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Immunological Tolerance
- Failure to mount an immune response to a particular antigen
- An active response to a particular epitope and is just as specific as an adaptive immune response
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Two important general properties of immune tolerance are:
- it can be acquired or learned
- immature lymphocytes are more susceptible to tolerance induction mechanisms
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2 forms of immune tolerance:
- Natural or "Self" Tolerance - the failure of the immune system to attack the body's own proteins and other self antigens (GOOD)
- Induced Tolerance - a state of non-responsiveness to external antigens that has been induced by deliberately manipulating the immune system
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Mechanisms for induction of self tolerance
- Central Tolerance - occurs during the developmental stages of lymphocytes; in the bone marrow for B lymphocytes and the thymus for T lymphocytes
- Peripheral Tolerance - generally occurs among lymphocytes outside the primary lymphoid organs after their initial developmental phase
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T Lymphocyte Central Tolerance: Clonal Deletion
- a mechanism for the negative selection of developing T lymphocytes
- is especially important in eliminating self-reactive T cell clones
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T Lymphocyte Peripheral Tolerance: clonal anergy
the functional "silencing" of T lymphocyte clones, without physically deleting them from the T cell repertoire.
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Potential mechanisms for T lymphocyte peripheral tolerance induction:
- lack of costimulation
- failure to encounter self antigens
- resistant to activation-induced cell death (AICD) signals
- T cell regulation
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B Lymphocyte Tolerance: Clonal deletion
most likely occurs in the bone marrow as B cells begin to mature and encounter antigen before they are functionally competent
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B Lymphocyte Tolerance: Clonal Anergy
- Two general mechanisms for the induction of clonal anergy in B cells:
- 1. loss of Ig receptor expression
- 2. persistent Ig receptor expression
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Possible Mechanisms for Immune Regulation
- T cell-mediated regulation - via T regulatory cells
- Idiotypic/Clonotypic regulation - an intricate network of interactions between Ig idiotypes and TCR clonotypes
- Antibody feedback - high levels of antibody of a given specificity can either prevent triggering of an immune response or shut down an ongoing immune response
- Cytokine regulation - can result in either stimulatory or inhibitory effects by cytokines principally from T cells and macrophages
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autoantigen
any "self" or autologous protein that can trigger an immune response
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autoimmunity
the response of the immune system to an autoantigen; results from a breakdown in specific unresponsiveness to "self" antigens known as "self tolerance"
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autoimmune disease
accumulation of the pathologic changes that occur as a result of the adverse effects of an autoimmune response; can be difficult to sort out primary from secondary effects
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How are autoimmune diseases classified?
- one of three types (II, III, IV)
- based on the immunological effector mechanism mediating the disease and similarities in their tissue damaging effects to related hypersensitivity reactions
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Type II autoimmune disease
mediated by antibodies specific for cell surface components or the extracellular matrix
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Type III autoimmune disease
mediated by the formation of immune complexes
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Type IV autoimmune disease
mediated by effector T cells
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Mechanisms of Autoimmunity
What are the 3 main hypotheses concerning the induction and maintenance of self tolerance?
What are the 2 main proposed mechanisms for the "breaking" of self tolerance:
- removal and/or silencing of autoreactive lymphocytes
- antigen-specific T cell regulation
- idiotype/anti-idiotype network interaction
- increased MHC expression on APCs
- antigenic mimicry
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Relative risk
indicates the increased frequency of disease occurrence found in those persons who express the HLA marker of interest compared to those who do not express that particular HLA marker
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What are markers for Type 1 diabetes susceptibility? Why?
- HLA-DR3 and HLA-DR4
- this is because these genes are close in linkage with the HLA-DQbeta genes.
- people heterozygous for DQ2 and DQ8 are most susceptible to type 1 diabetes
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Linkage Disequilibrium
- this results in preferential allele associations due to the inheritance of a particular haplotype
- thus the molecular basis for HLA-DQbeta disease association in IDDM is linked to expression of the DR3 and DR4 allele.
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Other factors implicated in the cause of autoimmune disease:
- antigen mimicry
- virus infection - latent virus infections can lead to later onset of autoimmunity
- altered self components - through modification, degradation of cellular proteins, exposure where they are normally inaccessible
- physiological factors - aging, hormonal influence
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possible causes of tissue damage in autoimmune disease
- antibodies
- complement
- immune complexes
- T lymphocytes
- macrophages
- NK cells
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