Paper I
Question
Mention mechanisms of autoimmunity
Answer
Autoimmunity results from a breakdown of self-tolerance, allowing the immune system to attack the body’s own tissues. Proposed mechanisms include:
- Failure of central/peripheral tolerance — defective clonal deletion of self-reactive T/B cells in the thymus/bone marrow, or failure of peripheral control mechanisms (anergy, regulatory T-cell suppression), allows autoreactive lymphocyte clones to persist and become activated.
- Molecular mimicry — structural similarity between a microbial antigen and a self-antigen leads to cross-reactive immune responses against self-tissue following infection (e.g., rheumatic fever — antibodies against streptococcal M protein cross-react with cardiac tissue).
- Release of sequestered (hidden) self-antigens — antigens normally hidden from the immune system (immunologically privileged sites) are released into circulation following trauma/infection, triggering a response since the immune system was never tolerized to them (e.g., sympathetic ophthalmia).
- Polyclonal B-cell activation — certain infections/superantigens non-specifically activate B cells, including autoreactive clones, bypassing normal T-cell-help checkpoints.
- Genetic susceptibility — strong association with particular HLA alleles (e.g., HLA-DR3/DR4 with Type 1 diabetes, rheumatoid arthritis) and immune-regulatory gene polymorphisms.
- Defective regulatory T-cell function — reduced number/function of Tregs fails to adequately suppress autoreactive effector lymphocytes.
- Epitope spreading — an initially restricted response against one self-epitope broadens over time to target additional epitopes, amplifying tissue damage.
- Environmental/hormonal factors — infection, UV light, and drugs can precipitate disease in genetically susceptible individuals; the female preponderance of many autoimmune diseases suggests a hormonal influence.