Immuno: Autoinflammatory and Autoimmune diseases 2

Question 1

Describe the pathophysiology of Graves’ disease

Answer 1

Excessive production of thyroid hormones mediated by IgG antibodies that stimulate the TSH receptor

NOTE: negative feedback does not override the antibody stimulation, it is a type II hypersensitivity

Question 2

Which antibodies is Hashimoto’s thyroiditis associated with?

Answer 2

Anti-TPO antibodies

Anti-thyroglobulin antibodies

NOTE: there can be present in normal people

Question 3

What histological feature have been observed in the pancreas of non-obese diabetic mice?

Answer 3

CD8+ T cell infiltration of the pancreas

The CD8+ T cells bind to peptides presented by MHC Class I

Question 4

List some autoantibodies that are found in type I diabetes mellitus.

Answer 4

• Anti-GAD
• Anti-IA2
• Anti-islet cell
• Anti-insulin

NOTE: the detection of these antibodies does not currently play a part in diagnosis of diabetes mellitus

Question 5

Outline the pathophysiology of pernicious anaemia.

Answer 5

Patients develop antibodies against intrinsic factor which leads to failure of absorption of vitamin B12

Question 6

What is a major complication of vitamin B12 deficiency?

Answer 6

Subacute degeneration of the spinal cord (involving the posteroir and lateral columns)

NOTE: other neurological features include peripheral neuropathy and optic neuropathy

Question 7

Which antibodies are useful in the diagnosis of pernicious anaemia?

Answer 7

Anti-parietal cell antibodies

Anti-intrinsic factor antibodies

Question 8

Outline the pathophysiology of myasthenia gravis.

Answer 8

Patients develop antibodies against nicotinic acetylcholine receptors leading to failure of depolarisation of the motor endplate

Myasthenia gravis is characterised by fluctuating weakness - muscles become progressively weaker during periods of activity and slowly improve after periods of rest

NOTE: neonates of mothers with myasthenia gravis may experience transient neonatal myasthenia

Question 9

Which investigations may be used in the diagnosis of myasthenia gravis?

Answer 9

EMG studies are usually abnormal

Tensilon test - administer very short-acting acetylcholinesterase inhibitor (e.g. edrophonium bromide) which causes a rapid improvement in symptoms.

Question 10

Which antibodies may be present in myasthenia gravis?

Answer 10

Anti-nicotinic acetylcholine receptor antibodies

Question 11

What type of hypersensitivity reaction is myasthenia gravis?

Answer 11

Type II hypersensitivity

Question 12

Outline the pathophysiology of Goodpasture’s syndrome.

Answer 12

Caused by anti-glomerular basement membrane antibodies

Leads to lung and kidney damage

NOTE: antibodies can be detected using fluorescein conjugated anti-human immunoglobulin

Question 13

List some genetic polymorphisms that predispose to rheumatoid arthritis.

Answer 13

• HLA DR1
• HLA DR4
• PTPN22
• PAD 2 and PAD 4 polymorphisms
• Polymorphisms affecting TNF, IL1, IL6 and IL10

Question 14

What is a key common feature amongst HLA alleles that are associated with rheumatoid arthritis?

Answer 14

They share a sequence at position 70-74 of the HLA DR-beta chain (shared epitope)

This enables binding of HLA to arthritogenic peptides (particularly citrullinated peptides)

Question 15

Describe the role of PAD in the pathogenesis of rheumatoid arthritis.

Answer 15

Peptidylarginine deaminases (2 and 4) are involved in the deamination of arginine to form citrulline

Polymorphisms that are associated with increased citrullination leads to a high load of citrullinated peptides

Question 16

List some environmental factors that contribute to the pathogenesis of rheumatoid arthritis

Answer 16

• Smoking is associated with the development of erosive disease (due to increased citrullination)
• Gum infection by Porphyromonas gingivalis is associated with rheumatoid arthritis as it expresses PAD, thereby promoting citrullination

Question 17

Name and describe the antibodies that are often detected in the diagnosis of rheumatoid arthritis.

Answer 17

• Anti-cyclic citrullinated peptide antibodies - bind to peptides where arginine has been converted to citrulline, 95% specific, 60-70% sensitive
• Rheumatoid factor - IgM antibody directed against Fc region of human IgG - less specific than anti-CCP

NOTE: there are IgA and IgG variants of RF

Question 18

Describe B cell involvement in the pathophysiology of rheumatoid arthritis.

Answer 18

• Type II - antibodies bind to citrullinated peptides leading to activation of macrophages, NK cells and complement
• Type III - immune complexes form and get deposited leading to complement activation

Question 19

Outline the roles of T cells in the pathophysiology of rheumatoid arthritis.

Answer 19

APCs present peptides to CD4+ T cells which then produce IFN-gamma and IL17

These cytokines act on fibroblasts and macrophages

This leads to the production of MMPs, IL1 and TNF-alpha

Question 20

What happens to joints affected by rheumatoid arthritis?

