12. Autoimmune diseases 1

Question 1

Autoimmunity

Answer 1

= immune responses to self-antigens; can lead to autoimmune disease

failure of tolerance

Question 2

Tolerance

Answer 2

a state of immunological non-reactivity to an antigen

Question 3

what are autoimmune diseases?

Answer 3

adaptive immune responses to self-antigens leading to tissue damage

Question 4

Selection of adaptive immune lymphocytes

Answer 4

Gene segments randomly give repertoir

Then positive selection (to ensure receptors are useful) and negative selection (to reduce autoreactivity) to generate naive B and T cell receptors (small number of cells for each antigen, lots of receptors overall)

clonal expansion of best populations after infection

resolution of infection then death or memory cells

Question 5

Permissive negative selection result

Answer 5

Broad repertoire
Lower risk of infection
Higher risk of autoimmunity

Question 6

Rigorous negative selection result

Answer 6

Low risk of autoimmunity
Poor repertoire
Increased susceptibility to infection

Question 7

Negative selection ideal outcome

Answer 7

peripheral tolerance, but some potentially autoreactive T cells inevitable produced

Question 8

Peripheral tolerance mechanisms

Answer 8

Immunological hierarchy
Antigen segregation
Peripheral anergy
Regulatory T cells
Cytokine deviation
Clonal exhaustion

Failure of peripheral tolerance mechanisms may allow activation of potentially
Auto-reactive T cells, leading to the development of autoimmune disease

Question 9

Immunological hierarchy

Answer 9

CD4 T cell will not be activated unless antigen is presented in an ‘inflammatory’ context with TLR ligation

Question 10

Antigen segregation

Answer 10

Physical barriers to sequestered antigen (‘immunological privilege’)

Question 11

Peripheral anergy

Answer 11

Weak signalling between APC/ CD4 T cell without co-stimulation causes T cells to become non-responsive

Question 12

Regulatory T cells

Answer 12

CD25+FoxP3 positive T cells and other types of regulatory T cells actively suppress immune responses by cytokine and juxtacrine signalling

Question 13

Cytokine deviation

Answer 13

Change in T cell phenotype eg Th1 to Th2 may reduce inflammation

Question 14

Clonal exhaustion

Answer 14

Apoptosis post-activation by activation-induced cell death

Question 15

Autoantibodies: a pathogenic mechanism in AID

Answer 15

Gell and Coombes Type II hypersensitivity

Diseases where an antibody is clearly pathogenic and disease/ tissue damage directly

Criteria:

• Disease can be transferred between experimental animals by infusion of serum, or during gestation to cause problems in fetus/ neonate
• Removal of antibody by plasmapharesis is beneficial
• A pathogenic antibody can be identified and characterised

Question 16

Autoimmune cytopenias

Answer 16

E.g. autoimmune haemolytic anaemia
Red blood cells plus anti-RBC autoantibodies leads to:
- FcR+ cells in fixed mononuclear phagocytic system -> phagocytosis and RBC destruction
-Complement activation and intravascular haemolysis -> lysis and RBC destruction

Autoimmune thrombocytopaenia

Question 17

Autoimmune hyperthyroidism aka Graves Disease

Answer 17

Symptoms: tachycardia, palpitations, tremor, anxiety, heat intolerance etc
Goitre
Grave’s ophthalmopathy due to poorly-understood retro-orbital inflammation

Has all the characteristics of an antibody-mediated disease:

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

Question 18

Grave’s thyroiditis pathophysiology

Answer 18

Pituitary gland secretes TSH which acts on thyroid to induce release of TH, which act on pituitary in neg feedback to shutdown production of TSH to stop more TH

Autoimmune B cell makes antibodies against TSH receptor that also stimulate TH production, TH shuts down TSH production but no effect on autoantibody production, so continues to cause excess TH production

Question 19

Antibody-mediated autoimmune disease: myasthenia gravis

Answer 19

Muscle weakness and fatigability

Eyelids, facial muscles, chewing, talking and swallowing most often affected

Question 20

Myasthenia gravis pathophysiology

Answer 20

normally ACh binds to AChR leading to Na+ influx causes muscle contraction

In MG: autoantibodies to AChR bind them leading to AChR internalised and degraded, and no Na+ influx and no muscle contraction

Question 21

Spontaneous urticaria

Answer 21

IgG FcεR1 antibody cross-links mast cell receptor causing degranulation. Manifests with hives and swelling

Question 22

Pathogenic mechanisms in AID: T cells

Answer 22

Gell and Coombes Type IV hypersensitivity

Tissue damage is directly mediated by T cell-dependent mechanisms:

• T cells activate macrophages and other elements of innate immunity:
• CD8 T cells damage tissue directly

Much more difficult to demonstrate autoreactive T cells in vitro than it is to demonstrate antibody

