten
• Haptens are small molecules that elicit an
immune response only when attached to a large
carrier such as a protein; the carrier may be one
that also does not elicit an immune response by
itself.
• Once the body has generated antibodies to a
hapten-carrier adduct, the small-molecule hapten
may also be able to bind to the antibody, but it
will usually not initiate an immune response;
usually only the hapten-carrier adduct can do
this.
 Antigens classification
• Antigens can be classified according to their source:
• Exogenous antigens Exogenous antigens are antigens
that have entered the body from the outside, The
immune system's response to exogenous antigens is
often subclinical. By endocytosis or phagocytosis,
exogenous antigens are taken into the antigen-
presenting cells (APCs) and processed into fragments.
APCs then present the fragments to T helper
cells (CD4+) by the use of class II
histocompatibility molecules on their surface.
 Antigens classification
• Endogenous antigens are generated within normal
cells as a result of normal cell metabolism, or because
of viral or intracellular bacterial infection. The
fragments are then presented on the cell surface in the
complex with MHC class I molecules. Endogenous
antigens include xenogenic (heterologous),
autologous and idiotypic or allogenic (homologous)
antigens.
• Autoantigens is usually a normal protein or protein
complex (and sometimes DNA or RNA) that is
recognized by the immune system of patients suffering
from a specific autoimmune disease.
 Antigens classification
• Neoantigens are those that are entirely absent
from the normal human genome.
• Viral antigens For virus-associated tumors, such
as cervical cancer and a subset of head and neck
cancers, epitopes derived from viral open reading
frames contribute to the pool of neoantigens
• Tumor antigens are those antigens that are
presented by MHC class I or MHC class
II molecules on the surface of tumor cells.
 Major histocompatibility
complex (MHC)
• Antigen presenting cells present antigens in the form
of peptides on histocompatibility molecules. For T-Cell Receptor
(TCR) recognition, the peptide must be processed into small
fragments inside the cell and presented by a major
histocompatibility complex (MHC).
• The major histocompatibility complex (MHC) is a set of cell surface
proteins essential for the acquired immune system to recognize
foreign molecules in vertebrates, which in turn
determines histocompatibility. The main function of MHC
molecules is to bind to peptide fragments derived from pathogens
and display them on the cell surface for recognition by the
appropriate T-cells. MHC molecules mediate interactions
of leukocytes, also called white blood cells. In humans, the MHC is
also called the human leukocyte antigen (HLA)
 MHC
• The MHC is a genetic locus whose principal
products function as the peptide display
molecules of the immune system. In every
individual, different clones of T cells can see
peptides only when these peptides are
displayed by that individual’s MHC molecules.
This property of T cells is called MHC
restriction.
 Class I and class II MHC

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 MHC
• There are two major classes of MHC molecules, both of which
consist of an a and a b chain, but from different sources.
• MHC class I molecules (MHC I) consist of one membrane-
spanning a chain (heavy chain) produced by MHC genes, and
one b chain (light chain or b2-microglobulin) produced by the b2-
microglobulin gene. MHC class II molecules (MHC II) consist of two
membrane-spanning chains, a and b, of similar size and both
produced by MHC genes. In each case, the MHC molecule has a
groove that binds a peptide, which it can then present at the cell
surface to a T cell to elicit an immune response, because T cells only
recognise antigens as complexes with MHC molecules. The two
classes of MHC proteins differ not only in their structure, but more
importantly in their functional roles within the immune system: the
two types of MHC molecules are specialised to present different
types of antigens, thereby eliciting different responses.
 Molecular Map of the Human Major
Histocompatibility Complex
• The human MHC, designated HLA, is encoded on the short arm of chromosome 6.
The genes encoding the Class I HLA heavy chains (shown in blue) are clustered at
the telomeric end of the complex. The genes encoding the Class II HLA α and β
chains (shown in green) plus the genes encoding the LMP1/2, TAP1/2, and
Tapascin (TAPBP) molecules (shown in orange) are clustered at the centromeric
end of the complex. In between the Class I and the Class II genes are additional
genes designated Class III (shown in red). These include genes encoding the
cytochrome P450 21-hydroxylase (CYP21B), an inactive cytochrome P450
pseudogene (CYP21Ps), complement components C4, C2 and factor B (Bf), tumor
necrosis factor (TNF), and the two lymphotoxin chains (LTA, LTB). There are two
isoforms of complement C4 designated C4A and C4B. C4A interacts more
efficiently with macromolecules containing free amino groups (protein antigens),
whereas C4B interacts more efficiently with macromolecules containing free
hydroxyl groups (glycoproteins and carbohydrates). There are genes encoding two
additional HLA Class I-like molecules designated MICA and MICB (shown in purple)
located between the Class III genes and the classical Class I genes. Non-functional
pseudogenes are shown in gray and further designated by italics.
MHC class I and class II

MHC class I MHC class II

Comprised of an MHC- Comprised of MHC-
encoded achain and a b2- encoded aand b chains
microglobulin chain
Present on most cells Present only on antigen-
presenting cells
Bind endogenous antigens Binds exogenous antigens
synthesized in a cell
Present antigen to cytotoxic Present antigen to helper T cell
T cell lymphocytes lymphocytes
Bind CD8 adhesion molecules Bind CD4 adhesion molecules
on cytotoxic T cells on helper T cells
Presence of foreign or over- Presence of foreign antigens
abundant antigens targets cell induces antibody production,
for destruction and attracts immune cells to
area of infection
Phagocytosis
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c
 Phagocytosis Definition

• Phagocytosis, or “cell eating”, is the process by which a cell

engulfs a particle and digests it. The word phagocytosis comes
from the Greek phago-, meaning “devouring”, and -cyte,
meaning “cell”.
• Phagocytosis was first observed by E´ lie Metchnikoff (1) more
than 100 years ago. Since then, it has been recognized as a
critical component of the innate and adaptive immune
responses to pathogens.
• Since then, it has been recognized as a critical component of
the innate and adaptive immune responses to pathogens.
• In addition, more recent studies have revealed that
phagocytosis is crucial for tissue homeostasis and
remodeling.
 Phagocytosis
• Phagocytosis is a process of ingestion of particles
larger than 0.5 μm in diameter. It begins with
membrane receptors binding to the microbe.
phagocytosis involves the recognition and binding of
prey by receptors on the cell surface.
• Foreign bodies such as bacteria or fungi can be cleared
from infection sites by professional phagocytes such as
neutrophils, macrophages, and dendritic cells.
• Neutrophils and macrophages ingest (phagocytose)
microbes and destroy the ingested microbes in
intracellular vesicles .
 Phagocytosis
• Phagocytosis thereby contributes to the first
line of defense against infection. It also plays a
key role in the initiation of the adaptive
immune response; by promoting the release
of proinflammatory cytokines, engagement of
phagocytic targets can attract lymphoid cells.
• Moreover, professional phagocytes can
present to lymphoid cells antigens derived
from the degradation of engulfed particles.
 The Steps Involved in Phagocytosis

• Step 1: Activation of the Phagocyte

• Resting phagocytes are activated by inflammatory
mediators such as bacterial products (bacterial
proteins, capsules, LPS, peptidoglycan, teichoic
acids, etc.), complement proteins, inflammatory
cytokines, and prostaglandins. As a result, the
circulating phagocytes produce surface
glycoprotein receptors that increase their ability
to adhere to the inner surface of capillary walls,
enabling them to squeeze out of the capillary and
be attracted to the site of infection.
 Phagocytosis steps

• Step 2:
• In the immune system, chemotaxis may occur.
Chemotaxis is the movement of phagocytes toward a
concentration of molecules. Immune cells pick up
chemical signals and migrate tward invading bacteria
or damaged cells.
• Step 3:
• The cell attaches to the particle that it will ingest.
Attachment is necessary for ingestion to occur. Some
bacteria can resist attachment, making it harder for
them to be taken into the cell and destroyed.
 Phagocytosis Steps
• Step 4:
The cell ingests the particle, and the particle is
enclosed in a vesicle (a sphere of cell membrane
with fluid in it) called a phagosome. The
phagosome transports the particle into the cell.
• Step 5:
A lysosome fuses with the phagosome and the
particle is digested. Lysosomes are vesicles that
contain hydrolytic enzymes that break down
molecules. A phagosome fused with a lysosome is
called a phagolysosome.
 Phagocytosis Steps
• Step 6:
Cellular waste, such as broken down molecules
that the cell cannot reuse, is discharged from
the cell by the process of exocytosis. Exocytosis
is the opposite of endocytosis; it is when cellular
waste products travel in vesicles to the surface
of the cell membrane and are released, thereby
exiting the cell.
 Process of phagocytosis

A cell ingests a particle, breaks it down with the

enzymes in lysosomes, and expels waste products
through exocytosis.
 Complement system
• The term “complement” means to supplement.
Complement system is part of the innate immune
system. However, it can be recruited and brought into
action by the adaptive immune system.
• The complement system is a collection of circulating
and membrane-associated proteins that are important
in defense against microbes. Many complement
proteins are proteolytic enzymes, and complement
activation involves the sequential activation of these
enzymes, sometimes called an enzymatic cascade.
 Nonspecific defense system

