Effector Functions of T Lymphocytes Body_ID: HC005019 One of the earliest responses of CD4+ helper T cells is secretion of the cytokine IL-2 and expression of high-affinity receptors for IL-2. IL-2 is a growth factor that acts on these T lymphocytes and stimulates their proliferation, leading to an increase in the number of antigen-specific lymphocytes. Some of the progeny of the expanded pool of T cells differentiate into effector cells that can secrete different sets of cytokines and thus perform different functions. The best defined subsets of CD4+ helper cells are the TH1 and TH2 subsets. TH1 cells produce the cytokine IFN-γ, which activates macrophages and stimulates B cells to produce antibodies that activate complement and coat microbes for phagocytosis. TH2 cells produce IL-4, which stimulates B cells to differentiate into IgE-secreting plasma cells; IL-5, which activates eosinophils; and IL-13, which activates mucosal epithelial cells to secrete mucus and expel microbes. A third subset, called TH17, has been described recently that produces the cytokine IL-17, which promotes inflammation, and is believed to play an important role in some T cell-mediated inflammatory disorders. These effector cells migrate to sites of infection and accompanying tissue damage. When the differentiated effectors again encounter cell-associated microbes, they are activated to perform the functions that are responsible for elimination of the microbes. The key mediators of the functions of helper T cells are the surface molecule called CD40 ligand (CD40L), which binds to its receptor, CD40, on B cells and macrophages, and various cytokines. Differentiated CD4+ effector T cells of the TH1 subset recognize microbial peptides on macrophages that have ingested the microbes. The T cells express CD40L, which engages CD40 on the macrophages, and the T cells secrete the cytokine, IFN-γ, which is a potent macrophage activator. The combination of CD40- and IFN-γ-mediated activation results in the induction of potent microbicidal substances in the macrophages, including reactive oxygen species and nitric oxide, leading to the destruction of ingested microbes. TH2 cells elicit cellular defense reactions that are dominated by eosinophils and not macrophages. As we discuss below, CD4+ helper T cells also stimulate B-cell responses by CD40L and cytokines. Body_ID: P005043 Activated CD8+ lymphocytes differentiate into CTLs that kill cells harboring microbes in the cytoplasm. These microbes may be viruses that infect many cell types, or bacteria that are ingested by macrophages but have learned to escape from phagocytic vesicles into the cytoplasm (where they are inaccessible to the killing machinery of phagocytes, which is largely confined to vesicles). By destroying the infected cells, CTLs eliminate the reservoirs of infection.
Figure 5-16 Recognition and rejection of organ allografts. In the direct pathway, donor class I and class II MHC antigens on antigen-presenting cells (APCs) in the graft (along with costimulators, not shown) are recognized by host CD8+ cytotoxic T cells and CD4+ helper T cells, respectively. CD4+ cells proliferate and produce cytokines (e.g., IFN-γ), which induce tissue damage by a local delayed-hypersensitivity reaction. CD8+ T cells responding to graft antigens differentiate into CTLs that kill graft cells. In the indirect pathway, graft antigens are displayed by host APCs and activate CD4+ T cells, which damage the graft by a local delayed-hypersensitivity reaction and stimulate B lymphocytes to produce antibodies.
Mr. Mallappa H Shalavadi
HSK College of
Immunity refers to protection against infections
Immune system is the collection of cells and molecules
that are responsible for defending us against the
countless pathogenic microbes in our environment.
430 B.C: Peloponesian War, Thucydides describes plague –
the ones who had recovered from the disease could nurse
the sick without getting the disease a second time
15th centurry: Chinese and Turks use dried crusts of
smallpox as ”vaccine”
1798: Edward Jenner – smallpox vaccine
Noticed that milkmades that had contracted cowpox did
NOT get smallpox
Test on an 8 year old boy, injected cowpox into him
Follwed by exposure to smallpox
Vaccine was invented (latin vacca means ”cow”)
Two types of adaptive immune responses: humoral immunity, mediated
by soluble antibody proteins that are produced by B lymphocytes, and
cell-mediated (or cellular) immunity, mediated by T lymphocytes
When the immune system is inappropriately triggered or not properly
controlled, the same mechanisms that are involved in host defense
cause tissue injury and disease.
