Autoimmunity

Question 1

Autoimmune response?

Answer 1

Response to one or more self antigens in absence of self tolerance, triggering normal immune responses
Because self antigens can’t be cleared, the response is chronic

Question 2

AD stats?

Answer 2

Affect 5-8% of pop
More than 80 types, varied symptoms, targeting many different tissues
Chronic
Rheumatoid arthritis is one of the most common

Question 3

Classifying ADs?

Answer 3

Organ specific e.g. myelin sheath in CNS axons in MS
OR
Systemic - affects multiple tissues where antigens are widespread

Autoimmune haemolytic anaemia can be organ specific, or systemic if combined with SLE

Question 4

Immunological features of ADs

Answer 4

Autoreactive CD4+ Th cells
Auto-antibodies
Cellular infiltrate where T and B cells congregate

Question 5

Pathologies of AD?

Answer 5

Primary - direct immune action e.g. Hashimoto’s - destruction of thyroid organ
Secondary - consequences of primary i.e. Hashimoto’s is hypothyroidism

Question 6

Experimental autoimmune encephalomyelitis?

Answer 6

EAE studied in mice to give model for MS, via T cell disease mechanisms
Mediated by Th17 and Th1 specific for MBP, as transferral of these to a healthy animal induces the disease - therefore cell driven

Question 7

T cell mediated disease mechanisms?

Answer 7

Th17/1/2
Proinflammatory cytokines
Damage epithelial barrier
CD8 cytotoxic action
Macrophages
Inflammatory response
Antibody responses

Question 8

Complement mediated lysis?

Answer 8

e.g. autoimmune haemolytic anaemia

Anti-rbc auto-antibodies binds rbs, fix complement, and generate lysis

Question 9

Opsonisation and phagocytic removal?

Answer 9

e.g. autoimmune thrombocytopenia
Anti-platelet auto antibodies bind platelets
Acts as opsonin -phagocytosis (macrophages bind with FcR)

Question 10

Alteration of function diseases?

Answer 10

Graves Disease - stimulate receptors with agonists
TSH receptor auto antibodies = thyroid hormone overproduction

Myasthenia Gravis - inhibition of function
Auto antibodies block Ach binding/internalise sodium channels so no muscle contraction

Pernicious anaemia - blocking function
Intrinsic factor auto-antibodies block B12 absorption

Question 11

Deposition of immune complexes?

Answer 11

Systemic lupus erythematosus

Deposit in small blood vessel walls throughout body - inflammatory response giving varied symptoms

Question 12

Examples of tolerance failures?

Answer 12

AIRE and FOXP3 mutations

Question 13

Concordance/genetic basis to AD

Answer 13

Twin studies - greater in identical, less than 50%, so both
Most ADs are multigenic, which several contributors
Many of those genes are polymorphic

NOT due to mutations - due to polymorphisms, expressing different alleles

Several genes add up

Question 14

Relative risk?

Answer 14

Extent to which an allele increases susceptibility

Question 15

What do genetic factors affect?

Answer 15

Autoantigen availability and clearance e.g. MHCII
(about 50% of risk)
Apoptosis
Signalling thresholds
Cytokine expression/signalling
Tregs
Sex - often X linked

Question 16

Role of environment in ADs?

Answer 16

Microbial agents i.e. pathogens may resemble self-antigens
Vitamin D (suppress Th17)
Drugs - bind self to make it seem foreign
Toxins
Microbiota/hygiene e.g. microbiome, lack of exposure

Infections - Epstein Barr virus interacts with gene loci associated with AD

Question 17

Loss of self-tolerance mechanisms?

Answer 17

Bypassing T helpers

Tolerance loss

Question 18

Bypassing Ths?

Answer 18

B cells mitogens stimulate auto-antibody production
e.g. bacterial products like LPS can stimulate plasma differentiation
Not antigen specific - any B cell
Transient - lost when mitogen leaves

Question 19

Tolerance loss?

Answer 19

Where pathogens and self antigens are similar: With microbe, B cells that can act on self are stimulated with T help, as the shared novel epitope recruits them
e.g. rheumatic fever

OR
Drug induced/chemical induced changes:
Drug/chemical binds self-antigen and modifies it to give a foreign T cell epitope
Should be transient with presence of drug, but may become chronic in susceptible individuals: positive feedback loop with non-clearance of self-antigens, epitope spreading = broader response