• The anatomical barriers are very effective in preventing colonization of

tissues by microorganisms.
• However, when there is damage to tissues the anatomical barriers are
breached and infection may occur. Once infectious agents have penetrated
tissues, another innate defense mechanism comes into play, namely acute
inflammation.
• Humoral factors play an important role in inflammation, which is
characterized by edema and the recruitment of phagocytic cells.
 Nonspecific humoral immune system
• The complement system
– The complement system is a primary mediator of the humoral
immune response that enables the body to produce an inflammatory
response, lyse foreign cells, and increase phagocytosis.
– The complement system, like the blood coagulation system, consists of
a group of proteins that normally are present in the circulation as
functionally inactive precursors. These proteins make up 10% to 15%
of the plasma protein fraction.
– For a complement reaction to occur, the complement components
must be activated in the proper sequence.
– Uncontrolled activation of the complement system is prevented by
inhibitor proteins.
 The Activation Pathways of
Complement
• The complement cascade may be activated by
any of three pathways:
• The alternative pathway is triggered when
some complement proteins are activated on
microbial surfaces and cannot be controlled,
because complement regulatory proteins are
not present on microbes (but are present on
host cells). This pathway is a component of
innate immunity.
 Complement activation
• The classic pathway of complement activation is initiated by antibody
bound to antigens on the surface of microbes or through soluble immune
complexes.
• The alternate and the lectin pathways do not use antibodies and are part
of the innate immune defenses.
– The alternate pathway of complement activation is initiated by the
interaction with certain polysaccharide molecules characteristic of
bacterial surfaces.
– The lectin-mediated pathway is initiated following the binding of a
mannose-binding protein to mannose-containing molecules commonly
present on the surface of bacteria and yeast.
• The activation of the three pathways produces similar effects on C3 and
subsequent complement proteins.
 The Activation Pathways of
Complement
• The classical pathway is triggered after antibodies
bind to microbes or other antigens and is thus a
component of the humoral arm of adaptive
immunity.
• The lectin pathway is activated when a plasma
protein, mannose-binding lectin, binds to
terminal mannose residues on the surface
glycoproteins of microbes. This lectin activates
proteins of the classical pathway, but because it is
initiated by a microbial product, in the absence of
antibody, it is a component of innate immunity
 The Activation Pathways of
Complement
• Three pathways lead to activation of complement. The Classical Pathway
is initiated by complexes of IgM, IgG1, or IgG3 with antigens. This activates
proteolysis of C1 that cleaves C4 and C2 to form the classical pathway C3
convertase.
• The Mannose Lectin Pathway is activated by interaction of mannan-
containing microbes with MBL, which activates MASP-1 and MASP-2 to
cleave C4 and C2, again forming a C3 convertase.
• The Alternative Pathway is initiated by interactions between microbial
antigens and inhibitory complement regulatory proteins. This permits
autoactivation of the pathway in which C3 interacts with factor B and
factor D to generate the alternative pathway C3 convertase.
• These convertases all cleave C3 to generate the anaphylatoxic C3a
fragment and depositing C3b on the activating microbial particle or
immune complex. This opsonizes the particle for phagocytosis and
initiates the activation of the membrane attack complex. The C5a
fragment that is proteolytically released from C5 also is a highly
anaphylatoxic molecule that induces intense local inflammation.
 -
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components
• Anaphylatoxins: C3a,C4a and C5a are
anaphylatoxins.It is a susbstance that induces
degranulation of mast cell and/or basophils,
causing release of pharmacologically active
susbstances including Histamine.
• Histamine has several important physiological
actions that are associated with anaphylaxis
and other allergic reactions
 complement system functions
• The complement system serves three functions in host defense.
• First, C3b coats microbes and promotes the binding of these
microbes to phagocytes, by virtue of receptors for C3b that are
expressed on the phagocytes. Thus, microbes that are opsonized
with complement proteins are rapidly ingested and destroyed by
phagocytes.
• Second, some proteolytic fragments of complement proteins,
especially C5a and C3a, are chemoattractants for phagocytes, and
they promote leukocyte recruitment (infl ammation) at the site of
complement activation.
• Third, complement activation culminates in the formation of a
polymeric protein complex that inserts into the microbial cell
membrane, disturbing the permeability barrier and causing either
osmotic lysis or apoptotic death of the microbe
 CYTOKINES OF INNATE IMMUNITY
• In response to microbes, dendritic cells, macrophages,
and other cells secrete cytokines that mediate many of
the cellular reactions of innate immunity. In innate
immunity, the principal sources of cytokines are
dendritic cells and macrophages activated by
recognition of microbes
• Binding of bacterial components such as LPS or of viral
molecules such as double-stranded RNA to TLRs of
dendritic cells and macrophages is a powerful stimulus
for cytokine secretion by the cells. Cytokines also are
produced in cell-mediated immunity.
 Cytokines of innate immunity.
Cytokine Principal cell source(s) Principal cellular targets
and biologic effects
Tumor necrosis factor Macrophages, T cells Endothelial cells: activation
(TNF) (inflammation,
coagulation) Neutrophils:
activation Hypothalamus:
fever Liver: synthesis of
acute phase proteins
Muscle, fat: catabolism
(cachexia) Many cell types:
apoptosis
Interleukin (IL-1) Macrophages, endothelial Endothelial cells: activation
cells, some epithelial cells (inflammation,
coagulation)
Hypothalamus: fever Liver:
synthesis of acute phase
proteins T cells: TH17
differentiation
• P.p.41-45 (Basic Immunology, Abbul Abbas)
Immunology
Nino Amaglobeli
namaglobel@gmail.com
lecture N4
Antibodies
 Antibody
• Antibodies are large Y-shaped proteins. They are recruited by the
immune system to identify and neutralize foreign objects like bacteria
and viruses.
• Each antibody has a unique target known as the antigen present on
the invading organism. This antigen is like a key that helps the
antibody in identifying the organism. This is because both the
antibody and the antigen have similar structure at the tips of their “Y”
structures.
 Antibody Structure
Manilficturer of Antibodies
• Antibodies are proteins with around 150 kDa molecular weight. They have
a similar basic structure comprising of four polypeptide chains held
together by disulfide bonds. These four polypeptide chains form a
symmetrical molecular structure. There is a hinge in the center between
heavy chains to allow flexibility to the protein. There are:
• Two light chains – Containing around 220 amino acids
• Two heavy chains – Containing around 440 amino acids.
• Light and heavy chains
• There are two types of light chain among all classes of immunoglobulin, a
lambda chain and a kappa chain. Both are similar in function. Each type of
immunoglobulin has a different type of heavy chain. Depending on the
heavy chains they are classified into five classes.
 Antibody Structure

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 Domains of the immunoglobulin

• The Ig monomer is a "Y"-shaped molecule. It has four polypeptide chains - two

identical ''heavy chains'' and two identical ''light chains''. There are five types of
mammalian Ig heavy chain denoted by the Greek letters: α, δ, ε, γ, and μ. These
form respectively IgA, IgD, IgE, IgG and IgM.
• The Ig has a paratope at the amino terminal end of the antibody monomer. This
exists at the variable domains from the heavy and light chains. The variable
domain is the FV region and is the most important region for binding to
antigens. At this region are variable loops of β-strands. On the light chain are
three loops - VL and on the heavy chain are three loops VH. These are responsible
for binding to the antigen. These loops are referred to as the complementarity
determining regions (CDRs). These CDRs are also called idiotypes.
• The base of the Y modulates the immune cell activity. This region is called the ''Fc
(Fragment, crystallizable) region''. In this area are two heavy chains that
contribute two or three constant domains depending on the class of the
antibody.
 Antibody functions

• The antibody binds to specific antigens. This signals the other cells of
the immune system to get rid of the invading microbes. The strength
of binding between the antibody and an antigen at a single binding
site is known as the antibody’s affinity for the antigen. The affinity
between the antibody and the antigen binding site is determined by
the type of bond formed.
• Since an antigen can have multiple different epitopes, a number of
antibodies can bind to the protein. When two or more antigen
binding sites are identical, an antibody can form a stronger bond with
the antigen.
Affinity and Avidity
• Different antibody molecules produced in response to a particular
antigenic determinant may vary considerably in their tightness of binding
to that determinant (i.e., in their affinity for the antigenic determinant).
• The strength with which one antigen-binding surface of an antibody binds
to one epitope of an antigen is called the affinity of the interaction. Affinity
often is expressed as the dissociation constant (Kd), which is the molar
concentration of an antigen required to occupy half the available antibody
molecules in a solution; the lower the Kd, the higher the affinity
• Each antibody molecule can bind 2 to 10 epitopes of an antigen, or
epitopes on 2 or more neighboring antigens. The total strength of binding
is much greater than the affinity of a single antigen-antibody bond and is
called the avidity of the interaction.
 Antibody valence

• The valence of an antibody is the maximum number of antigenic

determinants with which it can react. Valence is important for
binding affinity, as having two or more binding sites for an antigen can
dramatically increase the tightness of binding of the antibody to
antigens on a bacteria or virus. This combined effect, avidity, results
from synergy of the binding strengths of each binding site. Avidity is
the firmness of association between a multideterminant antigen and
the antibodies produced against it.
 Five classes of antibody

• Antibodies or immunoglobulins come in a variety of forms. Based on

differences in the amino acid sequences at the constant region of the
heavy chains they are further classified into five classes. These are:
• IgG - containing gamma heavy chain
• IgM – containing mu heavy chain
• IgA - containing alpha heavy chain
• IgD – containing delta heavy chain
• IgE – containing epsilon heavy chain
Antibody Classes

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 Antibody functions

• The antibody binds to specific antigens. This signals the other cells of
the immune system to get rid of the invading microbes. The strength
of binding between the antibody and an antigen at a single binding
site is known as the antibody’s affinity for the antigen. The affinity
between the antibody and the antigen binding site is determined by
the type of bond formed.
• Since an antigen can have multiple different epitopes, a number of
antibodies can bind to the protein. When two or more antigen
binding sites are identical, an antibody can form a stronger bond with
the antigen.
 Monoclonal Antibodies
• In B lymphocytes, membrane-bound Ig molecules are noncovalently
associated with two other proteins, called Igα and Igβ, and the three
proteins make up the BCR complex. When the B cell receptor recognizes
antigen, Igα and Igβ transmit signals to the interior of the B cell that initiate
the process of B cell activation
• The realization that one clone of B cells makes an antibody of only one
specificity has been exploited to produce monoclonal antibodies, one of
the most important technical advances in immunology, with far-reaching
implications for clinical medicine and research. To produce monoclonal
antibodies, B cells, which have a short life span in vitro, are obtained from
an animal immunized with an antigen and fused with myeloma cells . Thus,
by fusing the two cell populations and culturing them with the drug, it is
possible to grow out fused cells derived from the B cells and the myeloma,
which are called hybridomas.
 Ig G
• These are monomeric structures that exist as single molecules. These
are the most versatile immunoglobulins and can carry out all
functions of Ig molecules. This forms the largest portion in the serum
and is also found in extravascular spaces. This is the only
immunoglobulin that crosses the placenta. It also fixes molecules
called complements. It binds to cells and enhances phagocytosis.
functionsIgG Neutralization of microbes and toxins Opsonization of
antigens for phagocytosis by macrophages and neutrophilsActivation of
the classical pathway of complementAntibody-dependent cellular
cytotoxicity mediatedby NK cellsNeonatal immunity: transfer of
maternal antibodyacross placenta and gutFeedback inhibition of B cell
activation
 IgA

• These are also monomeric structures. They are found in secretions as

a dimer having a J chain. IgA can move across mucosa without
degradation. It is the second most abundant Ig in serum. It is the
major class of Ig in secretions i.e. in tears, saliva, colostrum (initial
breast milk), mucus etc. and is important in mucosal immunity. It
binds to PMN cells and lymphocytes. It does not normally fix
complement.
• Activation Mucosal immunity: secretion of IgA into lumens
ofgastrointestinal and respiratory tracts, neutralization of microbes
and toxins. activationMucosal immunity: secretion of IgA into lumens
ofgastrointestinal and respiratory tracts, neutralization of microbes
and toxins
 IgM

• These have an extra domain on the mu chain (CH4) and another

protein covalently bound via S-S. These exist is J shapes as polymers.
Usually they form pentamers or clusters of 5. It is the first Ig to be
made by fetus. It is the third most abundant Ig in serum. Activation of
the classical pathway of complement. Eosinophil It fixes with
complements and is a good agglutinating Ig that leads to elimination
of microbes. It is also able to bind some cells via Fc receptors.
 IgD

• These exist as monomers. They have low serum levels. It is found

primarily on B cells surface and serves as a receptor for antigens. It
does not fix complement.
 IgE

• These occur as monomers. This is the least common Ig in serum. They

bind very tightly to Fc receptors on basophils and mast cells before
interacting with antigens. Thus they are involved in allergic reactions.
It plays a role in parasitic helminthic diseases. complementEosinophil-
and mast cell-mediated defenseABagainst helminths
• P.p.69-76;101-106; (Peter Lydyard)
• P.p 82-85 (Abbul Abbas)
Immune response
 Objectives
• Role of antigen presenting cells in cellular
immune response
• Role of lymphocytes in cellular immune
response
• Mechanisms involved in cellular immune
response
• Types cytokines and their role in cellular
immune response
 T cell mediated Immune response

• T lymphocytes perform multiple functions in

defending against infections by various kinds of
microbes. A major role for T lymphocytes is in
cell-mediated immunity, which provides defense
against infections by intracellular microbes. In
several types of infections, microbes may find a
haven inside cells, from where they must be
eliminated by cell-mediated immune responses (
 The role of T cells in immune
responses
• Provides immunity to (i) intracellular bacteria (ii) viruses, (iii) fungi, (iv) protozoa
and (v) tumors
• T cells have evolved to protect us against intracellular microbes (viruses and some
bacteria) and to help B-cell responses. The specific T-cell receptor for antigen (TCR)
recognizes protein antigens that have been processed into peptides and bound to
MHC molecules.
• This self MHC restriction results from positive selection during maturation of T
cells in the Thymus.
• Helper (CD4+) T cells recognize peptide antigens bound to MHC class II molecules
on dendritic cells, macrophages, and B cells. Cytotoxic (CD8+) T cells recognize
peptides bound to MHC class I
molecules.
• The T-cell repertoire is generated and selected for survival in the thymus.
Recognition of the peptide antigen by the TCR results in signaling leading to
transcription of genes encoding cytokines and their receptors
• Effector molecules such as IFNγ that activate macrophages and induce IgG class
switch are produced by Th1 cells. IL-4 is produced by Th2 cells and is mainly
important for B-cell proliferation.
 Phases of T cell Responses
Induction and effector phases
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 Phases of T cell Responses
Steps in the activation of T
lymphocytes
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 T cell receptor (TCR) and B cell
receptor (BCR)
• The set of associated plasma membrane antigen receptor
and signaling molecules in B lymphocytes is called the B cell
receptor (BCR) complex, and in T lymphocytes it is called
the T cell receptor (TCR) complex.
• When antigen molecules bind to antigen receptors of
lymphocytes, the associated signaling proteins of the
receptor complexes are brought into proximity. As a result,
enzymes attached to the cytoplasmic portions of the
signaling proteins catalyze the phosphorylation of other
proteins. Phosphorylation triggers complex signaling
cascades that culminate in the transcriptional activation of
many genes and the production of numerous proteins that
mediate the responses of the lymphocytes.
TCR-CD3 complex

