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.