Outline the processes that enable central and peripheral immune tolerance.
- Self-reactive T or B cells are destroyed.
- Central tolerance - destroy self-reactive T or B cells before they enter the circulation.
- Peripheral tolerance - destroy or control any self-readctive T or B cells which do enter the circulation.
Outline how T cells are selected in the thymus.
- T cells don't bind MHC - death by neglect - apoptosis.
- T cells bind MHC too strongly - apoptosis - negative selection.
- T cells bind self-MHC weakly - positive selection - signal to survive.
Explain the 3 different mechanisms of peripheral tolerance.
- Antigen present in too low a concentration to reach the threshold for T cell receptor triggering.
- Immunologically privileged sites - eye, brain.
- Naive T cells need costimulatory signals in order to become activated.
- Most cells lack costimulatory proteins + MHC class II.
- Naive T cells become anergic when they encounter MHC/peptide without costimulatory protein.
- A subset of helper T cells - Treg (T regulatory cells) - inhibit other T cells.
Outline 4 therapeutic strategies used in autoimmune disease.
- Anti-inflammatories - NSAID, corticosteroids.
- T + B cell depletion.
- Therapeutic antibodies - block adhesion.
- Antigen-specific therapies in development - e.g. glatiramer acetate - increases Treg.
Autoimmune diseases mediated by which Ig can cross the placenta? Name 2 examples.
- IgG - small enough to cross the placenta.
- Myasthenia gravis, Graves' disease.
Outline the pathophysiology of Graves' disease.
- Autoantibodies bind to TSH receptor.
- This stimulates excessive TSH production.
- Results in hyperthyroidism.
- Disease can be transferred with IgG antibodies.
Give 4 reasons why self tolerance might break down?
- Loss of/problem with regulatory cells.
- Release of sequestered antigen.
- Modification of self - e.g. citrullination.
- Molecular mimicry - e.g. rheumatic fever - antibodies against streptococcus pyogenes cross-react with cardiac muscle.
Outline the involvement of MHC in autoimmune disease.
- MHC is associated with more disease than any other region of the genome.
- Each copy of chromosome 6 carries 3 different MHC class I and 3 MHC class II genes.
- High levels of genetic variation - polymorphism.
Name 2 examples of organ-specific and systemic autoimmune diseases.
- Organ-specific - Grave's disease, T1DM.
- Systemic - systemic lupus erythematosus (SLE), rheumatoid arthritis.
Outline the mechanisms of T cell damage in autoimmune pathology and give 2 examples of conditions where T cells are implicated.