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 ANTIGEN RECOGNITION AND
COSTIMULATION
• The initiation of T cell responses requires
multiple receptors on the T cells recognizing
ligands on APCs
• The T cell receptor (TCR) recognizes MHC-
associated peptide antigens.
• • CD4 or CD8 coreceptors on the T cells
recognize MHC molecules on the APC and help
the TCR complex to deliver activating signals
 l- a ij
CD4 and CD8 co-receptor structure

an
Receptors and ligands involved in T cell
activation
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 Antigen Presentation
Antigen Presentation

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Maturation

T lymphocytes
Maturation

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Cell-mediated Immunity
Mechanism of CMI
Antigen recognition by T cells
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Cell-mediated Immunity
Mechanism of CMI
Antigen recognition by T cells

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antigens presented with
MHC molecules on the
I surface of APCs by TCR
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. recognize a one antigen
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 Mechanism of CMI
Antigen recognition by T cells

«Antigen recognition by
TCR provides stimulatory
signol {Signal 1) to the T
cell
oBinding of B7 molecule
on APC with CD28
molecule on T cell
provides Co-slimulolory
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cell
Cell-mediated Immunity
Mechanism of CMI
T cell activallon

oWhen T cells receive

both stimulatory (Signal
1) and Co--stimulatory
"L. IL (Signal 2) signals they
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olt the T cells receive only
the stimulatory signal
without Co--stimulatory
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Cell-mediated Immunity
Mechanism of CMI
T cell differentiation
~Activated T cells start to
proliferate, synthesize and
secrete |L-2 and express IL-
2 receptors on cell surface
oAfter several divisions they
differentiate to effector
and memory T cell
populations
aMemory T cells have long
life span [20- 30 years)
and provide immunity if

ierson reeexiosed
is
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 T cells differentiation
• Effector T cells are short-lived (few days to weeks)
cells and carry out specialized functions e.g.
• • CD8+ effector T cells: Induce apoptosis of virus
infected and tumour cells (Cytotoxic killing)
• • CD4+ effector T cells: Secrete cytokines that
cause macrophage activation to kill intracellular
pathogens and to help TC cell and B cell
activation T cells differentiation Mechanism of
CMI
Antigen Elimination by Cell-mediated
Immunity
Antigen Elimination by CMI
CD4+ Effector T cells

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With influence of cytokines
M
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cells differentiate to THl cells
THl cells release cytokines
o
e.g. interferon- y (IFN- y)
o IFN‘y activates macrophages
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Antigen Elimination by Cell-mediated
Immunity
Antigen Elimination by CMI
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Antigen Elimination by Cell-mediated
Immunity
Antigen Elimination by CMI
CD4+ Effector T cells

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Activated macrophages have more phagocytic and killing

activity and they phagocytose and kill intracellular pathogens
effectivel
Regulatory role of Th cells
Regulatory role of TH cells
1’N cells help Tc cell activation

Naive cytotoxic T cells (cytotoxic T cell precursor) require

cytokines from TN cells for activation
Regulatory role of Th cells
Regulatory role of TH cells
T" cells help B cells

Activation of naive B cells

require
.Direct interaction with TH cells
by
-Antigen in Class II MHC and
TCR
- CD40 and CD4OL

TH
- B7 and CD28
cells help B cells RUMQémwlimmuge respon5i
 Regulatory Role of TH cells

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help Tc cell activation
Thus THl cells regulate CMI
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 Interaction betweenthe components of the immune system

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 Cytokines

Protein molecules secreted by

cells that regulate function of
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lymphocytes and other
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Cytokines play key role in the
complex interaction between
 Cytokines

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 Cytokines

o Cytokines secreted by some leukocytes and

acting on other leukocytes are called
interleukins
o Cytokine secreted by lymphocytes are called
lymphokines
o Cytokines secreted by monocytes and
macrophages are sometimes called
monokines
o Cytokines that cause chemotaxis of
leukocytes are called chemokines
• P.p.104-105; 110-115;119-123; 136-148;
(peter lydyard)
• P.p.104-126 (Abbul Abbas)
B cell and Immune response
 B cells

• B cells are formed in the bone marrow. B cells have particular sites
(receptors) on their surface where antigens can attach.
• B cells are the major cells involved in the creation of antibodies that
circulate in blood plasma and lymph, known as humoral immunity.
• In mammals there are five types of antibody IgA, IgD, IgE, IgG, and
IgM, differing in biological properties.
• Each has evolved to handle different kinds of antigens.
• Upon activation, B cells produce antibodies, each of which
recognizes a unique antigen, and neutralize specific pathogens.
 B cells
• The B-cell response to antigens has two stages:
– Primary immune response:
• When B cells first encounter an antigen, the antigen attaches to a
receptor, stimulating the B cells.
• Some B cells change into memory cells, which remember that specific
antigen, and others change into plasma cells. Helper T cells help B cells in
this process.
• Plasma cells produce antibodies that are specific to the antigen that
stimulated their production. After the first encounter with an antigen,
production of enough of the specific antibody takes several days. Thus,
the primary immune response is slow.

– Secondary immune response

• Whenever B cells encounter the antigen again, memory B cells very
rapidly recognize the antigen, multiply, change into plasma cells, and
produce antibodies. This response is quick and very effective.
B cells

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 Primary and secondary phases of the humoral
immune response to the same antigen.

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 Active Versus Passive Immunity
• Active or acquired immunity
– Can be achieved through exposure to a specific antigen.
– It is acquired through immunization or actually having a disease.
– Active immunity, although long lasting once established, requires a
few days to weeks after a first exposure to become sufficiently
developed to contribute to the destruction of the pathogen
 Active Versus Passive Immunity
• Passive immunity
– Is immunity transferred from one source to another source. (e.g. An
infant receives passive immunity naturally from the transfer of
antibodies from its mother in utero and through a mother’s breast
milk.)
– Passive immunity also can be artificially provided by the transfer of
antibodies produced by other people or animals.
– Some protection against infectious disease can be provided by the
injection of hyperimmune serum, which contains high concentrations
of antibodies for a specific disease, or immune serum or gamma
globulin, which contains a pool of antibodies for many infectious
agents.
– Passive immunity produces only short-term protection that lasts
weeks to months.
 Antibody
• Antibodies are large Y-shaped proteins. They are
recruited by the immune system to identify and
neutralize foreign objects like bacteria and
viruses.
• Each antibody has a unique target known as the
antigen present on the invading organism. This
antigen is like a key that helps the antibody in
identifying the organism. This is because both the
antibody and the antigen have similar structure
at the tips of their “Y” structures.
 Antibody Structure
Manuficturer of Antibodies
• Antibodies are proteins with around 150 kDa molecular weight.
They have a similar basic structure comprising of four polypeptide
chains held together by disulfide bonds. These four polypeptide
chains form a symmetrical molecular structure. There is a hinge in
the center between heavy chains to allow flexibility to the protein.
There are:
• Two light chains – Containing around 220 amino acids
• Two heavy chains – Containing around 440 amino acids.
• Light and heavy chains
• There are two types of light chain among all classes of
immunoglobulin, a lambda chain and a kappa chain. Both are
similar in function. Each type of immunoglobulin has a different
type of heavy chain. Depending on the heavy chains they are
classified into five classes.
Antibody Structure (IgG)

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 Domains of the immunoglobulin

• The Ig monomer is a "Y"-shaped molecule. It has four polypeptide chains -

two identical ''heavy chains'' and two identical ''light chains''. There are
five types of mammalian Ig heavy chain denoted by the Greek letters: α, δ,
ε, γ, and μ. These form respectively IgA, IgD, IgE, IgG and IgM.
• The Ig has a paratope at the amino terminal end of the antibody
monomer. This exists at the variable domains from the heavy and light
chains. The variable domain is the FV region and is the most important
region for binding to antigens. At this region are variable loops of β-
strands. On the light chain are three loops - VL and on the heavy chain are
three loops VH. These are responsible for binding to the antigen. These
loops are referred to as the complementarity determining regions (CDRs).
These CDRs are also called idiotypes.
• The base of the Y modulates the immune cell activity. This region is called
the ''Fc (Fragment, crystallizable) region''. In this area are two heavy chains
that contribute two or three constant domains depending on the class of
the antibody.
 Five classes of antibody

• Antibodies or immunoglobulins come in a variety

of forms. Based on differences in the amino acid
sequences at the constant region of the heavy
chains they are further classified into five classes.
These are:
• IgG - containing gamma heavy chain
• IgM – containing mu heavy chain
• IgA - containing alpha heavy chain
• IgD – containing delta heavy chain
• IgE – containing epsilon heavy chain
IgM, IgG, IgA, Ig D and IgE

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 Ig G
• These are monomeric structures that exist as
single molecules. These are the most versatile
immunoglobulins and can carry out all functions
of Ig molecules. This forms the largest portion in
the serum and is also found in extravascular
spaces. This is the only immunoglobulin that
crosses the placenta. It also fixes molecules called
complements. It binds to cells and enhances
phagocytosis. IgG provides the majority of
antibody-based immunity against invading
pathogens.
 IgA

• These are also monomeric structures. They are

found in secretions as a dimer having a J chain.
IgA can move across mucosa without
degradation. It is the second most abundant Ig in
serum. It is the major class of Ig in secretions i.e.
in tears, saliva, colostrum (initial breast milk),
mucus etc. and is important in mucosal immunity.
IgA is a secret antibody and express in dimer IgA.
It is found in mucosal areas, such as the gut,
respiratory tract and urogenital tract. It binds to
PMN cells and lymphocytes. It does not normally
fix complement.
 IgM

• These have an extra domain on the mu chain

(CH3) and another protein covalently bound via
S-S. IgM expressed on the surface of B cells and in
a secreted form with very high avidity. These exist
is J shapes as polymers. Usually they form
pentamers or clusters of 5. It is the first Ig to be
made by fetus. It is the third most abundant Ig in
serum. It fixes with complements and is a good
agglutinating Ig that leads to elimination of
microbes. It is also able to bind some cells via Fc
receptors.
Ig M
 IgD

• These exist as monomers. They have low

serum levels. It is found primarily on B cells
surface and serves as a receptor for antigens.
It does not fix complement.
• IgD functions as mainly as an antigen receptor
on B cells that have not been exposed to
antigens. It has been shown to
activate basophils and mast cells to produce
antimicrobial factors.
 IgE

• These occur as monomers. This is the least

common Ig in serum. They bind very tightly to Fc
receptors on basophils and mast cells before
interacting with antigens. Thus they are involved
in allergic reactions. It plays a role in parasitic
helminthic diseases.
• IgE binds to allergens and triggers histamine
release from mast cells and basophiles, and is
involved inallergy. Also protects against parasitic
worms.
 Other components of antibodies

• Thus antibodies are glycoproteins rather than

proteins alone. The immunoglobulins exists as
monomers (e.g. only one Ig unit) or as
dimmers (two molecules. E.g. IgA) or as
tetramers (four molecules e.g. teleost fish
IgM) or exists as pentamers (five molecules
e.g. in mammalian IgM)
Immune Response- A complex
Mechanisms