The reaction of the cells of innate and adaptive immunity may be
manifested as inflammation.
Pathogens and disease
CELLS AND TISSUES OF THE IMMUNE
The cells of the immune system consist of
Lymphocytes, which are the mediators of adaptive
Antigen-presenting cells (APCs), which capture and
display microbial and other antigens to the lymphocytes.
Various effector cells, which perform the task of
eliminating the antigens (typically, microbes), the
ultimate "effect" of the immune response.
Lymphocytesare present in the circulation and
in various lymphoid organs.
Although all lymphocytes appear morphologically identical, there
are actually several functionally and phenotypically distinct
Lymphocytes develop from precursors in the generative lymphoid
T lymphocytes are so called because they mature in the
thymus, whereas B lymphocytes mature in the bone marrow.
Each T or B lymphocyte expresses receptors for a single
antigen, and the total population of lymphocytes (numbering about
1012 in humans) is capable of recognizing tens or hundreds of
millions of antigens.
This enormous diversity of antigen recognition is generated by the
somatic rearrangement of antigen receptor genes during
lymphocyte maturation, and variations that are introduced during
the joining of different gene segments to form antigen receptors.
Thymus-derived, or T, lymphocytes are the effector cells of cellular
immunity and provide important stimuli for antibody responses to
T cells constitute 60% to 70% of the lymphocytes in peripheral
T cells do not detect free or circulating antigens.
Instead, the vast majority (>95%) of T cells recognize only peptide
fragments of protein antigens that are displayed on other cells
bound to proteins of the major histocompatibility complex.
TCRs are noncovalently linked to a cluster of five invariant
polypeptide chains, the γ, δ, and ε proteins of the CD3 molecular
complex and two δ chains.
The CD3 proteins and δ chains do not themselves bind antigens;
instead, they interact with the constant region of the TCR to
transduce intracellular signals after TCR recognition of antigen.
T cells express a number of other invariant functionassociated molecules.
Like CD4 and CD8 are expressed on distinct T-cell subsets
and serve as coreceptors for T-cell activation.
During antigen recognition, CD4 molecules on T cells bind to
invariant portions of class II MHC molecules on selected
CD4+ T cells are "helper" T cells because they secrete
soluble molecules (cytokines) that help B cells to produce
antibodies and also help macrophages to destroy
The central role of CD4+ helper cells in immunity is
highlighted by the severe compromise that results from the
destruction of this subset by human immunodeficiency virus
CD8+ T cells can also secrete cytokines, but they play a more
important role in directly killing virus-infected or tumor cells,
and hence are called "cytotoxic" T lymphocytes (CTLs).
Lymphocyte antigen receptors. A, The T-cell receptor (TCR) complex and other molecules
involved in T-cell activation. The TCRα and TCRβ chains recognize antigen (in the form of
peptide-MHC complexes expressed on antigen-presenting cells), and the linked CD3
complex initiates activating signals. CD4 and CD28 are also involved in T-cell activation.
(Note that some T cells express CD8 and not CD4; these molecules serve analogous roles.)
B, The B-cell receptor complex is composed of membrane IgM and the associated signaling
proteins Igα and Igβ. CD21 is a receptor for a complement component that promotes B-cell
The human MHC, known as the human leukocyte antigen (HLA)
complex, consists of a cluster of genes on chromosome 6.
Plays important role in regulation of immunity.
First discovered on leukocytes.
On the basis of their chemical structure, tissue distribution, and
function, MHC gene products fall into three categories
Class I MHC
molecules are encoded by three closely linked
loci, designated HLA-A, HLA-B, and HLA-C.
Each of these molecules is a heterodimer, consisting of a polymorphic
44-kD α chain noncovalently associated with a 12-kD nonpolymorphic
β2-microglobulin (encoded by a separate gene on chromosome 15).
The extracellular portion of the α chain contains a cleft where foreign
peptides bind to MHC molecules for presentation to CD8+ T cells.
