Autoimmune diseases 1

Question 1

What are autoimmune diseases?

Answer 1

Adaptive immune responses to self-antigens contribute to tissue damage. represents failure of tolerance.

Question 2

What are the consequences of positive and negative selection?

Answer 2

Positive selection -> ensures receptors useful

Negative selection -> reduces auto reactivity

Question 3

Why is the adaptive immune system prone to autoimmunity?

Answer 3

Negative selection -> some potentially auto-reactive T cells inevitably produced -> peripheral tolerance mechanisms.
Compromise:
Rigorous -> low risk of autoimmunity, poor repertoire,
increased susceptibility to infection.
Permissive -> broad repertoire, lower risk of infection,
higher risk of autoimmunity.

Question 4

What are the peripheral tolerance mechanisms?

Answer 4

Immunological hierarchy -> CD4 T cell won’t be activated unless antigen is presented in ‘inflammatory’ context with TLR ligation.
Antigen segregation -> physical barriers to sequestered antigen (‘immunological privilege’).
Peripheral anergy -> weak signalling between APC/ CD4 T cell without co-stimulation causes T cells to become non-responsive.
Regulatory T cells -> CD25+FoxP3 positive T cells + other types of regulatory T cells actively suppress immune responses by cytokine + juxtacrine signalling.
Cytokine deviation -> change in T cell phenotype eg Th1 to Th2 may reduce inflammation
Clonal exhaustion -> apoptosis post-activation by activation-induced cell death

Question 5

What may failure of peripheral tolerance mechanisms allow?

Answer 5

Activation of potentially auto-reactive T cells -> development of autoimmune disease

Question 6

Give examples of organ-specific autoimmune diseases?

Answer 6

Type 1 DM, pemphigus, pemphigoid, Graves disease
Hashimotos thyroiditis, autoimmune cytopenias ->
anaemia, thrombocytopenia.

Question 7

Give examples of multi-system autoimmune diseases?

Answer 7

Systemic lupus erythematosis, rheumatoid arthritis,

Sjogrens syndrome

Question 8

What is the type II hypersensitivity classification of AID and it’s criteria?

Answer 8

Autoantibodies.
Diseases where antibody is clearly pathogenic -> causes disease / tissue damage directly.
Can be transferred between experimental animals by infusion of serum or during gestation -> problems in foetus / neonate.
Removal of antibody by plasmapharesis is beneficial.
Pathogenic antibody can be identified + characterised.

Question 9

What are the sequence of events that lead to autoimmune cytopenias?

Answer 9

RBCs + anti-RBC autoantibodies ->
FCR+ cells in fixed mononuclear phagocytic system -> phagocytosis + RBC destruction -> autoimmune haemolytic anaemia /
Complement activation + intravascular haemolysis -> lysis + RBC destruction -> autoimmune thrombocytopaenia

Question 10

What are the characteristics of the antibody-mediated Graves’ disease?

Answer 10

Neonatal hyperthyroidism if mother is affected
Serum transfers disease between experimental animals
Antibody detected + characterised

Question 11

What are the sequence of events that lead to Graves’ disease?

Answer 11

Pituitary secretes TSH -> TH release -> acts on pituitary to shut production of TSH -> suppresses further TH synthesis.
Autoimmune B cell makes antibodies against TSH receptor -> stimulates TH production -> shuts down TSH production, no effect on autoantibody production which continues to cause excessive TH production.

Question 12

What are the signs and symptoms of myasthenia gravis?

Answer 12

Muscle weakness + fatiguability.
Eyelids, facial muscles, chewing, talking + swallowing most often affected
Ptosis at rest, becomes worse after patient closes + opens eyes repeatedly.

Question 13

How does myasthenia gravis affect the neuromuscular junction?

Answer 13

ACh internalised + degraded, no Na influx -> no muscle contraction

Question 14

What causes spontaneous urticaria?

Answer 14

IgG FcεR1 antibody cross-links mast cell receptor causing degranulation -> hives + swelling

Question 15

What is the type IV hypersensitivity classification of AID and it’s criteria?

Answer 15

T cells
Tissue damage directly mediated by T cell-dependent mechanisms.
T cells activate macrophages + other elements of innate immunity.
CD8 T cells damage tissue directly.
Much more difficult to demonstrate auto-reactive T cells in vitro.
Experimental models rely on genetically susceptible animals that are sensitised by exposure to self-antigen with adjuvant.

Question 16

What are the T cell mediated autoimmunity diseases?

Answer 16

Autoimmune hypothyroidism (Hashimotos thyroiditis).
Commonest cause of hypothyroidism in industrialised countries, esp. women >30.
Autoimmune destruction of thyroid -> organ infiltrated by CD4 + CD8 T cells.
Coeliac + T1 DM

Question 17

What are the features of the monogenic disorder APACED?

Answer 17

Autoimmune polyglandular syndrome
candidiasis + ectodermal dystrophy
AIRE gene regulates ectopic expression of tissue-specific antigens in thymus.
AIRE mutations -> failure of negative selection. associated with organ-specific autoimmune diseases (T1DM, vitiligo, alopecia, autoimmune adrenal disease etc).
Candidiasis is key feature.
Due to antibodies to IL-17 –> important cytokine in host defence against fungi at mucosal surfaces.

Question 18

What are the features of the monogenic disorder -DiGeorge syndrome?

Answer 18

Failure migration 3th/ 4th branchial arches.
Full phenotype: absent parathyroids (low calcium, tetany),
cleft palate, congenital heart defects, thymic aplasia (low T cell numbers, immunodeficiency), micro-deletions, chromosome 22, variable presentation -> huge spectrum of immunodeficiency from mild-SCID-like, autoimmunity is common.

Question 19

What are the features of the monogenic disorder - IPEX?

Answer 19

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (mutation). exceedingly rare -> (FoxP3) gene.
Abrogates production of CD4, CD25, FoxP3+, regulatory T cells.
Inflammatory bowel disease, dermatitis, organ-specific autoimmunity.

Question 20

Outline the HLA system

Answer 20

APCs present processed peptide to T cells in combination with highly polymorphic MHC (HLA) molecules.
Encoded by HLA system on chromosome 6:
Class I: A, B, C
Class II: DR, DP and DQ
Strong association between expression of HLA + some autoimmune diseases.

Question 21

What are the features of coeliac disease?

Answer 21

Very common inflammatory disease of small bowel with GI + extra-GI features.
More common in women.
Characteristics of autoimmune disease, but unusually triggered by exogenous antigen (gluten) if pre-disposed.
Malabsorption -> loose stool, weight loss, vitamin deficiency, anaemia, poor growth in children.
Total villous atrophy, crypt hyperplasia + lymphocyte infiltration in advanced disease.

Question 22

Which antigen triggers coeliac disease and what do affected patients express?

Answer 22

Dietary gliadin (wheat, rye + barley) degraded by gut tissue transglutamine 2 enzyme during digestion -> gliadin peptides -> fits inside groove of DQ2.
HLA DQ2/ 8 molecules can present these peptides to T cells if appropriate T cell receptors are present
HLA-DQ2, HLA-DQ8 or both.

Question 23

Outline the pathogenesis of coeliac disease

Answer 23

Damage is mediated by T cells, antibodies produced but don’t contribute to tissue damage.
Inflammation resolves with strict gluten avoidance.