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Coordination
 Stages of Antibody mediated
immune response

- Contain three stages

1 The entry of antigen, its distribution and
fate in the tissues and its contact with
appropriate immunocompetent cells
2 The secretion of antigen by cells and the
control of the antibody forming process
3 The secretion of antibody its distribution
in tissues and body fluids and
manifestations of its effects.
 Production of Antibodies

it involves 4 step
Lag phase
— fate'
entry of pathogen its distribution and
in tiissue

,
Contactwith immunocompetent cells
Log Phase
Steady rise in the titre ofantibody
A

Plateau phase
— synthesis
Equilibrium between antibody
and catabolism

-
Decline phase
catabolism exceeds production and
thus titre falls
 Primary and Secondary Response

- Antibody response to l itial antigenic stimulus is called

primary response
— differs both quantitatively and qualitatively
— slow, sluggish and short lived
— Long lag phase and low titre or antibody
— Predominantly lgM
Subsequent to primary response is call secondary
response
— Prompt, powerful and prolonged
— short or negligible lag phase
— much higher level of antibodies tor longer period
— Predominantly lgG
 Primary and Secondary Response

‘ Duration of lag phase and persistence of antigen

vary with nature of antigen
Diptheria toxoid: 2-3 weeks
7

Pneumococcal polysaccharide —few hrs

7

--Non living vaccine — given in multiple

Priming dose: first injection of antigen
dose

- Booster dose: subsequent injection orantigen

‘ Live vaccine: sufficient for multiplication of

organism in the body which provides continuous
antigenic stimulus
 Production of Antibodies

Antigen enters
Antigen presentiru cells (AFC) acivated
7

,
Macrophage
Dendritic cells
7

APE binds with Major histocompatablity complex (MHC) II

Immature T-cell binds with earlier formed complex with the
P

help of T-cell receptor (TCR)

Whole complex produces signal for activation of CD‘ cells

Acltlilsation
of C00 cells Maturation of T helper cell (TH-
7

ce 5
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Forms IL»2, lL-4, lL-5 8t lL-6: B-cell maturation and

subsequently release of plasma cells
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,
—
Plasma cells forms antibudles
some orthe plasma cells— memory cells
 Production of Antibodies

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 Monoclonal Antibodies

-
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f Pmtetns

(Nobel Prize 1984 ) i Ulltllecell

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Asingle antibody
forming cell or clone .1f"\
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 Mitogens

- A mitcgen is a chemical substance that

encourages a cell to commence cell division.

- B-cell mitcgens: lectin glycoproteins and

lipopolysacharide (LPS)
' T-cell mitogens: phytohaemagglutinin (PHA)
 Cell-mediated Immunity

-
-
Specific immune response that do not involve antibody
It participates in following immunological funtions
— Delayed hypersensitivity
— immunity in inrections caused by obligate and facultative
intracellular parasites

-- Bacteria: Tuberculosis, Leprosy, Listeriosis, Brucellosts.

Fungl7 Hrstopiasmosis, Cocccidiomysosis, aiastomycosis

-- Parasites Leishmaniasis, Trypanosomiasis

7

virus-measlesand mumps
— Transplantation immunity
— immunological surveillance to immunity against
malignancy
— Pathogenesis ofAutoimmune diseases: thyroiditis,
encephalomyelitis
 Induction of Cell Mediated Immunity

Depends on Nature ofAntigenic stimulus

Best developed after following infection with
intracellular parasites
Live vaccines highly stimulating
Killed vaccine not very effective, but effective
if contains adjuvant.
 Induction of Cell Mediated Immunity

Antigen enters
2. Antigen presenting cells (APC) — acivated
— Macrophage
— Dendritic cells
3. APC binds with Major histocompatablity complex
(MHc)i
4. Immature T-cell binds with earlier formed complex with
the help of T-cell receptor (TCR)
5‘ Whole complex initiate the formation of CD4 (helper) St
(203 cells (cytotoxic)
— Former helps releases of lymphokines which activates
—
macrophage eats away interceiiuiar parasites
— cos cells - recognize antigen on surface of virus, infected
cells, tumor cells, aiiogrart cells with MHC |and secretes
lymphokines and destroy target cells
 Cytokines
Signalling proteins and glycoproteins that are used
extensively'in cellular communicati n.
It regulates immunological, inflammatory and reparative
host response
It acts like hormone and neurotransmitter
Differ from former in being produced not by specialized
glands but by widely distributed cells such as lymphocytes,
macrophage, platelets and fibroblast
Its grouped in 5 class
— colony stimulating factors icsr)
interleukin (IL) lL(1713)
.
— Tumor NecrosisfactorlTNF)
7

— interferon (INF)
— factor
Others: Transforming growth rector (TGF) a Leukemia inhibitory
(LIF)
 Interleukin (IL)
lL-l
Secreted by macrophages, monocytes and few other
A

muitinucieated giant cell (MGC)

Stimulated by antigen, toxinsm injury and inflammatory
A

processes
inhibited by cyciosporin A, corticosteroid and prostagiandins
A

Stimulates tAceii for production mm and other lymphokines

A

eAceii proliferation and antibody synthesis

A

Neutrophil chemotaxis and phagocytosis

A

Endogenous pyrogens
A

iL-2
Powerful modulator of immune response
A

Major activator ofT and B cells

A

Stimulates cytotoxic T cells and NK cells

A

treatment ofcertairi kind of cancers

A
 Interleukin (IL)
in
Growth factorfor bone marrow stemm cells
A

Stimulates multilineage hematopoiesis

A

Also known as muiticoiony stimulating factor mutti-CSF

A

IL~4
Activates resting aAceiis and differentiate it
A

Growth rectorrortceiis and mast cells

A

Enhances cytotoxicTcells
A

—
Role in atopic hypersensitivity augments lg E synthesis
A

lL-5
Proliferation ofactivated B cells
A

induces maturation ofeosinophils

A

lL-6
Produced by stimulated T and 5 cells, macrophages and fibroblasts
A

—
induces immunoglobuliri synthesis activated aAceiis
A
 Colony stimulating factors (CSF)

Stimulates growth and differentiation of

pluripntent stem cells in bone marrow
Induces cascades of other cytokines
Adjusting the rate of production of blood cells
according to requirements
— Massive granulocyte response seen in pyogenic
infection
Treating hematcpoietic dysfunction in
infections and malignancies
 Tumor Necrosis factor (TNF)

Two types TNF or and TNF [3

Principally formed by activated macrophages and
monocytes
Induces hemorrhagic necrosis
—
Cachetin: Serum factor wasting syndrome
(cachexia)
Manifestation of endotoxic shock
Immunomodulatory influence on other cytokines
TNF 6: produced principally by T7he|per cells,
effects similar to TNF a
 Interferon (IFN)
Antiviral agent, 3 classes
' IFN r1
produced by leukocytes
A

Treatvariousviral infections: certain cases of acute and chronic

7

hepatitis c and chronic hepatitis B

IFN (3
produced by fibroblast
A

-
virusinfected epithelial cells
7

IFNy
Produced in response to mitogens, antigen or exposure to iLAz
A

Macrophage activation and Augmentation ofneutrophil

A

Monocyte function and AntiAtumor activity

A

treatment - iepromatous leprosy, ieishmaniasis, toxoplasmosis

A

and certain tumours such as melanoma and Kaposi‘s sarcoma.

Regulation of the Immune response
Central and Pheripheral Tolerance
Immunology
Nino Amaglobeli
namaglobel@gmail.com
lecture N8
 Tolerance
• Immunological tolerance is the state of unresponsiveness to a
particular antigen which is primarily established in T- and B-
lymphocytes. The clonal receptors of lymphocytes are generated by
random recombination of the many genes that code for the antigen
binding regions. This creates the need to sort out dangerous
receptors that could recognize and destroy self tissues. The
breakdown of immunological tolerance to self-antigens is the cause
of autoimmune diseases.
• Normally we do not make immune responses against our own
tissue, a concept known as "self-tolerance". Determining how the
immune system distinguishes between self and foreign antigens to
make the decision between tolerance and immunity has been a
subject of detailed investigation during the past 50 years
 Generation of autoreactive antigen
receptors during lymphocyte
•
development
The specificity of the antigen receptors of T cells and B cells
is the result of random shuffling of the many genes that
encode the antigen-binding site of these receptors.
• Similar considerations apply to B-cell re-ceptors. Cells
expressing such receptors are often called self-reactive
lymphocytes.
• The immune system has to fulfill two contradictory
requirements: on the one hand the repertoire of different
antigen receptors needs to be as large as possible to avoid
‘holes in the repertoire’ that could be exploited by
pathogens to evade immune detection. On the other hand,
the receptor repertoire must be shaped to prevent the
immune system from attacking the organism that harbors
it.
 Generation of autoreactive antigen
receptors during lymphocyte
development
• This paradox was recognized at the beginning
of the last century by Paul Ehrlich who coined
the term ‘horror autotoxicus’ for the necessity
to avoid immunological reactions against self-
antigens. Tolerance is the process that
eliminates or neutralizes such autoreactive
cells, and a breakdown of this system can
cause autoimmunity.
 Central and peripheral tolerance
TOLERANC CENTRAL
PERIHALTONC
 Central tolerance
• Central tolerance is the process whereby
immature T and B cells acquire tolerance to
self antigens during maturation within the
primary lymphoid organs/tissues (thymus and
bone marrow, respectively). It involves the
elimination of cells with receptors for self
antigens (negative selection
 Mechanisms of tolerance to self-
antigens
• (i) Central tolerance by clonal deletion: Central tolerance refers to
mechanisms of tolerance acting during lymphocyte development in
the thymus or bone marrow. Experimental studies show that
central tolerance is mostly due to the elimination or inactivation of
those T and B cells that recognise self-antigens. These cells are
destroyed or inactivated after they have expressed receptors for
self-antigens and before they develop into fully immunocompetent
lymphocytes. Deletion of self-reactive cells at an early stage in their
development has been termed 'clonal abortion' or 'clonal deletion'.
In early foetal life, self-reactive lymphocytes that are part of the
developing immune systemare deleted when exposed to self-
antigens. As mentioned above, new immunologically competent
cells are generated throughout life and these must be continuously
deleted or inactivated also
 Positive and Negative selection
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• Transgenic animal models demonstrate that central mechanisms are indispensable
for induction of self-tolerance
• CD4-CD8- (double negative) T-cell progenitors enter the thymic cortex and
rearrange their receptors to become CD4+CD8+ (double positive) thymocytes
• Positive and negative selection occurs in the thymus T-cells with a receptor that
bind with moderate affinity to self-peptide-MHC complexes on thymic epithelia
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(single positive)
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medulla: T-cells with a receptor that bind with high avidity to autoantigens on
thymic epithelia undergo apoptosis
• The autoantigens are host tissue proteins expressed on thymic epithelia under
regulation of the transcription factor autoimmune regulator (AIRE)
• Many T-cells are eliminated: of the potential 109 receptor specificities in the
thymus, only a fraction are present in peripheral tissues
• AIRE deficiency results in organ-specific autoimmunity, including APS-1 (damage to
parathyroid and adrenal glands)
Positive and Negative selection
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• CD4+ T cells that recognize self-antigens
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 Peripheral Tolerance
• Since not all self-reactive lymphocytes are eliminated by
central tolerance mechanisms (due primarily to the
absence of most self antigens in the primary lymphoid
organs), self-reactive lymphocytes are anergized or deleted
in the peripheral tissues. Peripheral T cells are made
unresponsive (anergic) through the absence of the second
signal (essential for T-cell activation) given by co-
stimulatory molecules (i.e., CD80, CD86) on APCs.
Peripheral B cells may become anergic and unable to
develop into plasma cells as a result of the absence of co-
stimulatory signals from T cells. Moreover, under
appropriate conditions, activated T cells expressing Fas
ligand (FasL) may kill Fas-expressing B cells (and, perhaps,
other T cells) through activation-induced cell death (AICD).
 Peripheral T-Cell Selection

