Main pathogenetic mechanisms used to develop and maintain tolerance to self antigens

What are the main pathogenetic mechanisms used to develop and maintain tolerance to self antigens?

Most autoimmune diseases require the presence of self-reactive CD4+ T lymphocytes that have lost their tolerance to self-antigens. Mechanisms to maintain tolerance are:

• Central tolerance.

• Thymic selection of T cells: during this process, the autoimmune regulator, AIRE gene, is responsible for orchestrating intrathymic presentation of self-antigens bound to MHC HLA class I and II molecules. Those T cells that react too strongly with the MHC-self-antigen complexes are deleted (clonal deletion) during negative selection. This is particularly important for such antigens as major blood groups and MHC. T cells capable of reacting to other self-antigens may not be deleted and can gain access to the periphery.

• Receptor-editing of BCRs: this process occurs during B-cell maturation in the bone marrow. B cells that interact too strongly with self-antigens undergo death by apoptosis. To avoid apoptosis, receptor editing modifies the sequence of L-chain (more than H-chain) V and J genes so that the BCR has a different specificity and will not recognize the self-antigen. Some estimate that 20% to 50% of B cells that come from the bone marrow have had receptor editing of their BCR. There is some evidence that TCRs may also undergo receptor editing.

• Peripheral tolerance.

• Clonal anergy: self-reactive T cells that encounter self-antigen presented by HLA molecules in the periphery may not receive necessary second costimulatory signals. These T cells may be tolerized to the antigen and remain unresponsive. This anergic state may be terminated if costimulatory signals are upregulated during a nonspecific infection, tissue injury, or inflammatory state involving the innate immune system.

• Immunologic ignorance: self-reactive T cells may not have a TCR that reacts well enough with the MHC/peptide complex to become activated. This anergic state may be breached if the antigen is changed in some manner such as during an infection.

• Tregs and Bregs: some Tregs suppress self-reactive T cells by cell-to-cell contact of membrane-bound molecules like CTLA-4. Other Tregs are induced and exert suppressive effects by secreting cytokines, IL-10 and TGF-β. Some Bregs (e.g., B10 cells) secrete IL-10.

• Idiotype network theory: a network of antibodies exists naturally or an antiidiotypic antibody directed against the self-reactive antibody idiotype can be generated which are capable of neutralizing self-reactive antibodies.

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