In general, class I MHC molecules bind to peptides derived from
proteins synthesized within the cell (e.g., viral antigens).
Because class I MHC molecules are present on all nucleated cells, all
virus-infected cells can be detected and eliminated by CTLs.
The HLA complex and the structure of HLA molecules. A, The location of
genes in the HLA complex. The sizes and distances between genes are not to
scale. The class II region also contains genes that encode several proteins
involved in antigen processing (not shown). B, Schematic diagrams and
crystal structures of class I and class II HLA molecules. LT, leukotriene;
TNF, tumor necrosis factor.
Class II MHC
molecules are encoded by genes in the HLA-D
region, which contains at least three subregions: DP, DQ, and DR.
Class II MHC molecules are heterodimers of noncovalently linked
polymorphic α and β subunits
Unlike in class I, the tissue distribution of class II MHC-expressing
cells is quite restricted; they are constitutively expressed mainly on
APCs (notably, dendritic cells), and macrophages, and B cells.
In general, class II MHC molecules bind to peptides derived from
proteins synthesized outside the cell (e.g., those derived from
extracellular bacteria). This allows CD4+ T cells to recognize the
presence of extracellular pathogens and to orchestrate a protective
Class III MHC
include some of the complement components
(C2, C3, and Bf); genes encoding tumor necrosis factor (TNF) and
lymphotoxin (LT, or TNF-β) are also located within the MHC.
Not associated with Ag identification.
Bone marrow-derived, or
B, lymphocytes comprise
10% to 20% of the
They are also present in
bone marrow and in the
follicles of peripheral
lymphoid tissues (lymph
nodes, spleen, tonsils,
B cells are the only cell
lineage that synthesize
antibodies, also called
B cells recognize antigen via monomeric membrane-bound
antibody of the immunoglobulin M (IgM) class, associated with
signaling molecules to form the B-cell receptor (BCR) complex.
Whereas T cells can recognize only MHC-associated peptides, B
cells can recognize and respond to many more chemical
structures, including proteins, lipids, polysaccharides, nucleic
acids, and small chemicals; furthermore, B cells (and
antibodies) recognize native (conformational) forms of these
B cells express several invariant molecules that are responsible
for signal transduction and for activation of the cells --- These
molecules include the CD40 receptor, which binds to its ligand
expressed on helper T cells, and CD21, which recognizes a
complement breakdown product that is frequently deposited on
After stimulation, B cells differentiate into plasma cells, which
secrete large amounts of antibodies, the mediators of humoral
are gamma globulins called
immunoglobulins (abbreviated as
160,000 and 970,000.
They usually constitute about 20
per cent of all the plasma
All the immunoglobulins are
composed of combinations of
light and heavy polypeptide
chains. Most are a combination of
two light and two heavy chains.
Enzymatic Digestion Of
Digestion With Papain Yields
2 identical Fab and 1 Fc
Fab Because Fragment That is Antigen Binding
Fc Because Found To Crystallize In Cold Storage
No Fc Recovery, Digested Entirely
Mercaptoethanol Reduction (Eliminates
Disulfide Bonds) And Alkylation Showed
There are five classes, or isotypes, of immunoglobulins
Antibody Classes And Biological
Most abundant immunoglobin 80% of
IgG1,2,3,4 (decreasing serum
IgG1, IgG3 and IgG4 cross placenta
IgG3 Most effective complement activator
IgG1 and IgG3 High affinity for FcR on
phagocytic cells, good for opsonization
Antibody Classes And Biological
5-10% of serum immunoglobulin
mIgM (also IgD) expressed on B-cells as
Pentameric version is secreted
First Ig of primary immune response
High valence Ig (10 theoretical), 5 empirical
More efficient than IgG in complement
Antibody Classes And Biological
10-15% of serum IgG
Predominant Ig in secretions
○ Milk, saliva, tears, mucus
5-15 g of IgA released in secretions!!!!