•Mechanisms of peripehral T-cell tolerance include:

• A. Clonal deletion
• B. Ignorance
• C. Anergy
• D. Immune regulation
•Tolerance mechanisms can also result in inappropriate tolerance to
non-self antigens.
 Clonal Deletion
• The best-studied mechanism eliminating
activated T-cell clones is activation-induced cell
death
• T-cells activated by antigen-presenting cells
express IL-2 and IL-2R for autocrine facilitation of
proliferation
• Activated T-cells also increase their expression of
death receptors (e.g. Fas) and their ligands
• Ligation of Fas leads to T-cell apoptosis via the
caspase pathway, thereby ending the immune
response
 Ignorance

• Although peripherally, T-cells from healthy individuals

can react with self-antigens in vitro, this does not
commonly occur in vivo
• It is thought that T-cells ignore certain self-antigens
because they are located in immune-privileged sites or
because they have low immunogencitiy (low levels of
expression or low binding affinity
• the immune system is not normally exposed to ocular
antigens, but trauma to a single eye releases
autoantigens that activate autoreactive immune cells,
leading to severe granulomatous inflammatory of both
eyes
 Anergy
• This is a major mechanism inactivating peripheral autoreactive T-cell clones
• Anergic T-cell clones cannot respond to cognate antigenic stimuli: they do not
produce IL-2 or IL-2R
• Multiple proposed mechanisms explain this block in T-cell activation :
• Disruption of the interaction between the T-cell co-receptor CD28 and APC co-
stimualtory molecules CD80/86
• Interaction of CTLA-4 with CD80/86, negatively regulating T-cell activation
• T-cells displaying CD28 tend to be activated by APC, while T-cells displaying CTLA-4
tend to become anergic
• Under physiologic conditions, T-cells express CD28 on initial encounter with APC
• Shortly after such stimulation, they start displaying CTLA-4, which has a higher
binding affinity than CD28 for CD80/86 than does CD28
• CTLA-4 knockout mice develop profound lympho-proliferative disease
 T-cell anergy
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 Regulatory T cells (Tregs)
• Many immune responses, particularly those
directed against self antigens, are regulated
through a subset of CD4+ T cells that express a
high level of surface CD25 (the a chain of the
IL-2 receptor). Activated T cells and B cells also
express CD25, but Tregs do not express several
markers of activated lymphocytes and
characteristically express the forkhead box P3
(FoxP3) transcription factor that controls their
development and function.
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 Mechanisms of tolerance to self-
antigens
• (ii) Peripheral tolerance by deletion and inactivation
(anergy): Peripheral tolerance refers to mechanisms
acting on mature lymphocytes after they have left the
primary lymphoid organs. Not all genes are expressed
in the thymus so developing T cells cannot be exposed
to allself-antigens. Therefore, additional mechanisms
for tolerising selfreactive mature T cells are necessary.
Mechanisms of peripheral B cellself-tolerance are also
necessary because after stimulation with antigen B
cells expand and undergo somatic mutation,
generating a population of B cells with new antigen
specificities. Some of these cells may be specific for
self-antigens.
 Mechanisms of tolerance to self-
antigens
• (iii) Suppressor T cells: The principal
mechanisms of tolerance to self-antigens are
clonal deletion and anergy. It has been
suggested that there may be a back-up
mechanism called suppression. This is a form
of dominant tolerance because suppressor
cells specific for a given antigen are able to
inactivate other lymphocytes specific for the
same antigen
 B-cell Tolerance

• During normal B-cell development, a set of processes help

induce B-cell central tolerance
• Education of B-cells and elimination of self-reactive B-cell
clones is somewhat different from that of T-cells
• B-cells are still immature when they relocate from bone
marrow to spleen T-cell zones
• Autoreactive B-cells are not necessarily eliminated during
negative selection in the bone marrow
• B-cells that recognise autoantigens are eliminate via
apoptosis or become anergic
• Autoreactive B-cells that escape negative selection become
part of the a maximally-diverse immune repertoire
 B-cell Peripheral Tolerance
• Peripheral tolerance mechanisms (in secondary lymphoid
tissues) exist for various reasons:
• Imperfect T-cell tolerance: in most autoimmune diseases,
B-cells are T-cell dependent, requiring help from pre-
activated cognate autoreactive T-cells
• T-independent B-cells can be activated by autoantigens
without T-cell help
• Microbial antigens structurally similar to autoantigens can
lead B-cells to produce cross-reactive antibodies in a
phenomenon known as molecular mimicry
• B-cells hypermutate their receptors on activation, so there
is a second chance that they may become self-reactive
Induction of immunity or tolerance
• What determines immunity versus tolerance? In general,
mature human T cells are extremely difficult to tolerise,
which means that following transplantation lifelong
immunosuppressive therapy is usually required. The
reasons for these differences are not clear but a few
suggestions are laid out below.
• (i) Inflammatory mediators potentiate immune responses
by upregulating accessory signals and cytokines thereby
promoting immunogenicity versus tolerance.
• (ii) The immune stem has been designed to respond to
infectious agents, which are replicating rapidly so that the
quantity of antigen present varies rapidly. As has been
pointed out earlier, there are signals for switching immune
responses off as well as on
p.p.150-159
THANK YOU
IMMUNODEFICIENCY

N.Amaglobeli
 IMMUNODEFICIENCY
Lecture Outlines
Define immunodeficiency
Classification
Specific non specific
Primary and secondary
B cell deficiency & Examples
T Cell deficiency & Examples
SCID
Drug induced immunodeficiency
 IMMUNODEFICIENCY
• It is the absence or failure of normal function
of one or more elements of the immune system
• some of these diseases may result from genetic
abnormalities in one or more components of the
immune system ; these are called congenital (or
primary) immunodeficiencies.
• Other defects in the immune system may result from
infections, nutritional abnormalities, or medical
treatments that cause loss or inadequate function of
various components of the immune system; this are
called acquired (or secondary) immunodeficiencies.
 Congenital (Primary)
Immunodeficiencies
• Congenital immunodefi ciencies are caused by genetic
defects that lead to blocks in the maturation or
functions of different components of the immune
system
• Primary immunodeficiencies are inherited
defects of the immune system
• These defects may be in the specific or
nonspecific immune mechanisms
• They are classified on the basis of the site of
lesion in the developmental or differentiation
pathway of the immune system
 Features of immunodeficiency
diseases
Type of Histopathologic and Common infectious
immunodeficiency laboratory abnormalities consequences
B cell deficiencies Absent or reduced follicles Pyogenic bacterial
and germinal centers in infections
lymphoid organs.
Reduced serum Ig levels.
May be reduced T cell
zones.
T cell deficiencies May be reduced T cell Viral and other intracellular
zones in lymphoid organs. microbial infections (e.g.,
Reduced DTH (delayed- Pneumocystis jiroveci,
type hypersensitivity) atypical mycobacteria,
reactions to common fungi).
antigens. Virus-associated
Defective T cell malignancies
proliferative responses to (e.g., EBV-associated
mitogens in vitro lymphomas)
Innate immune Variable, depending on Variable; pyogenic
 DEFECTS IN LYMPHOCYTE
MATURATION
• Many congenital immunodefi ciencies are the
result of genetic abnormalities that cause
blocks in the maturation of B lymphocytes, T
lymphocytes, or both.
• Disorders manifesting as defects in both the B
cell and T cell arms of the adaptive immune
system are classified as severe combined
immunodeficiency (SCID).
 B cell immunodeficiencies
Disease Functional deficiencies Mechanism of defect
X-linked Decrease in all serum Ig Block in maturation
agammaglobulinemia isotypes; reduced beyond pre-B cells,
B cell numbers because of mutation in B
cell tyrosine kinase
Ig heavy chain IgG1, IgG2, or IgG4 absent; Chromosomal deletion at
deletions sometimes associated with 14q32
absent IgA or IgE (Ig heavy chain locus)
 B cell immunodeficiencies
• The most common clinical syndrome caused by a block
in B cell maturation is X-linked agammaglobulinemia
(first described as “Bruton’s agammaglobulinemia”).
• B cells in the bone marrow fail to mature beyond the
pre-B cell stage, resulting in a marked decrease or
absence of mature B lymphocytes and serum
immunoglobulins.
• The disease is caused by mutations in the gene
encoding a kinase called the B cell tyrosine kinase or
Bruton tyrosine kinase (Btk), resulting in defective
production or function of the enzyme.
Mechanism B cell immunodeficiencies
• The enzyme is activated by the pre-B cell receptor
expressed in pre-B cells, and it delivers
biochemical signals that promote maturation of
these cells.
• The gene for this enzyme is located on the X
chromosome.
• Therefore, women who carry a mutant allele of
the BTK gene on one of their X chromosomes are
carriers of the disease, and male offspring who
inherit the abnormal X chromosome are affected
 T cell immunodeficiencies
Disease Functional deficiencies Mechanism of defect
DiGeorge syndrome Decreased T cells; normal Anomalous development
B cells; normal or of 3rd and 4th branchial
decreased serum Ig pouches, leading to thymic
hypoplasia
 T cell immunodeficiencies
• Selective defects in T cell maturation are quite
rare. The most frequent of these is the
DiGeorge syndrome, which results from
incomplete development of the thymus (and
the parathyroid glands) and a failure of T cell
maturation.
 DISORDERS of T CELLS
• DiGeorge's syndrome:
It the most understood T-cell immunodeficienc
Also known as congenital thymic aplasia/hypoplasia
Associated with hypoparathyroidism, congenital
heart disease, fish shaped mouth.
 Defects results from abnormal development of
fetus during 6th-10th week of gestation when
parathyroid, thymus, lips, ears and aortic arch are
being formed
T cell deficiencies with variable degrees of B
cell deficiency
1- Ataxia-telangiectasia:
• Associated with a lack of coordination of
movement (ataxis) and dilation of small blood
vessels of the facial area (telangiectasis).
• T-cells and their functions are reduced to
various degrees.
• B cell numbers and IgM concentrations are
normal to low.
• IgG is often reduced
• IgA is considerably reduced (in 70% of the
cases).
• There is a high incidence of malignancy,
particularly leukemia in these patients.
• The defects arise from a breakage in
chromosome 14 at the site of TCR and Ig
heavy chain genes
2- Wiskott-Aldrich syndrome:

• Associated with normal T cell numbers with reduced

functions, which get progressively worse.
• IgM concentrations are reduced but IgG levels are
normal
• Both IgA and IgE levels are elevated.

• Boys with this syndrome develop severe eczema.

• They respond poorly to polysaccharide antigens and
are prone to pyogenic infection.
MHC DEFICIENCY
(Bare leukocyte syndrome):
• Due to defect in the MHC class II transactivator
(CIITA) protein gene, which results in a lack of class-II
MHC molecule on APC.
• Patients have fewer CD4 cells and are infection
prone !.
• There are also individuals who have a defect in their
transport associated protein (TAP) gene and hence
do not express the class-I MHC molecules and
consequently are deficient in CD8+ T cells.
Defects of the phagocytic system

Defects of phagocytic cells (numbers and/or functions)

can lead to increased susceptibility to a variety of
infections.
1- Cyclic neutropenia:
It is marked by low numbers of circulating neutrophil
approximately every three weeks. The neutropenia
lasts about a week during which the patients are
susceptible to infection. The defect appears to be
due to poor regulation of neutrophil production.
2- Chronic granulomatous disease (CGD):
CGD is characterized by marked
lymphadenopathy, hepato- splenomegaly and
chronic draining lymph nodes.
• In majority of patients with CGD, the
deficiency is due to a defect in NADPH oxidase
that participate in phagocytic respiratory
burst.
3- Leukocyte Adhesion Deficiency:
o Leukocytes lack the complement receptor CR3 due to
a defect in CD11 or CD18 peptides and consequently
they cannot respond to C3b opsonin.
o Alternatively there may a defect in integrin
molecules, LFA-1 or mac-1 arising from defective
CD11a or CD11b peptides, respectively.
o These molecules are involved in diapedesis and
hence defective neutrophils cannot respond
effectively to chemotactic signals.
4- Chediak-Higashi syndrome:
• This syndrome is marked by reduced (slower
rate) intracellular killing and chemotactic
movement accompanied by inability of
phagosome and lysosome fusion and
proteinase deficiency.
• Respiratory burst is normal.
• Associated with NK cell defect, platelet and
neurological disorders
Disorders of complement system:

Complement abnormalities also lead to

increased susceptibility to infections.
There are genetic deficiencies of various
components of complement system, which lead
to increased infections.

