Paper I
Question
Discuss various mechanisms of autoimmunity.
Answer
Mechanisms of autoimmunity — breakdown of self-tolerance allowing the immune system to attack the body’s own tissues:
- 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, where antibodies against streptococcal M protein cross-react with cardiac tissue).
- Release of sequestered (hidden) self-antigens — antigens normally hidden from the immune system in immunologically privileged sites (eye, testis) are released into circulation following trauma/infection, triggering a response since the immune system was never tolerized to them.
- Polyclonal B-cell activation — certain infections/superantigens can 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, HLA-B27 with ankylosing spondylitis) and polymorphisms in immune-regulatory genes.
- Defective regulatory T-cell function — reduced number/function of Tregs fails to adequately suppress autoreactive effector lymphocytes.
- Epitope spreading — an initially restricted immune response against one self-epitope broadens over time to target additional epitopes on the same or related self-molecules, amplifying tissue damage.
- Hormonal and environmental factors — the female preponderance of many autoimmune diseases suggests a hormonal influence; environmental triggers (infection, UV light, drugs) can precipitate disease in genetically susceptible individuals.