Serum mainly monomeric, polymers
possible not common though
Secretions, as dimer or tetramer+J-chain
polyptetide+secretory component (Poly
IgA Antibody Transport Across Cell
Antibody Classes And Biological
Very low serum concentration, 0.3g/mL
Participate in immediate hypersensitivities
reations. Ex. Asthma, anaphylaxis, hives
Binds Mast Cells and Blood Basophils
Binding causes degranulation
Antibody Classes And Biological
Expressed on B-cell Surface
IgM and IgD, Expressed on B-cell
We Do Not Know Any Other
Biological Effector Activity
Low serum concentrations, ~30g/mL
Cross-Linkage of Bound IgE Antibody With Allergen
Mechanisms of Action of Antibodies
Antibodies act mainly in two ways to protect the body against
(1) by direct attack on the invader
(2) by activation of the “complement system” that then has multiple
means of its own for destroying the invader.
The antibodies can inactivate the invading agent in one of several
ways, as follows:
1) Agglutination, in which multiple large particles with antigens on
their surfaces, such as bacteria or red cells, are bound together into
2) Precipitation, in which the molecular complex of soluble antigen
(such as tetanus toxin) and antibody becomes so large that it is
rendered insoluble and precipitates
3) Neutralization, in which the antibodies cover the toxic sites of the
4) Lysis, in which some potent antibodies are occasionally capable of
directly attacking membranes of cellular agents and thereby cause
rupture of the agent
Site of action
2 or 4
tears, small intestine,
nasal, breast milk)
•Stop bacteria adhering to
•Prevents bacteria forming
colonies on mucous
Allergies ------ Greek = altered reactivity
1906 – von Pirquet coined term: hypersensitivity
Hypersensitivity reactions – „over reaction‟ of
the immune system to harmless environmental
“ Defined as a state of exaggerated immune
response to an antigen”
Immune responses are capable of causing
tissue injury and diseases that are called
Hypersensitivity reactions – originally
divided into 2 categories: immediate and
I. Immidiate type
Reaction occurs immediately within sec/min after Ag
Mediated by humoral Ab.
Further divided 3 types
Type 1, 2 & 3.
II. Delayed type
Reaction slower in onset and develops within 24-48 hrs
and effects are prolonged
Mediated by cellular response.
Mechanisms of Immunologically Mediated Diseases
Immediate (type Anaphylaxis, allergies,
I) hypersensitivity bronchial asthma
Production of IgE antibody,
immediate release of vasoactive
amines and other mediators from
mast cells; recruitment of
inflammatory cells (late-phase
Vascular dilation, edema,
AntibodyAutoimmune hemolytic Production of IgG, IgM →binds to Phagocytosis and lysis of
mediated (type II) anemia; Goodpasture
antigen on target cell or tissue,
cells; inflammation; in
phagocytosis or lysis of target cell some diseases, functional
by activated complement or Fc
receptors; recruitment of
cell or tissue injury
mediated (type III) forms of
Deposition of antigen-antibody
activation →recruitment of
Immediate (Type I) Hypersensitivity
Immediate hypersensitivity is a tissue reaction that occurs rapidly
(typically within minutes) after the interaction of antigen with IgE
antibody that is bound to the surface of mast cells in a sensitized
The reaction is initiated by entry of an antigen, which is called an
allergen because it triggers allergy.
Many allergens are environmental substances that are harmless for
Some individuals apparently inherit genes that make them
susceptible to allergies.
This susceptibility is manifested by the propensity of these
individuals to make strong TH2 responses and, subsequently, IgE
antibody against the allergens.
The IgE is central to the activation of the mast cells and release of
mediators that are responsible for the clinical and pathologic
manifestations of the reaction.
Immediate hypersensitivity may occur as a local reaction
(e.g., seasonal rhinitis, or hay fever) or severely debilitating
(asthma) or may culminate in a fatal systemic disorder
Sequence of events in immediate (type
Antibody-Mediated Diseases (Type II
Antibody-mediated (type II) hypersensitivity
disorders are caused by antibodies directed
against target antigens on the surface of cells or
other tissue components.
The antigens may be normal molecules intrinsic
to cell membranes or extracellular matrix, or they
may be adsorbed exogenous antigens (e.g., a
Blood cells commonly affected here.