The most serious among these is the C3

deficiency which may arise from low C3
synthesis or deficiency in factor I or factor
H.
 Severe combined immunodeficiency
(SCID)
Disease Functional deficiencies Mechanism of defect

X-linked SCID Markedly decreased T Cytokine receptor common

cells;normal or increased B γchain gene mutations,
cells;reduced serum Ig defective T cell maturation
due to lack of IL-7 signals
Autosomal Progressive decrease in ADA or PNP deficiency
recessive SCID T and B cells (mostly T); leads to accumulation of
due to ADA, reduced serum Ig in ADA toxic metabolites in
PNP deficiency deficiency, normal B cells lymphocytes
and serum Ig in PNP
deficiency
Autosomal Decreased T and B cells; Defective maturation of T
recessive SCID reduced serum Ig and B cells; genetic basis
due to other causes unknown in most cases;
may be mutations in RAG
genes
SEVERE COMBINED IMMUNODEFICENCY

 In about 50% of SCID patients the immunodeficiency

is x-linked whereas in the other half the deficiency is
autosomal.
 They are both characterized by an absence of T cell
and B cell immunity and absence (or very low
numbers) of circulating T and B lymphocytes.
 Patients with SCID are susceptible to a variety of
bacterial, viral, mycotic and protozoan infections.
 Mechanism Severe combined
immunodeficiency (SCID)
• Several different genetic abnormalities cause severe combined
immunodefi ciencies. About half of these cases are X-linked,
affecting only male children. About 50% of the cases of X-linked
SCID are caused by mutations in a signaling subunit of a receptor
for cytokines.
• This subunit is called the common γ chain (γc), because it is a
component of the receptors for numerous cytokines, including
interleukin (IL)-2, IL-4, IL-7, IL-9, and IL-15.
• When the γc chain is not functional, immature lymphocytes,
especially pro-T cells, cannot proliferate in response to the major
growth factor for these cells
• The consequence of this block is a profound decrease in the
numbers of mature T cells, defi cient cell-mediated immunity, and
defective humoral immunity because of absent T cell help (even
though B cells may maturealmost normally)
 Mechanism Severe combined
immunodeficiency (SCID)
• autosomal SCID are caused by mutations in an enzyme
called adenosine deaminase (ADA), which is involved in
the breakdown of purines.
• Defi ciency of ADA leads to the accumulation of toxic
purine metabolites in cells that are actively
synthesizing DNA, namely, proliferating cells.
• ADA defi ciency results in a block in T cell maturation
more than in B cell maturation; defective humoral
immunity is largely a consequence of the lack of T cell
helper function.
• The cause of about 50% of both X-linked and
autosomal cases of SCID is not known.
 SECONDARY
IMMUNODEFICIENCY
IMMUNODEGECIENCY CAUSED BY DRUGS

CORTICOSTEROIDS
 Cause changes in circulating leukocytes
 Depletion of CD4 cells
 Monocytopenia
 Decreased in circulating eosinophils and
basophils
 Inhibition of T cell activation and B cell
maturation
 Inhibit cytokine synthesis
METHOTREXATE
Structural analogue of folic acid
Blocks folic acid dependent synthetic
pathways essential for DNA synthesis
Prolonged use for treatment reduces
immunoglobulin synthesis
CYCOLOSPORIN
Have severe effects on T cell signaling
and functions
It binds to immunophilins which are
believed to have a critical role in signal
transduction
Also inhibit IL 2 dependent signal
transduction
 OTHER CAUSES

Malnutrition

Minerals

Vitamins

Obesity
Immunology
Nino Amaglobeli
namaglobel@gmail.com
lecture N9
Autoimmunity
POINTS TO BE DISCUSSED
• Autoimmunity versus autoimmune disease
• Features autoimmune disease (AD)
• Organ-specific and non organ-specific AD
• Experimental animal models
• Genetic background of AD
• Effects of environment on the induction of AD
• Cellular mechanisms and treatment of AD
THE ASSOCIATION OF AUTOIMMUNITY WITH
DISEASE
• The immune system has tremendous diversity and because the
repertoire of specificities express by the B- and T-cell populations is
generated randomly, it is bound to include many which are specific
for self components. Thus the body must establish self-tolerance
mechanisms, to distinguish between self and non-self determinants,
so as to avoid autoreactivity. However, all mechanism has a risk of
breakdown. The self-recognition mechanisms are no exception, and a
number of disease have been identified in which there is
autoimmunity, due to copious production of autoantibodies and
autoreactive T cells.
THE SPECTRUM OF AUTOIMMUNE DISEASES
• The antibodies associated with Hashimoto’s thyroiditis and primary
myxoderma react only with the thyroid, so the resulting lesion is
highly localized. By contrast, the serum from patients with diseases
such as systemic lupus erythematosus (SLE) reacts with many, if not
all, of the tissues I the body. In SLE, one of the dominant antibodies is
directed against the cell nucleus . These two diseases represent the
extremes of the autoimmune spectrum .
• The common target organs in organ-specific disease include the
thyroid, adrenals, stomach and pancreas. The non-organ-specific
diseases, which include the rheumatological disorders,
characteristically involve the skin, kidney, joints and muscle .
Mechanisms of induction of autoimmune
disease
• In any individual it is possible to find T cells which react to high
concentrations of self-antigens. The important point is that T cells are
tolerant to normal, physiological levels of self-antigen. However, in
some people, this state of tolerance breaks down and self destructive
autoimmune disease develops. Why does self-tolerance breakdown?
It appears to be multifactorial, with contributions fromgene defects,
which confer autoimmune susceptibility, and envronmental factors
• When these changes in self-antigen are combined with a genetically
programmed defect in immune regulation, autoimmune disease may
result
mechanisms by which autoantibodies can
produce autoimmune disease:
• There are five principle mechanisms by which autoantibodies can produce autoimmune disease:
• 1. Complement dependent lysis of the target cell. Paroxysmal cold haematuria (a formof
autoimmune haemolytic anaemia originally described in association with congenitalsyphilis but
now more commonly observed in patients with mumps or measles) is an example of autoimmune
disease mediated by complementfixing IgM antibodies.
• 2. Opsonisation. This is the mechanismof most forms of haemolytic anaemia as the density of Ig
is insufficient to allow cross-linking and activation of C1q.
• 3. Formation of immune complexes. e.g. Glomerulonephritis with serumsickness. Due to the
negative charge of the glomerular basement membrane, immune complexes with a net positive
charge tend to deposit there.
• 4. Blockade of receptors for physiological ligands. e.g. Myasthenia gravis (anti-acetylcholine
receptor antibodies), pernicious anaemia (anti-intrinsic factor antibodies).
• 5. Stimulation of cellsurface receptors. e.g. Graves' disease (antibodies mimic actions of TSH).
 Two types of autoimmune disease

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Hashimoto’s thyroiditis
• One of the earliest examples in which the production of autoantibodies
was associated with disease in a given organ is Hashimoto’s thyroiditis. It is
a disease of the thyroid which is most common in middle-aged women and
often lead to formation of a goiter and hypothyroidism. The gland is
infiltrated, sometimes to an extraordinary extent, with inflammatory
lymphoid cells. These are predominantly mononuclear phagocytes,
lymphocytes and plasma cells, and secondary lymphoid follicles are
common. The serum of patients with Hashimoto’s disease usually contains
antibodies to thyroglobulin. These antibodies are demonstrable by
agglutination and by precipitin reactions when present in high titre. Most
patients also have anti bodies directed against a cytoplasmic or microsome
antigen, also present on the apical surface of the follicular epithelial cells
and now known to be thyroid peroxidase, the enzyme which iodinates
thyroglobulin.
AUTOIMMUNE DISEASE-
KEY CONCEPTS
• Recognition of autoantigens by lymphocytes is critical
• Tissue destruction not just autoimmune cells must be present
• AD involve self-reactive T cells
• AD induction almost always depends on triggering of autoreactive
CD4+ T cells
MECHANISMS OF BREAKING OF
SELF-TOLERANCE
• Disruption of self or tissue barrier
• Infection of antigen presenting cell
• Binding of pathogen to self antigen
• Molecular mimicry
• superantigen
EXAMPLES OF ORGAN-SPECIFIC AND NON ORGAN-
SPECIFIC (SYSTEMIC)
AUTOIMMUNE DISEASE
ORGANIC-SPECIFIC NON ORGANIC-SPECIFIC
• Hashimoto thyroiditis • Systemic lupus (SLE)
• Thyrotoxicosis • Rheumatoid arthritis (RA)
• Addison’ s disease • Scleroderma
• Atrophic gastritis • Dermatomyositis
• Juvenile diabetes mellitus • Mixed connective tissue disease
(MCTD)
• Multiple sclerosis • Sjogren’s symptome
AD ARE COMLEX GENETIC TRAITS
• Multiple genes determine susceptibility to AD No particular gene is
necessary of sufficient for disease expression (relatively low gene
penetrance)
• MHC and multiple non-MHC genes are involved
• Epistasis (interaction of susceptibility genes)
• Genetic alleles increasing susceptibility are relatively frequent in the
general population
GENETIC FACTORS
Autoimmune disease can occur in families
• There is an undoubted family incidence of autoimmunity. This is largely
genetic rather than environmental, as many be seen from studies of
identical and non-identical twins, and from the associated of thyroid
autoantibodies with abnormalities of the X-chromosome.
• Within the families of patients with organ-specific autoimmunity, not only
is there a general predisposition to develop organ-specific antibodies, it is
also clear that other genetically controlled factors tend to select the organ
that is mainly affected. Thus, although relatives of Hashimoto patients and
families of pernicious anaemia patients both have higher than normal
incidence and titer of thyroid autoantibodies, the relatives of pernicious
anaemia patients have a far higher frequency of gastric autoantibodies,
indicating that there are genetic factors which differentially select the
stomach as the target within these families.
IMPACT OF ENVIRONMENTAL TRIGGERS ON
INDUCTION OF AD
• Virus clustering (RA, Sjogren’s s., SLE, MS) infectious microorganisms
(molecular mimicry-see later)
• Geographic clustering
• Sun exposure (SLE)
• Exogenous estrogens, sex hormones in genera
Controls on the development of autoimmunity
can be bypassed in a number of ways
• Molecular mimicry by cross-reactive microbial antigens can stimulate autoreactive B
and T cells
• Normally, naïve autoreactive T cells recognizing cryptic self epitopes are not switched on
because the antigen is only presented at low concentrations on ‘professional’ APCs or it
may bepresented on ‘non-professional’ APCs such as pancreatic β-islet cells or thyroid
epithelial cells, which lack B7 or other co-stimulator molecules .
• The autoimmune process may persist after clearance of the foreign antigen if the
activated B cells now focus the autoantigen on their surface receptors and present it to
normally resting autoreactive T cell which will then proliferate and act as helpers for
fresh B-cell stimulation .
• In this connection, it has been suggested that because processed MHC molecules may
represent a major fraction of the peptide epitopes presented to differentiating T cells
within the thymus, a significant proportion of positively selected cell which escape
negative selection and enter the periphery will be specific for weakly binding cryptic
MHC epitopes. One might therefore expect autoimmune responses to arise not
infrequently through activation of these cells by molecular mimicry.
MOLECULAR MIMICRY
• Definition:
determinants of infectious agent mimic a host antigen da sef-
reactive T-cell clones to attack host tissues
• Examples:
Rheumatic fever due to group A streptococcus
SLE due Epstein-Barr virus cross reactive with
nuclear Sm antigen
EPITOPE SPREADING
• Definition:
Initial response to one self determinant (one peptide) could expand to
involve additional determinants on the same molecule as well as
additional self proteins. It explains how a response to one cryptic
epitope can mature into a full-blown autoimmune response
• Examples:
• - anti RO/SS-A to anti-La/SS-B –lead to lupus-like disease
HLA CLASS II EXPRESSION ON TISSUE CELLS IN
AUTOIMMUNE DISEASES
• Hashimoto thyroiditis – follicular cells of the thyroid
• Type I diabetes – beta cells of Langerhans islets
• Primary Biliary cirrhosis – cells of biliary duets
• Autoimmune hepatitis - hepatocytes
HLA CLASS II EXPRESSION ON TISSUE CELLS IN
AUTOIMMUNE DISEASES - 2
• Rheumatoid arthritis – synovial cells
• Sjogren’ syndrome- epithelium of salivary duets
• Multiple sclerosis – glial cells
• Chronic iridoscleritis – pigment epithelium of retina
• Crohn’s disease – epithelium of small intestine
OTHER FACTORS FAVORING AUTOIMMUNITY
1. Overproduction and/or dysregulation of cytokines
2. Disturbances of apoptosis
3. Adjuvant effect of microorganisms
4. Pre-existing defects in the target organ
5. Direct stimulation of autoreactive cells by foreign antigen
DIAGONOSTIC AND PROGNOSTIC VALUE OF
AUTOANTIBODIES
• Wherever the relationship of autoantibodies to the disease process,
they frequently provide valuable markers for diagnostic purposes. A
particularly good example is the test for mitochondrial antibodies,
used in diagnosing primary biliary cirrhosis Exploratory laparotomy
was previously needed to obtain this diagnosis, and was often
hazardous because of the age and condition of the patients
concerned.
• Autoantibodies often have predictive value. For instance, individuals
testing positively for antibodies to both insulin and glutamic acid
decarboxylase have a high risk of developing insulin-dependent
diabetes.
TREATMENT
• Often, in organ-specific autoimmune disorders, the symptoms can be
conrolled by administration of thyroxine, and thyrotoxicosis by
antithyroid drugs. In pernicious anaemia, metabolic correction is
achieved by injection of vitamin B12, and in myasthenia gravis by
administration of cholinesterase inhibitors. If the target organ is not
completely destroyed, it may be possible to protect the surviving cells
by transfection with FasL or TGFβ genes. Where function is
completely lost and cannot be substituted by hormones, as many
occur in lupus nephritis or chronic rheumatoid arthritis, tissue grafts
or mechanical substitutes may be appropriate. In the case of tissue
grafts, protection from the immunological processes which
necessitated the transplant may be required.
THERAPY OF AUTOIMMUNE DISEASES:
I.SELF-ANTIGEN SPECIFIC

