Autoimmune diseases 1

Question 1

Autoimmunity

Answer 1

Immune response to self antigens

Question 2

Autoimmune diseases

Answer 2

Adaptive immune responses to self antigens contribute to tissue damage

Question 3

Tolerance

Answer 3

A state of immunological non-reactivity to an antigen

Question 4

Immunological hierarchy

Answer 4

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

Question 5

Antigen segregation

Answer 5

Physical barriers to sequestered antigen (immunological privilege)

Question 6

Peripheral anergy

Answer 6

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

Question 7

Regulatory T cells

Answer 7

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

Question 8

Cytokine deviation

Answer 8

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

Question 9

Clonal exhaustion

Answer 9

Apoptosis post activation by activation induced cell death

Question 10

Organ specific autoimmune diseases

Answer 10

Type 1 diabetes mellitus

Pemphigus, pemphigoid

Graves disease

Hashimotos thyroiditis

Autoimmune cytopenias: anaemia, thrombocytopenia

Question 11

Non-organ specific autoimmune diseases

Answer 11

Systemic lupus erythematosis

Rheumatoid arthritis

Question 12

Type II hypersensitivity

Answer 12

Antibody is clearly pathogenic

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 a
identified and characterised

Question 13

Autoimmune hyperthyroidism (Graves disease)

Answer 13

Symptoms of hyperthyroidism (tachycardia, palpitations, tremor, anxiety, heat intolerance)

Goitre

Grave’s opthalmopathy due to poorly understood retre-orbital inflammation

All the characterisitcs of an antibody mediated disease

• neonatal hyperthyroidism if mother is affected
• serum transfers disease between experimental animals
• antibody detected and characterised

Question 14

Grave’s thyroiditis

Answer 14

Pituitary gland secretes thyroid stimulating hormones, which acts on the thyroid to induce the release of thyroid hormones

Thyroid hormones act on the pituitary to shut down production of TSH, suppressing further thyroid hormone synthesis

Autoimmune B cells make antibodies against TSH receptor that also stimulate thyroid hormone production

Thyroid hormones shut down TSH production

Thyroid hormones shut down TSH production but have no effect on autoantibody production, which continues to cause excessive thyroid hormone production

Question 15

Myasthenia gravis

Answer 15

Muscle weakness and fatigability

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

Ptosis at rest, becoming markedly worse after patient asked to close and open eyes repeatedly

Question 16

Myasthenia gravis: neuromuscular junction

Answer 16

Acetylcholine receptors internalised and degraded

No Na+ influx, no muscle contraction

Question 17

Spontaneous urticaria

Answer 17

IgG FcεR1 antibody cross links mast cell receptor causing degranulation

Manifests with hives and swelling

Question 18

Type IV hypersensitivity

Answer 18

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 19

T cell mediated autoimmunity: autoimmune hypothyroidism (Hashimotos thyroiditis)

Answer 19

Commonest cause of hypothyroidism in industrialised countries

Particularly women over 30

Autoimmune destruction of thyroid: organ infiltrated by CD4 and CD8 T cells

Question 20

Other predominantly T cell mediated autoimmune diseases

Answer 20

Coeliac

Type 1 diabetes mellitus

Question 21

Monogenic disorders and autoimmunity: APACED (autoimmune polyglandular syndrome, candidiasis and ectodermal dystrophy)

Answer 21

AIRE gene regulates ectopic expression of tissue specific antigens in thymus

AIRE mutations result in failure of negative selection

Strongly associated with organ specific autoimmune disease

Candidiasis also a key feature

Question 22

DiGeorge syndrome

Answer 22

Failure migration 3rd/ 4th branchial arches

Full phenotype:

• absent parathyroids (low calcium, tetany)
• cleft palate
• congenital heart defects
• thymic aplasia

Microdeletion chromosomes 22

Variable presentation

Question 23

Monogenic disorders and autoimmunity: IPEX (immune dysregulation, polyendorcrinopathy, enteropathy, X linked)

Answer 23

Exceedingly rare X linked mutation affecting Forkhead p3 gene

Abrogates production of CD4 and CD25 and FoxP3 regulatory T cells

Key features

• inflammatory bowel disease
• dermatitis
• organ specific autoimmunity

Question 24

Monogenic disorders and autoimmunity: classical complement deficiency

Answer 24

Immune complexes are cleared by phagocytes; process enhanced by pagocyte Fc receptors and C3b receptors

Deficiency of C1q/C2/C4 predispose to lupus, preseumably because immune complexes cannot be cleared effectively

In addition to lupus, some patients may suffer from recurrent bacterial infections

Question 25

The HLA system

Answer 25

APCs present processed peptide to T cells in combination with highly polymorphic MHC molecules

Encoded by HLA system on chromosome 6

• class I: A, B, C
• class II: DR, DP and DQ

Complex nomenclature used to describe tissue type in an individual

Strong association between the expression of HLA molecules and some autoimmune diseases

Question 26

Coeliac disease

Answer 26

A very common inflammatory disease of the small bowel with GI and extra-GI features

• up to 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 27

Coeliac disease microscopy

Answer 27

Total villous atrophy

Crypt hyperplasia

Lymphocyte infiltration in advanced disease

Virtually all affected individuals express

• HLA-DQ2
• HLA-DQ8

Question 28

HLA and coeliac

Answer 28

Dietary gliadin 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 29

Coeliac pathogenesis

Answer 29

The damage is mediated by T cells; note that antibodies are produced, but do not 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