Opsonization of cells by antibodies and complement
components, and ingestion of opsonized cells by phagocytes.
Inflammation induced by antibody binding to Fc receptors of
leukocytes and by complement breakdown products.
antibodies disturb the normal function of receptors. In these
examples, antibodies against the thyroid-stimulating hormone (TSH)
receptor activate thyroid cells in Graves disease, and acetylcholine
(ACh) receptor antibodies impair neuromuscular transmission in
Examples of Antibody-Mediated Diseases (Type II Hypersensitivity)
proteins (Rh blood group phagocytosis of
antigens, I antigen)
proteins (gpllb:Illa integrin) phagocytosis of
Proteins in intercellular
Antibody-mediated Skin vesicles
junctions of epidermal
cells (epidermal cadherin) proteases, disruption
Immune Complex Diseases
(Type III Hypersensitivity)
Antigen-antibody (immune) complexes that are
formed in the circulation may deposit in blood
vessels, leading to complement activation and acute
The antigens in these complexes may be exogenous
antigens-microbial proteins, or endogenous antigensnucleoproteins.
The formation of immune complexes does not equate
with hypersensitivity disease; antigen-antibody
complexes are produced during many immune
phagocytosed, representing a normal mechanism of
It is only when these complexes are produced
in large amounts, persist, and are deposited in
tissues that they are pathogenic.
Pathogenic immune complexes may form in the
circulation and subsequently deposit in blood
vessels, or the complexes may form at sites
where antigen has been planted.
Immune complex-mediated injury is systemic
when complexes are formed in the circulation
and are deposited in several organs
(e.g., kidneys, joints, or skin) if the complexes
are formed and deposited in a specific site.
Systemic Immune Complex Disease
systemic immune complex
disease can be divided into
The sequential phases in the
induction of systemic immune
complex mediate- d diseases
(type III hyper- sensitivity).
Local Immune Complex Disease
A model of local immune complex diseases
is the Arthus reaction, an area of tissue
necrosis resulting from acute immune
The reaction is produced experimentally by
injecting an antigen into the skin of a
(i.e., preformed antibodies against the
antigen are already present in the
Because of the initial antibody excess,
immune complexes are formed as the
antigen diffuses into the vascular wall;
these are precipitated at the site of injection
and trigger the same inflammatory reaction
and histologic appearance as in systemic
immune complex disease.
Arthus lesions evolve over a few hours and
reach a peak 4 to 10 hours after injection,
when the injection site develops visible
occasionally followed by ulceration.
Examples of Immune Complex-Mediated Diseases
Streptococcal cell wall Nephritis
antigen(s); may be
"planted" in glomerular
Hepatitis B virus
Nephritis, skin lesions,
T-Cell-Mediated (Type IV) Hypersensitivity
Cell mediated reaction.
This group of diseases has received great interest because many of
the new, rationally designed biologic therapies for immune-mediated
inflammatory diseases have been developed to target abnormal T-cell
Several autoimmune disorders, as well as pathologic reactions to
environmental chemicals and persistent microbes, are now known to
be caused by T cells.
Two types of T-cell reactions are capable of causing tissue injury and
(1) Delayed-type hypersensitivity (DTH), initiated by CD4+ T cells
(2) Direct cell cytotoxicity, mediated by CD8+ T cells.
In DTH, TH1-type CD4+ T cells secrete cytokines, leading to
recruitment of other cells, especially macrophages, which are the
major effector cells of injury.
In cell-mediated cytotoxicity, cytotoxic CD8+ T cells are responsible
for tissue damage.
A classic example of DTH is the tuberculin reaction,
elicited by antigen challenge in an individual already
sensitized to the tubercle bacillus by a previous infection.
Between 8 and 12 hours after intracutaneous injection of
tuberculin (a protein extract of the tubercle bacillus), a
local area of erythema and induration appears, reaching a
peak (typically 1-2 cm in diameter) in 24 to 72 hours
(hence the adjective, delayed) and thereafter slowly
Histologically, the DTH reaction is characterized by
perivascular accumulation ("cuffing") of CD4+ helper T
cells and macrophages.