• Antibodies vs. autoreactive TCR

• Vaccine containing autoreactive TCR
• Administration of peptides –TCR antagonists
• Parenteral infusion autoantigen or cDNA
• Oral administration of autoantigen
THERAPY OF AUTOIMMUNE DISEASES:
II.SELF-ANTIGEN SPECIFIC
1. Monoclonal antibodies vs. T cells-CD2, CD3, CD4
2. Antibodies vs. CD28, CD40L (modulation of T cell-APC interaction)
3. Antibodies vs. cell adhesion molecules (VLA-4, ICAM-1) and
chemokines
4. Intravenous infusion of immunoglobulin (IVIG)
5. Neutralization of proinflammatory cytokines
6. Administration of anti-inflammatory cytokines
THANK YOU

p.p.243-260
Caucasian International University

A Hypersensitivity

p.p.in book 221-242

Prof N.Amaglobeli
The Immune system can either be
The Immune system can either be:

Sufficient – normally protects us against most attacks from microbes

Insufficient – leading to infections ie. immunodeficiency

Harmful – an overactive immune response can give rise to tissue

damage (autoimmune diseases, hypersensitivity)

Tissue damaging reactions mediated by the immune system –

IMMUNOPATHOLOGY
 Hypersensitivity

Inappropriate stimulation of the adaptive immune

system, resulting in tissue damage from inflammatory
reactions, and even death.
Types I-V mechanisms:
types I, II, III, V – antibody mediated
type IV – T-cell mediated
Learning objectives:

By the end of this lecture you should be able to:

1) Describe the mechanism of type 1 hypersensitivity.

2) List 3 mediators released during mast cell degranulation and
3 synthesised after degranulation
3) Identify different allergens that can trigger type I
hypersensitivity
4) Describe management strategies for type 1 hypersensitivity
5) Describe the mechanism of type II hypersensitivity
6) List 3 diseases where their pathogenesis involves type II
hypersensitivity?
7) Describe the mechanism for type III hypersensitivity
8) List 3 diseases where the pathogenesis involves type III
hypersensitivity
9) Describe the mechanism of type IV hypersensitivity.
10)List 3 diseases that involve type IV hypersensitivity
Immediate hypersensitivity:
initiated in a sensitised recipient (from previous
contact with Ag) within minutes of further
exposure to Ag (eg skin tests)

Ab-mediated eg Type I

Delayed hypersensitivity (DTH):

appears only after some days (48-72hr)

T-cell mediated – Type IV

 ‘Immediate’ ‘Delayed’
Type 1 Type IV

Raised wheal, 5-7 mm diam Red indurated lesion, around 5

about 15 minutes mm diam, at 24-48 hours
Dermatophagoides pteronyssinus – house dust mite
allergens in faecal particles eg proteases
 Bee
Sting

dbones.com Roitt et al: Immunology 6E

Hydatid cyst – Echinococcus granulosus
 TABLE Ibvl COMMON AllERGENS (ANTIGENS)
ASSOCIATED WITH TVPE I
HYPERSENSITIVITY

Pmmm
Wag" serum rand:
Nuls

Vacant: Sufnnd
Egg:
Hunt mam
yc gum
Peas. buns
M llk
Ragweed
'l'vmolhy grass Insm {mamas
Bud! (lees Bee VEHDI‘H
WW venom
Ant wnnm
PcnIuUm Cuckraach calyx
Sulfunamlde: mm mm
Local ancsthults
memes Mum’ spare:

Ammt may and dandy

• Serum IgE levels elevated
ng/ml
normal newborn <3
9 months – 3 years ~ 75
adult ~ 200 (65-1800)

asthmatic children 500 – 1000

atopic dermatitis ~ 2000
Ascaris children 4400 (240-14300)

• evolution of mechanism
for local inflammatory responses to helminths entering
skin (schistosomes), gut (hookworms, Ascaris)
 Allergicresponse
Allergic response - - Sensitization
SensitizationPhase
Phase
A“ergen specwic
B can ‘9 \

m
C‘ass

, ’ Th1 ceu f
Auevgen
IgM/ng
B ceu

§©
E.

2
‘nmbn
/CD40

CD154
AHergen Enhance

+— % a
specmc
Th0 ceH Th2

©—>@(@ ceHO
Th2 cell

P‘msma
APC Th2 \gE
Th2 ce‘l Th2 cell memovy
Th2 cell B ceHs Ce”

\gE
From Instant Notes in Immunology – Lydyard, Whelan
From
and Fanger 2ndInstant 2004in Immunology – Lydyard,
editionNotes
Whelan and Fanger 3rd edition 2011 fl*«
 Type I – Allergic, IgE-Mediated
• Local responses
allergens: small water-soluble (glyco)proteins from -
pollens, house-dust mites, animal danders,
fungal spores, foods

hayfever, asthma, atopic dermatitis

• Systemic anaphylaxis
drugs (penicillin), insect venoms, foods - in circulation
rupture of hydatid cyst of Echinococcus granulosus
(dog tapeworm)
 Acute inflammation (and
Injury 3 type 1 hypersensitivity)

l
Direct damage
‘0 ”‘0“ Vesse‘ Enoomelmm of blood vesse‘ wan

000000000000 %
quiag‘andms NuncTNFKX‘
Histamme \Lrl
WISE?“
Leukomeneg oxwde MACROPHAGE

\L 1
,
‘
K\
Endotoxms
T‘SSUS C35‘ (353‘04a
damage ‘\
I ClassucaVaHematwe / Microbe
\ pathway /
\ /
Exotoxms /
\\ lgE/aHergen Neuropepudes / F‘uwd, edema exudate

\\\ /// (Contains nbnnogem

’
anuoomes etc)
\
\\\\\\

Hmd proleols damaged area

7

during repaw
From Instant Notes in Immunology –
Lydyard, Whelan and Fanger – Taylor and
Francis 2011
 Mast Cell
Types: mucosal, connective tissue (and basophil?)
Induced to release inflammatory mediators by:
allergen
Trigger mechanisms
C5a, C3a anaphylatoxins

allergen cross-linking
IgE on surface
FceRI receptors

Direct triggers:
Opiates, contrast media, mast-cell degranulation
vancomycin mediator reIease
Preformed and
newly generated
• IgE bound to Fce receptors on tissue mast cells
• and blood basophils
• allergen cross-links IgE
• increase in cell Ca2+,
• transient rise (1 min) in cAMP, then fall

mast cell, basophil release inflammatory mediators:

inflammatory responses:
vascular dilation, increased permeability
smooth muscle contraction, mucus secretion
i) Degranulation – release of preformed stores

histamine {vascular permeability,

5-hydroxytryptamine {smooth muscle contraction
tryptase, chymase {degrade microbial structures
acid hydrolases, cathepsins {tissue damage/remodelling
neutrophil chemotactic factor (IL8)
eosinophil chemotactic factor (ECF-A tetrapeptide)
Heparin storage matrix for histamine/ other basics
ii) Lipid mediators – from membrane phospholipids on
activation
* prostaglandins
from arachidonic acid by cyclooxygenase pathway
PGD2 – vasodilation, bronchoconstriction
neutrophil chemotaxis
* leukotrienes
from arachidonic acid by lipoxygenase pathway
LTC4, LTD4, LTE4 (SRS-A)
– prolonged bronchoconstriction, mucus secretion
vascular permeability
LTB4 – neutrophil chemotaxis
PAF (platelet activating factor)
- leukocyte chemotaxis and activation
- bronchoconstriction, vascular permeability
- platelet aggregation and mediator release
iii) cytokines – produced on activation

IL4, IL13 TH2 differentiation

IL5 eosinophil production, activation
TNFa, MIP-1a (several inflammatory effects – later)
IL3 mast cell proliferation
Inflammatory response in asthmatic bronchi
Maudvunl

hinlmum \ylommfl pmlhgundim MBF

on my..." ECF

Infiamma
brand-ill
Ian
hvplnaaniviiv

norm ammo mu infiltrate

wnslrimiun incrsusd mucus
incruud mulch
mmmc bmndtoqnsm

From Immunology 8th edition Male, D et al . Elsevier 2016

Severe urticaria rash
(mins → ~ 12hr)
 Mechanisms of type I hypersensitivity

’
Smooth muscle Cell

”-4
Small blood vessel

“com gland

Fc receptor \

w / \ forlgE
\ w
Blood platelets
0

r
Sensoryrnervc
ga

/
Memory cell Degmnulmion endings
Allergen Sensinml mast cell
specific
lgE Eosinophll
Diagnosis of Type 1 hypersensitivity

