Paper I
Question
Pathogenesis of autoimmune diseases
Answer
Autoimmune disease results from a breakdown of self-tolerance, allowing the immune system to mount a damaging response against the body’s own tissues/antigens.
Mechanisms of pathogenesis:
- 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 an infection (e.g., rheumatic fever, where antibodies against streptococcal M protein cross-react with cardiac myosin/valve tissue).
- Release of sequestered (previously hidden) self-antigens — antigens normally hidden from the immune system (in immunologically privileged sites, e.g., lens protein, sperm) 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 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 and rheumatoid arthritis, 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.
Effector mechanisms of tissue damage: autoantibody-mediated damage (Type II hypersensitivity, e.g., anti-TSH-receptor antibody in Graves’ disease), immune-complex deposition (Type III, e.g., SLE), and cell-mediated cytotoxicity (Type IV, e.g., Type 1 diabetes, multiple sclerosis).