Local secretion of cytokines by these mononuclear
inflammatory cells leads to increased microvascular
permeability, giving rise to dermal edema and fibrin
deposition; the latter is the main cause of the tissue
induration in these responses.
The tuberculin response is used to screen populations
for individuals who have had prior exposure to
tuberculosis and therefore have circulating memory T
cells specific for mycobacterial proteins.
Notably, immunosuppression or loss of CD4+ T cells
(e.g., resulting from HIV infection) may lead to a
negative tuberculin response even in the presence of a
In this form of T-cell-mediated hypersensitivity, CD8+ CTLs kill
antigen-bearing target cells.
As discussed earlier, class I MHC molecules bind to intracellular
peptide antigens and present the peptides to CD8+ T lymphocytes,
stimulating the differentiation of these T cells into effector cells called
CTLs play a critical role in resistance to virus infections and some
The principal mechanism of killing by CTLs is dependent on the
perforin-granzyme system. Perforin and granzymes are stored in the
granules of CTLs and are rapidly released when CTLs engage their
targets (cells bearing the appropriate class I MHC-bound peptides).
Perforin binds to the plasma membrane of the target cells and
promotes the entry of granzymes, which are proteases that
specifically cleave and thereby activate cellular caspases.
These enzymes induce apoptotic death of the target cells.
CTLs play an important role in the rejection of solid-organ transplants
and may contribute to many immunologic diseases, such as type 1
diabetes (in which insulin-producing β cells in pancreatic islets are
destroyed by an autoimmune T-cell reaction).
It is unresponsiveness to an antigen that is induced by
exposure of specific lymphocytes to that antigen.
Self-tolerance refers to a lack of immune responsiveness
to one's own tissue antigens.
During the generation of billions of antigen receptors in
developing T and B lymphocytes, it is not surprising that
receptors are produced that can recognize self-antigens.
Since these antigens cannot all be concealed from the
immune system, there must be means of eliminating or
controlling self-reactive lymphocytes.
Several mechanisms work in concert to select against
self-reactivity and to thus prevent immune reactions
against one's own antigens.
These mechanisms are broadly divided into two groups:
central tolerance and peripheral tolerance
Central tolerance----△ This refers to deletion of self-reactive T and B
lymphocytes during their maturation in central
△ Many autologous (self) protein antigens are
processed and presented by thymic APCs in
association with self-MHC.
△ Any developing T cell that expresses a receptor
for such a self-antigen is negatively selected
(deleted by apoptosis), and the resulting
peripheral T-cell pool is thereby depleted of selfreactive cells.
Immature B cells that recognize, with high affinity, selfantigens in the bone marrow may also die by apoptosis.
Some self-reactive B cells may not be deleted but may
undergo a second round of rearrangement of antigen
receptor genes and express new receptors that are no
longer self-reactive (a process called "receptor editing").
Many self-antigens may not be present in the thymus, and
hence T cells bearing receptors for such autoantigens
escape into the periphery.
There is similar "slippage" in the B-cell system as
well, and B cells that bear receptors for a variety of selfantigens, including thyroglobulin, collagen, and DNA, can
be found in healthy individuals
o Peripheral tolerance.
o Self-reactive T cells that escape negative selection in the thymus can
potentially wreak havoc unless they are deleted or effectively
o Several mechanisms in the peripheral tissues that silence such
potentially autoreactive T cells have been identified:
This refers to functional inactivation (rather than death)
of lymphocytes induced by encounter with antigens under certain
o Recall that activation of T cells requires two signals: recognition of
peptide antigen in association with self-MHC molecules on
APCs, and a set of second costimulatory signals (e.g., via B7
molecules) provided by the APCs.
o If the second costimulatory signals are not delivered, or if an
inhibitory receptor on the T cell is engaged when the cell encounters
self-antigen, the T cell becomes anergic and cannot respond to the
o B cells can also become anergic if they encounter antigen in the
absence of specific helper T cells
Suppression by regulatory T cells:
The responses of T lymphocytes to self-antigens may be
actively suppressed by regulatory T cells.
