58. Autoimmunity

Question 1

Organ-specific autoimmune diseases

Answer 1

• Graves disease – TSH receptors in thyroid

* Type 1 Diabetes – insulin producing cells of the pancreas

Question 2

HLA B27-associated spondyloarthropathies

Answer 2

• Spondyloarthropathies include: Ankylosing spondylitis, undifferentiated spondyloarthropathy, reactive arthritis, psoriatic arthritis, urethritis, iritis
• Spectrum of severity and HLA B27 association
• Associated with bowel inflammation

Question 3

Systemic autoimmune pathologies – Systemic lupus erythematosus (SLE)

Answer 3

Multi-system disease

characterised by autoantibodies to nuclear antigens eg double stranded DNA

It is a disease of relapse and remission

Question 4

What is autoimmunity?

Answer 4

The immune system has various regulatory controls to prevent it from attacking self proteins and cells.

Failure of these controls will result in immune attack of host components – known as autoimmunity.

Question 5

Immune tolerance

Answer 5

• Immune system does not attack self proteins or cells – it is tolerant to them
• CENRAL TOLERANCE – destroy self-reactive T or B cells before they enter the circulation
• PERIPHERAL TOLERANCE – destroy or control any self reactive T or B cells which do enter the circulation

Question 6

Expand on central tolerance

Answer 6

If immature B cells in bone marrow encounter antigen in a form which can crosslink their IgM, apoptosis is triggered

Question 7

T cell receptor and MHC binding

Answer 7

• Need to be able to select for T cell receptors which are capable of binding self MHC

BUT
- If binding to self MHC is too weak, may not be enough to allow signalling when binding to MHC with foreign peptides bound in groove

• If binding to self MHC is too strong, may allow signalling irrespective of whether self or foreign peptide is bound in groove

=> We need to find that intermediate level of affinity.

Question 8

How can a T cell developing in the thymus encounter MHC bearing peptides expressed in other parts of the body?

Answer 8

A specialised transcription factor allows thymic expression of genes that are expressed in peripheral tissues

Question 9

AutoImmune REgulator (AIRE)

Answer 9

Promotes self tolerance by allowing the thymic expression of genes from other tissues

Mutations in AIRE result in multi-organ autoimmunity

(Autoimmune Polyendocrinopathy Syndrome type 1)

Question 10

Peripheral tolerance

Answer 10

1) IGNORANCE
•Antigen may be present in too low a concentration to reach the threshold for T cell receptor triggering

•It could also be because the antigen is present in an immunologically privileged site e.g. eye, brain, where the immune system simply doesn’t go.

2) ANERGY
•If a naive T cell sees it’s MHC/peptide ligand without appropriate costimulatory protein it becomes anergic – i.e. it becomes less likely to be stimulated in the future even if co-stimulation is then present

3) REGULATION
•A subset of helper T cells known as Treg (T regulatory cells) inhibit other T cells ~ by releasing cytokines IL-10 and TGF-β

Question 11

Endocrine factors

Answer 11

• SLE is >10 times more common in females than males
• MS is approximately 10 times more common in females than males
• Diabetes is equally common in females and males
• Ankylosing spondylitis is approximately 3 times more common in males than females

Question 12

What might trigger a breakdown of self tolerance?

Answer 12

• Loss of/problem with regulatory cells
• Release of sequestered antigen (where they are not seen by the immune system)
• Modification of self
• Molecular mimicry

Question 13

Modification of self - Citrullination

Answer 13

• Citrullin is an amino acid, not coded for by DNA
• Arginine can be converted to citrulline as a post-translational modification by peptidylarginine deiminase (PAD) enzymes
• Citrullination may be increased by inflammation
• Autoantibodies to citrullinated proteins seen in rheumatoid arthritis. Now used for clinical diagnosis

Question 14

Molecular mimicry – rheumatic fever

Answer 14

• Disease is triggered by infection with Streptococcus pyogenes
• Antibodies to strep cell wall antigens may crossreact with cardiac muscle, causing a rheumatic fever

Question 15

Examples of antibodies in autoimmune pathology

Answer 15

1) GRAVES DISEASE
•Auto-antibodies bind Thyroid stimulating hormone (TSH) receptor and stimulate it, resulting in hyperthyroidism
•Disease can be transferred with IgG antibodies

2) MYASTHENIA GRAVIS
•Autoantibodies bind to acetylcholine receptor and block the ability of acetyl choline to bind
•Also lead to receptor internalisation and degradation
•Results in muscle weakness

3) IMMUNE COMPLEXES IN SLE AND VASCULITIS
•Autoantibodies to soluble antigens form immune complexes.
•These complexes are deposited in tissues e.g. blood vessels, joints, renal glomerulus.
•This can lead to activation of complement and phagocytic cells.
•Immune complexes depositing in kidney can lead to renal failure.

Question 16

Examples of autoimmune diseases mediated by IgG can be transferred across the placenta

Answer 16

•MYASTHENIA GRAVIS

• autoantibody = anti-AChR
• symptom = muscle weakness

•GRAVES’ DISEASE

• autoantibody = anti-TSHR
• symptom = hyperthyroidism

•THROMBOCYTOPENIC PURPURA

• autoantibody = anti-platelet antibodies
• symptom = bruising and haemorrhage

•NEONATAL LUPUS RASH AND/OR CONGENITAL HEART BLOCK

• autoantibody = anti-Ro and anti-La antibodies
• symptom = photosensitive rash and/or baradycardia

•PEMPHIGUS VULGARIS

• autoantibody = anti-desmoglein-3
• symptom = blistering rash

Question 17

T Cells in autoimmune pathology

Answer 17

•They can kill by:
- Direct killing by CD8+ CTL
- Self-destruction induced by cytokines such as TNFα
•There is also recruitment and activation of macrophages leading to bystander tissue destruction.

• CD4 cells providing help for Ab, and stimulate cytotoxicity against it.
• Multiple sclerosis
• Insulin dependent diabetes mellitus

Question 18

TH17 cells

Answer 18

• Th17 cells are helper T cells that produce the cytokine IL-17
• They are implicated in autoimmune diseases including spondyloarthropathy, MS and diabetes
• Highly inflammatory
• Produce cytokines which are involved in the recruitment, migration and activation of immune cells

Question 19

Therapeutic strategies

Answer 19

• Anti-inflammatories: NSAID, corticosteroids
• T & B cell depletion (RA: anti-CD4, anti-CD20)
• Therapeutic antibodies (anti-TNF; anti-VLA-4 (blocks adhesion of certain cells to endothelium, which would stop inflammation))
• Antigen specific therapies (in development) Glatiramer acetate, increases T-regs.