The Autoimmune Disease

Question 1

Outline the processes that enable central and peripheral immune tolerance.

Answer 1

• 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.

Question 2

Outline how T cells are selected in the thymus.

Answer 2

• 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.

Question 3

Explain the 3 different mechanisms of peripheral tolerance.

Answer 3

Ignorance:

• Antigen present in too low a concentration to reach the threshold for T cell receptor triggering.
• Immunologically privileged sites - eye, brain.

Anergy:

• 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.

Regulation:

• A subset of helper T cells - Treg (T regulatory cells) - inhibit other T cells.

Question 4

Outline 4 therapeutic strategies used in autoimmune disease.

Answer 4

1. Anti-inflammatories - NSAID, corticosteroids.
2. T + B cell depletion.
3. Therapeutic antibodies - block adhesion.
4. Antigen-specific therapies in development - e.g. glatiramer acetate - increases Treg.

Question 5

Autoimmune diseases mediated by which Ig can cross the placenta? Name 2 examples.

Answer 5

• IgG - small enough to cross the placenta.
• Myasthenia gravis, Graves’ disease.

Question 6

Outline the pathophysiology of Graves’ disease.

Answer 6

• Autoantibodies bind to TSH receptor.
• This stimulates excessive TSH production.
• Results in hyperthyroidism.
• Disease can be transferred with IgG antibodies.

Question 7

Give 4 reasons why self tolerance might break down?

Answer 7

1. Loss of/problem with regulatory cells.
2. Release of sequestered antigen.
3. Modification of self - e.g. citrullination.
4. Molecular mimicry - e.g. rheumatic fever - antibodies against streptococcus pyogenes cross-react with cardiac muscle.

Question 8

Outline the involvement of MHC in autoimmune disease.

Answer 8

• 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.

Question 9

Name 2 examples of organ-specific and systemic autoimmune diseases.

Answer 9

• Organ-specific - Grave’s disease, T1DM.
• Systemic - systemic lupus erythematosus (SLE), rheumatoid arthritis.

Question 10

Outline the mechanisms of T cell damage in autoimmune pathology and give 2 examples of conditions where T cells are implicated.

Answer 10

• Direct killing by CD8+ cytotoxic T lymphocytes.
• Self-destruction induced by cytokines e.g. TNF-α.
• Activation of macrophages - bystander tissue destruction.
• Multiple sclerosis, T1DM.