Activation-induced cell death:
Another mechanism of peripheral tolerance involves
apoptosis of mature lymphocytes as a result of selfantigen recognition.
T cells that are repeatedly stimulated by antigens in vitro
undergo apoptosis. One mechanism of apoptosis is the
death receptor Fas (a member of the TNF receptor
family) being engaged by its ligand coexpressed on the
The same pathway is important for the deletion of selfreactive B cells by Fas ligand expressed on helper T
Self-tolerance fails, resulting in reactions against one's
own cells and tissues that are called autoimmunity.
The diseases caused by autoimmunity are referred to as
Mechanisms of Autoimmunity
The breakdown of self-tolerance and the development of
autoimmunity are probably related to the inheritance of
various susceptibility genes and changes in tissues, often
induced by infections or injury, that alter the display and
recognition of self-antigens
Genetic Factors in Autoimmunity
There is abundant evidence that susceptibility genes play
an important role in the development of autoimmune
Expression of a particular MHC gene variable that can
contribute to autoimmunity.
Acute anterior uveitis
Primary Sjögren syndrome
Type 1 diabetes mellitus
HLA Allele (approximate %)
Two genetic polymorphisms have recently been shown
to be quite strongly associated with certain autoimmune
One, called PTPN22, encodes a phosphatase, and
particular variants are associated with rheumatoid
arthritis and several other autoimmune diseases.
Another, called NOD2, encodes an intracellular receptor
for microbial peptides, and certain variants or mutants of
this gene are present in as many as 25% of patients with
Crohn's disease in some populations.
Role of Infections and Tissue Injury
bacteria, mycoplasmas, and viruses, have been implicated
as triggers for autoimmunity.
Viruses and other microbes, particularly certain
bacteria such as streptococci and Klebsiella
organisms, may share cross-reacting epitopes with
self-antigens, such that responses to the microbial
antigen may attack self-tissues.
This phenomenon is called molecular mimicry.
It is the probable cause of a few diseases, the best
example being rheumatic heart disease, in which an
immune response against streptococci cross-reacts
with cardiac antigens.
Local tissue injury for any reason may lead to the
release of self-antigens and autoimmune responses
REJECTION OF TRANSPLANTS
The major barrier to transplantation of organs from one
individual to another of the same species (called
allografts) is immunologic rejection of the transplanted
Rejection is a complex phenomenon involving both celland
directed against histocompatibility molecules on the
The key to successful transplantation has been the
development of therapies that prevent or minimize
Rejection of allografts is a response to MHC
molecules, which are so polymorphic that no two
individuals in an outbred population are likely to express
exactly the same set of MHC molecules (except, of
course, for identical twins).
There are two main mechanisms by which the host
immune system recognizes and responds to the MHC
molecules on the graft.
Host T cells directly recognize the allogeneic (foreign) MHC
molecules that are expressed on graft cells.
Direct recognition of foreign MHC seems to violate the rule of
It is suggested that allogeneic MHC molecules (with any bound
peptides) structurally mimic self-MHC and foreign peptide, and
so direct recognition of the allogeneic MHC is essentially an
Because DCs in the graft express high levels of MHC.
Host CD4+ helper T cells are triggered into proliferation and
cytokine production by recognition of donor class II MHC
(HLA-D) molecules and drive the DTH response.
CD8+ T cells recognize class I MHC (HLA-A, -B) and
differentiate into CTLs, which kill the cells in the graft.
Host CD4+ T cells recognize donor MHC molecules after
these molecules are picked up, processed, and presented
by the host's own APCs.
This is similar to the physiologic processing and
presentation of other foreign (e.g., microbial) antigens.
This form of recognition mainly activates DTH pathways;
CTLs that develop by indirect recognition cannot directly
recognize and kill graft cells.
The indirect pathway is also involved in the production of
antibodies against graft alloantigens; if these antigens
are proteins, they are picked up by host B cells, and
peptides are presented to helper T cells, which then
stimulate antibody responses.