Immunology Ch 9 171-187
Immunological Tolerance and Autoimmunity
Immunological tolerance – ability of body to react to variety of microbes but not self-antigens
-lymphocytes are always generated that can recognize self-antigens
-if the mechanisms keeping lymphocytes from acting on self-antigens fails, autoimmunity occurs
-Immunological tolerance is lack of response to antigens that is induced by exposure of
lymphocytes to these antigens
-when cells with receptors for antigen encounter the antigen, they can either proliferate into
effector and memory cells (immunogenic), or be functionally inactivated or killed (tolerogenic)
-if antigen-specific lymphocytes do not react at all, it is called immunological ignorance
-immune tolerance may be induced when lymphocytes encounter antigens in generative
lymphoid organs, called central tolerance, or in secondary organs, called peripheral tolerance
-central tolerance is only to self-antigens in the bone marrow/thymus, and tolerance for
antigens not in these organs are induced by peripheral mechanisms
-CD4+ T helper cells are strong mediators of tolerance since they react to protein antigens
Central T lymphocyte tolerance – tolerance induced by cell death and generation of Tregs cells
-T cells in thymus have receptors for many antigens (self/foreign), if T cell reacts to self-antigen
displayed on MHC, that T cell triggers apoptosis before maturing (negative selection)
-affects self-reactive CD4 and CD8+ T cells recognizing MHCI and MHC2 molecules
-antigens inducing negative selection may include proteins that are abdundant throughout
body, such as plasma proteins and common cellular proteins
-a protein called AIRE (autoimmune regulator) is responsible for thymic expression of
peripheral tissue antigens
-mutations in AIRE cause autoimmune polyendocrine syndrome, where several
tissue antigens are not expressed in thymus, so immature T cells specific for
these antigens are not eliminated, and attack the antigens in peripheral tissues
-endocrine organs are major targets of this autoimmune attack
-some immature T cells recognizing self-antigens in thymus do not die but develop into
regulatory T cells and enter peripheral tissues
Peripheral T Cell Tolerance – induced when mature T cells recognize self-antigens in peripheral
tissues, leading to functional inactivation (anergy) or death, or suppression by regulatory T cells
-antigen recognition without costimulation results in T cell anergy or death or T reg targets
-signal 1 is always antigen; signal 2 is costimulatory on APCs as part of innate immune response
-without costimulatory signal, there is no immune response, and no autoimmunity results
Anergy – long-lived functional inactivation that occurs when T cells recognize antigens without
adequate co-stimulatory signals needed for full T cell activation
-these cells survive but are incapable of responding to antigen
-best 2 mechanisms of cell-intrinsic unresponsiveness are a block in signaling by TCR complex,
and the delivery of inhibitory signals from receptors other than the TCR complex
1. when T cells recognize antigens without costimulation, TCR complex may lose ability to
transmit activating signals (related to activation of ubiquitin ligases)
2. cells also engage one of inhibitory receptors such as (cytotoxic T cell antigen-4) CTLA-4 or
(programmed death protein 1) PD-1 which function to terminate T cell activation, resulting in T
cell anergy
-T cells recognize the same B7 costimulators that bind both CD28 and CTLA-4 for opposite
responses; choosing between CD28 and CTLA-4 depends on fact that CTLA-4 has higher affinity
for B7 molecules than CD28, so when B7 levels are low (when APCs display self-antigens),
receptor preferentially engaged is CTLA-4
-when B7 levels are high (in infections), CD28 is more engaged
-CTLA-4 functions to block and remove B7 from surface of APC to prevent costimulation of Tcells
Immune Suppression by T Regulatory Cells – Tregs develop in thymus or peripheral tissues on
recognition of self-antigens and block activation of harmful T cells specific for self-antigens
-Tregs express CD4 and high levels of CD25 (Tregs = CD4+/CD25+): CD25= α-chain of IL2 receptor
-development of Tregs requires transcription factor FoxP3, and mutation in FoxP3 causes
multiorgan, systemic autoimmune disease showing importance of Tregs
-human disease known by acronym IPEX: immune dysregulation, polydendocrineopathy,
enteropathy, X-linked syndrome
-survival of Tregs depends on IL-2, and generation depends on expression of TGF-β, which
stimulates FoxP3 transcription
Tregs suppress immune system through several mechanisms:
1. Some Tregs secrete cytokines IL-10, TGF-β to inhibit activation of T cells, macrophages,
and dendritic cells
2. Tregs express CTLA-4 which depletes B7 molecules from APCs = lack of costimulation
3. Tregs express IL-2 receptor may capture this essential T cell growth factor and reduce its
availability for responding T cells
Deletion: Apoptosis of Mature Lymphocytes – recognition of self-antigens triggers apoptotic
pathways resulting in elimination of self-reactive lymphocytes by two likely mechanisms
1. Antigen recognition induces pro-apoptotic proteins in T cells that induce cell death by
mitochondrial pathway, through which leakage out of mitochondria activate caspases;
this process is normally inhibited by anti-apoptotic proteins induced by costimulation.