Experimental models rely on genetically susceptible animals that are sensitised, often by exposure to a self-antigen with an adjuvant

Question 23

T cell-mediated autoimmunity: autoimmune hypothyroidism (Hashimotos thyroiditis)

Answer 23

Commonest cause of hypothyroidism in industrialised countries
Particularly women over 30
Autoimmune destruction of thyroid: organ infiltrated by CD4 and CD8 T cells

Question 24

Classification of AID with a few examples

Answer 24

Organ specific:
Type 1 diabetes mellitus
Pemphigus, pemphigoid
Graves disease
Hashimotos thyroiditis
Autoimmune cytopenias:
anaemia, thrombocytopenia

Non-organ specific: systemic lupus erythematosis, rheumatoid arthritis

Question 25

Do autoimmune diseases have one main pathogenic immune mechanism?

Answer 25

No, Multiple pathogenic immune mechanisms underlie autoimmune diseases need T cells, B cells and APCs This is particularly true of the chronic, multi-system autoimmune disorders such as rheumatoid arthritis (see symposium) and SLE, where multiple immune mechanisms become involved

Question 26

Genetics and autoimmunity

Answer 26

Evidence for importance: - Rare monogenic disorders of the immune system that are associated with autoimmune diseases - Mouse models rely on genetically susceptible strains eg NOD mouse - Enrichment in families, mostly attributable to HLA associations Environment clearly also important

Question 27

What is APACED?

Answer 27

A monogenic disorder leading to autoimmunity stands for autoimmune polyglandular syndrome, candidiasis and ectodermal dystrophy Caused by AIRE mutations resulting in failure of negative selection AIRE gene normally regulates ectopic expression of tissue-specific antigens in thymus APACED Strongly associated with organ-specific autoimmune diseases e.g. T1DM vitiligo, alopecia, autoimmune adrenal disease etc) Candidiasis also a key feature of the disease due to IL-17 autoantibodies which stops fungi at mucosa

Question 28

DiGeorge Syndrome

Answer 28

Failure migration 3th/ 4th branchial arches due to microdeletions chromosome 22 ``` Full phenotype: Absent parathyroids (low calcium, tetany) Cleft palate Congenital heart defects Thymic aplasia (low T cell numbers, immunodeficiency) ``` Variable presentation - May affect any of above in isolation - Huge spectrum of immunodeficiency from mild-SCID-like - Autoimmunity is also common

Question 29

IPEX

Answer 29

Monogenic disorder leading to autoimmunity immune dysregulation, polyendocrinopathy, enteropathy, X-Linked Exceedingly rare X Linked mutation affecting Forkhead p3 (FoxP3) gene Abrogates production of CD4+CD25+FoxP3+ regulatory T cells Key features: - Inflammatory bowel disease - Dermatitis - Organ-specific autoimmunity

Question 30

Monogenic disorders and autoimmunity: classical complement deficiency

Answer 30

Immune complexes are cleared by phagocytes; process enhanced by phagocyte Fc receptors and C3b receptors Deficiency of C1q/ C2/ C4 predispose to lupus, because immune complexes cannot be cleared effectively Can also suffer from recurrent bacterial infections

Question 31

The HLA system

Answer 31

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

Question 32

What does HLA B27 and HLA DR2 mean

Answer 32

HLA B27=expresses serotype 27 at B locus of HLA class I HLA DR2=expresses serotype 2 at locus 2 of HLA class II

Question 33

Coeliac disease

Answer 33

A very common inflammatory disease of the small bowel with gastrointestinal and extra-gastrointestinal features - <1% UK population affected - More common in women - Majority undiagnosed Characteristics of an autoimmune disease, but unusually triggered by an exogenous antigen (gluten) in pre-disposed individuals Main manifestations are malabsorption (loose stool, weight loss, vitamin deficiency, anaemia, poor growth in children) but myriad others now recognised

Question 34

Coeliac disease 2 histology and genetics

Answer 34

Total villous atrophy crypt hyperplasia lymphocyte infiltration in advanced disease Virtually all affected individuals express: HLA-DQ2 HLA-DQ8 .........or both

Question 35

Link between HLA and coeliac

Answer 35

Dietary gliadin (wheat, rye and barley) is degraded by gut tissue transglutamine 2 enzyme during digestion to produce gliadin peptides HLA DQ2/ 8 molecules can present these gliadin peptides to T cells if the appropriate T cell receptors are present

Question 36

Coeliac pathogenesis

Answer 36

Damage is mediated by T cells; antibodies are produced but don't contribute to tissue damage Inflammation resolves with strict gluten avoidance 30-50% of Europeans express HLA-DQ2 and/ or HLA-DQ8 – not clear which additional genetic/ environmental factors are important in coeliac