• Detection of IgE against specific allergens

• Skin tests against specific allergens
 Hygiene Hypothesis
•Intracellular infections in early childhood lead to
reduced risk of allergy later in life;
•children in Guinea-Bissau: those not vaccinated
against measles (and become infected) less likely to
develop allergies than those vaccinated;
• military students in Italy +ve for hepatitis A showed less
allergy compared to –ves;
•+ve tuberculin test result inversely related to future
development of allergies (asthma);
•induction of TH1-biased immunity causes reduction of
allergen-specific TH2 cells;
• use of antibiotics during infancy correlates with
increased risk of developing asthma;
• growing up on farms, exposure to livestock protects
against development of allergies;
Suggest: bacterial LPS interact with CD14/TLR4 cluster on APCs
with the release of IL12 favouring TH1 responses.
But: viral infections – rhinovirus, influenza A, RSV can increase
asthma with allergen exposure.
if infection occurs:
before allergen sensitisation, reduction in future
allergy risk is observed;
after development of allergic TH2 response,
increased allergy is detected.
 Treatment of type 1 Hypersensitivity
• Avoidance of allergens
• Anti histamines

Immunotherapy (desensitisation) Also SLIT

allergen injections |
Wyyyyyyy
allergic symptoms

rhinitis IgG and IgG4

lymphocyte responses

6 months 2 years
 Type II - Cytotoxic
Antibody formed against antigen on cell surfaces →
cell lysis by:
1) activation of the classical complement pathway
IgG, IgM Abs

anfibody

complement-
mediated lysis
2) ADCC – antibody-dependent cell-mediated
cytotoxicity by NK cells binding IgG Ab via their Fc
receptors
cell‘surface antigen

cytotoxic action

3) phagocytosis of RBCs, platelets – mediated by

Fc receptors on macrophages and C3b
(from complement activation)
 Kcells eosinophils neutrophils
platelets macrophages eosinophils
neutrophils macrophages

© Fleshandbones.com Rortt et al: Immunology 6E

 Fc receptor

C3 receptor
L neutrophil Miami" 2‘ phagocytosis 3. Iysosomefusion
adherence

basement
membrane

I. neutrophil ||. 'frustrated IIL extracellular

adherence phagocytosis’ enzyme release

© Fleshandbones.com Roitt at al: Immunology 6E

Examples of Type II hypersensitivity

• foreign tissue Ag in transplantation

- incompatible blood transfusion
- haemolytic disease of the newborn (HDNB)
- unmatched organ grafts
• self-Ags, in autoimmune diseases:
- autoimmune haemolytic anaemia
(AIHA – as in Mycoplasma pneumoniae infection)
- chronic thyroiditis
- Goodpasture’s syndrome – anti- basement
membrane
Haemolytic Disease of the Newborn
Ab response to RhD on foetal rbc, when mother RhD-ve

RhD'
mother

0‘.
Cm" ’1 A t
redcells

anti-RhD

RhD+ fetus RhD" fetus

at 1st birth IgG formed 2nd pregnancy

Ab crosses placenta
enlarged liver, spleen with rbc destruction
high bilirubin from haemoglobin breakdown
Rhesus Prophylaxis

deaths
per 1000
live births

Rhesus prophylaxis
introduced

1950 1960 1970 1990

year
Type III – Immune Complex mediated hypersensitivity
Type III – Immune Complex mediated hypersensitivity

Ag/Ab (IgG, IgM) complexes form in excess and deposit on (or

near) blood vessel walls in tissues causing local inflammation and
tissue damage (immune complex disease)
 Three categories of Immune complex disease

persistent microbial infected organlsl,

infection antigen kidney

.
aut0ImmunIty
I

_
self antigen
kidney, joint,
arteries, skin

inhaled mould, plant or lun

antigen animal antigen 9
© Fleshandbanes.com Roitt et al: Immunology 6E
Persistent infection with a weak antibody can lead
to immune complex disease

For example:

Streptococcus
Staphylococcus
Malaria
Leprosy
Viruses

Inhaled antigens – Pigeon fancier’s lung (pigeon antigens

Farmer’s lung (fungi in mouldy hay)

Examples of type III hypersensitivity

• localised:
farmer’s lung from spores of actinomycetes,
- Aspergillus fumigatus in mouldy hay
pigeon fanciers’ disease etc
• systemic:
post-Streptococcus pyogenes glomerulonephritis
infective endocarditis (oral Streps, Staph aureus)
quartan malaria (Plasmodium malariae)
syphilis
hepatitis B

Autoimmune diseases – RA, SLE

Deposition of immune complexes in blood vessel walls

immune

ages
W6C)

63
$9va
platelet
aggregation
deposition

microthrombus
tarmation ,-

I
k\
Q a
‘
’4 3
 Mechanism of inflammation
immune-complex
deposition
• complement activation →
C5a, C3a
→ release of mediators from
mast cells,macrophages
→ attract neutrophils etc
(C5a)
• neutrophils → FcRs, C3bR
→ enzymes, ROI, NO
blood basement
vessel membrane

• basophil, platelet binding by FcgR

→ further release of vasoactive amines
platelets → microthrombi
Glomerulus

immune complexes in SLE anti-basement membrane

in Goodpasture’s
Type IV – Cell-Mediated, Delayed

(T cell as apposed to antibody and complement)

 Intracellular pathogens and contact
TABLE 15-6 antigens that induce delayed-type
(type IV) hypersensitivity
Intracellular bacteria Intracellular viruses
Mycobacterium tuberculosis Herpes simplex
virus
Mycobacterium leprae Variola (smallpox)
Listeria monocytogenes Measles virus
Brucella abortus
Intracellular fungi Contact antigens
Pneumocystis carinii Picrylchloride
Candida albicans Hair dyes
Histoplasma capsulatum Nickel salts
Cryptococcus neoformans Poison ivy
Intracellular parasites Poison oak
Leishmania sp.
Table 1 5-6
Kuby IMMUNOLOGY, Sixth Edition
at 2007 H.Freeman and Company
 Type IV – Cell-Mediated, Delayed
Sensitisationhas
e
• Ag at surface taken up by antigen presenting cell
(dendritic cell) → Ag/MHC II complex
APC migrates to lymph node

• TH cells
@ © Macrophage
(usually TH1) Dendritic cell

are sensitised
(in lymph node) |L1.12
n AgIMHCII

CD4
by contact with
Ag/MHCII on
APC e |L2
•
Effector phase:

•Re-exposure to Ag/MHC II in tissues

memory TH cells → cytokines, chemokines

• Attraction of leukocytes
monocytes → activated macrophages
→ inflammatory mediators
- TNFa, enzymes, ROIs, NO
chemokines
cytotoxic T lymphocytes
 Granuloma Formation
1. Mycobacterial, TH1-type granulomas
Mycobacterium tuberculosis, M leprae infections
eg TB – bacteria persist in alveolar macrophages
Ag presented on MHCII to CD4+ TH1 cells
macrophages activated (IFNg)
• influx of monocytes to infection site
differentiate to macrophages, activated, retained
form granuloma (healed tubercule) to ‘seal off’ infected
macrophage
• The process is cytokine driven
TH1 cell → RANTES chemokine for monocytes
‘MIF’ retention of macrophages
macrophage → MCP-1 chemokine for monocytes
TNFa, IL1 ↑adhesins for extravasation
 Granuloma

persistant Ag in macrophage
(tissue necrosis)

macrophage (from blood

monocytes) - derived
'epithelioid cells'

\ eosinophils

'giant cells'

fibrosis calcification
 Granuloma structure
• persistent Ag in centre macrophages – necrosis
• macrophages (from blood monocytes) form
concentric rings of ‘epithelioid’ cells
• other cell types – eosinophils, T-cells
• giant cells – multinucleate
• fibrous connective tissue (fibrosis)
• calcification
CD8+ T cells: possible source of cytokines
lyse bacterial-infected macrophages
produce granulysin – bactericidal
gd-T cells: cytokine producing; cytotoxic
Tuberculin reaction
skin test for memory TH1 cells against mycobacterial Ag
purified protein derivative (PPD) from culture filtrate
→ skin
presented on dendritic cells
→ firm red swelling at 48-72hr; T cells, macrophages

« a.
 SKIN DISEASES 183

Table 9.3 Some agents responsible for allergic contact dermatitis

Agent Examples of exposure

Metals Nickel Clasps, necklaces, watch-straps

Chromate Cement (building site workers)
Cobalt”
Medications ’Para’-group chemicals Benzocaine-type anaesthetics, sulphonamide
antibiotics, PABA—containing substances
(e.g. sunscreens) and oral hypoglycaemic
agents (sulphonylureas)
Phenothiazines Phenothiazine—based antihistamines
Neomycin Topical antibiotics
Plastics Epoxyresins, acrylates Construction industry, glues
Rubber Accelerators Tyre industry, rubber gloves, shoes,
clothing, household ’grips’, etc.
Plants Poison ivy (USA only)
Primula
Chrysanthemum
Geranium
Cosmetics Perfumes
Preservatives
Lanolin
t»
5E Source of cobalt sensitivity is usually obscure but it may exist as a co-sensitivity with nickel (metal) or chromate (cement).
Contact hypersensitivity
- small chemicals – nickel, rubber, poison ivy and oak
conjugate with proteins
- presented on dendritic cells in epidermis
→ infiltrates of T cells, macrophages
→ eczema reaction at point of contact

Ni in buckle of watch strap Oedematous vesicles in epidermis

 Induction Elicitation

Hapten Hapten—carrier Re-exposure to hapten 4

protein complex

Release of
cytokines
(IL-2, lL-3,
IL-4, IFN-y, etc.)

Afferent
lymphatic

Efferent
immunoblast lymphatic

Pathogenesis of Allergic Contact Dermatitis

 Type V – Stimulatory (modification of type II)
(see also Autoimmunity)

Persistent activation of target cell membrane receptor

by autoAb, normally responding to hormone
TSH (thyroid stimulating hormone) receptor
by autoAb in thyrotoxicosis (Graves’ Disease)

continuous thyroxine release
 Graves’ disease – mechanism (type V
hypersensitivity)
(a) (b) a sell —> plasma cell

Pituitary Block TSH Pituitary Antibody to

8/)
production TSH receptor

., . 1‘f ’< ”l
Thyroid
.TSH
c
hormones
,(
)— Y

Block TSH
production .
TSH receptors 4
Thyrotd
°
hormones*—/
Thyroid follicle
 Type of Pathologic'immune Mechanisms of tissue
hypersensitivity mechanisms injury and disease

Immedlala TH? cells‘ lgE antibody mast cells. eosinophils

Mast cell<derived

335:?“va lIDid Iators

‘' ' me (vasoactlve
mediators, Amlriesi
Cywkines)

cytokinermedlated
inflammation (eosinophi
neutrcptiils)

Mediators-
Antibody- lSIM» lgG antibodies againstcell surface ar complement and Fe recapture

Summary:
mediated extracellular matrix antiieng mediatea
activation 0 en 0
em
as“
,iclmn’znerug
(Type II) ‘”"ammm°”

meanings“ Camplemem\,lfifi
”Hi/m (neutrophils.
macwnh:ges)
Opsonlzitiai’l and
Types 1-IV phagocytesis 01 cells
Abnormalities m cellular
tunctton, e g , ormcrie
receptor signaling

Immune
complex—
immune complexes 01 circulating antigens
and lgNl cr lgG antibodies deposrled in
Complement and Fe receptor»
mediated recmitmerit and
mediated vascular basement membrane activation of leukocytes
(Type III)

Antlgen-anlihddy complex
1 ctw T cells (delayed typehypersentnwny) t Macrophage activation
T cell— 2 CD5‘ CTLs (T cell—mediated cytmoxiciq) cytokine-mediated
mediated trttlammatnn
(Type IV) Macmpnage
2 Direct target cell killing,
cymkineamed itea
one. cm
rcell

Cnvynvhtflmhysnunaeis an insinuate/raw