a. Self antigens do not have costimulation, so anti-apoptotic factors not produced
2. Recognition of self-antigens may lead to coexpression of death receptors and their
ligands, which result in activation of caspases through the DEATH RECEPTOR PATHWAY
a. Best characterized death receptor/ligand pair is Fas (CD95) and Fas ligand (FasL)
expressed on activated T cells. FasL binding to Fas induces death in T and B cells
-Summary: self-antigens present in thymus, where microbes don’t normally migrate, so selfantigens are expressed on APCs without costimulation and innate immunity, favoring T cell
anergy or death, or suppression by Tregs
-microbes elicit 2nd signals and costimulation to promote T cell proliferation
B Cell Tolerance – self-polysaccharides, lipids, and nucleic acids are T-independent antigens not
recognized by T cells and must induce tolerance in B cells to prevent autoantibody production
Central B Cell Tolerance – when immature B cells interact with self-antigens in bone marrow, B
cells change receptor specificity (receptor editing) or are killed (negative selection)
-some B cells that recognize self-antigens in bone marrow may re-express RAG genes, resume Iglight chain recombination, and express a new Ig light chain
-this new light chain associates with previously expressed heavy chain to produce new
antigen receptor no longer specific for self-antigen; called receptor editing
-if editing fails, immature B cells that recognize self antigens with HIGH avidity receive death
signals and die by apoptosis
-if antigens are recognized in bone marrow at LOW avidity, B cells survive but become anergic
Peripheral B Cell Tolerance – mature B cells encountering self-antigens in peripheral lymphoid
tissues become incapable of responding to that antigen
-if B cells recognize antigen and do not receive T cell help, B cells become anergic because of a
block in signaling from antigen receptor
Autoimmunity – defined as immune response against self-antigens
Pathogenesis of Autoimmunity – principle factors in autoimmunity are inheritance of
susceptibility genes and environmental triggers such as infections
-possible that susceptibility genes interfere with pathways of self-tolerance and lead to
persistence of T and B lymphocytes
-can be caused by environmental stimuli
Genetic Factors – inherited risk for most autoimmune diseases is attributable to multiple gene
loci, of which the largest contribution is made by MHC genes
-many autoimmune diseases in humans and inbred animals are linked to particular MHC genes
-association between HLA alleles and autoimmune diseases was first indication that T
cells played an important role in these disorders
-incidence of disease is greater in people with particular HLA allele compared to normal
controls, but HLA is not the sole cause; it requires multiple alleles
-Polymorphisms in non-HLA genes are associated with various autoimmune diseases and may
contribute to failure of self-tolerance or abnormal activation of lymphocytes
-SNPs in tyrosine phosphatase PTPN22 may regulate both B and T activation and are
associated with numerous autoimmune diseases including rheumatoid arthritis, lupus,
diabetes mellitus type 1
-variants in cytoplasmic microbial sensor NOD-2 = reduced resistance to intestinal
microbes and associated with 25% of Crohn’s patients
-other polymorphisms include IL-2 receptor α-chain CD25 believed to influence balance
of effector and regulatory T cells; receptor for cytokine IL-23 (promotes development of
pro-inflammatory Th17 cells); and CTLA-4, key inhibitor in T cells
-some rare disorders are mendelian and only have 1 associated gene: AIRE, FoxP3, Fas
Role of Infections and Other Environmental Influences – infections may activate self-reactive
lymphocytes to trigger autoimmune diseases
-an infection may induce local innate immune response to increase co-stimulator and cytokine
production by tissue APCs
-these activated tissue APCs may be able to stimulate self-reactive T cells that encounter
self-antigens in tissues
-some infectious microbes may have antigens similar to self-antigens, and immune responses
against these antigens would cross-react and attack self-antigens (Molecular Mimicry)
-In rare disorders, Ab produced against microbial protein binds to self-proteins (rheumatic
fever, where Ab against streptococci cross-react with myocardial antigen to cause heart disease)
-Infections may also injure tissues and release antigens normally sequestered from immune
system, such as in testes or eye
-Some infections protect from autoimmunity
-Many autoimmune diseases are more common in women than men
-Local trauma occasionally leads to posttraumatic inflammatory reaction caused by release of
sequestered antigens from testes or eye
-Exposure to sunlight is trigger for development of autoimmune disease Lupus erythematosus in
which autoantibodies are produced against self nucleoproteins