Answer 20

• The synovium becomes inflamed forming a pannus
• This invades the articular cartilage and adjacent bone
• There is also an increased synovial fluid volume

Question 21

What are antinuclear antibodies and how are they tested?

Answer 21

Group of antibodies against nuclear proteins - they characterise the connective tissue autoimmune diseases

Tested by staining Hep-2 (human epidermoid cancer line) cells

NOTE: these are very common and are often present in healthy individuals

Question 22

List some genetic defects that may predispose to the development of SLE.

Answer 22

• Abnormalities in clearing apoptotic cells (polymorphisms in complement, MBL and CRP)
• Abnormalities in cellular activation (polymorphisms in genes encoding cytokines, chemokines, co-stimulatory molecules and intracellular signalling molecules)
• B cell hyperactivity and loss of tolerance
• Antibodies directed against particular intracellular proteins (could bind to nuclear or cytoplasmic antigens)

Question 23

Which type of hypersensitivity reaction is SLE?

Answer 23

Type III hypersensitivity - antibodies bind to antigens forming immune complexes which deposit in tissues (e.g. skin, joints, kidneys) and activate complement via the classical pathway

These antibodies can also stimulate cells that express Fc receptors

Question 24

What are the two types of ANA and how can they be distinguished?

Answer 24

• Anti-dsDNA - homogenous staining pattern, they are highly specific for SLE and high titres are associated with severe disease (useful for disease monitoring)
• Anti-ENA4 (extractable nuclear antigens such as ribonucleoproteins (e.g. Ro, La, Sm))

Question 25

Which disease are anti-Ro and anti-La antibodies characteristically found in?

Answer 25

Sjogren's syndrome NOTE: these antibodies are not helpful in monitoring disease activity

Question 26

List autoantibodies that are implicated in systemic sclerosis and idiopathic inflammatory myopathies

Answer 26

* Scl70, RNA polymerase, fibrrilarin - diffuse cutaneous systemic sclerosis * Mi2, SRP - idiopathic inflammatory myopathies

Question 27

Other than anti-dsDNA titre, which other quantifiable component can be measure as a surrogate marker for disease activity in SLE?

Answer 27

C3 and C4 - C4 will decrease before C3 NOTE: levels will be low in severe disease, we measure _unactivated_ complement proteins

Question 28

What triad defines antiphospholipid syndrome?

Answer 28

Recurrent venous or arterial thrombosis Recurrent miscarriage Thrombocytopenia NOTE: this can occur alone or in conjunction with autoimmune disease

Question 29

Which antibodies are tested for in antiphospholipid syndrome?

Answer 29

* Anti-cardiolipin antibody - immunoglobulins directed against phospholipids * Anti-beta2 glycoprotein-1 antibody - antibody specific for glycoprotein found associated with negatively charged phospholipids * Lupus anticoagulant - prolongation of phospholipid-dependent coagulation tests NOTE: lupus anticoagulant cannot be assessed if the patient is on anticoagulant therapy NOTE: all three tests should be performed as 40% of patients have disconcordant antibodies

Question 30

Which cells are particularly important in the pathophysiology of systemic sclerosis?

Answer 30

Th2 and Th17

Question 31

Outline the pathophysiology of systemic sclerosis.

Answer 31

Cytokines released by Th2 and Th17 leads to activation of fibroblasts and the development of fibrosis NOTE: polymorphisms in type I collagen alpha 2 chains, fibrillin 1 and TGF-beta may be implicated Cytokines can also activated endothelial cells and contribute to microvascular disease

Question 32

What are the main features of limited cutaneous systemic sclerosis?

Answer 32

Skin involvement does not extend beyond forearms **C**alcinosis **R**aynaud's phenomenon **E**sophageal dysmotility **S**clerodactyly **T**elangiectasia NOTE: also **pulmonary hypertension**

Question 33

What are the main features of diffuse cutaneous systemic sclerosis?

Answer 33

* Skin involvement extends beyond the forearms * CREST features * More extensive gastrointestinal disease * Interstitial pulmonary disease * Renal cysts

Question 34

Which antibodies are seen in limited and diffuse cutaneous systemic sclerosis?

Answer 34

Limited - anti-centromere Diffuse - anti-topoisomerase 2 (aka anti-Scl70)

Question 35

Describe the differences between the histology of dermatomyositis and polymyositis.

Answer 35

* Dermatomyositis - perivascular CD4+ T cell and B cells are seen, this can cause an immune complex-mediated vasculitis (type III response) * Polymyositis - CD8+ T cells surround HLA Class I expressing myofibres, CD8+ T cells kill these myofibres via granzyme/perforin (type IV response)

Question 36

Which antibodies are seen in dermatomyositis and polymyositis?

Answer 36

* Dermatomyositis: anti-aminoacyl tRNA synthetase (e.g. Jo-1), anti-Mi2 * Polymyositis: anti-aminoacyl tRNA synthetase antibody is cytoplasmic

Question 37

Which classification system is used for systemic vasculitides?

Answer 37

Chapel Hill

Question 38

Which small vessel vasculitides are associated with ANCA?

Answer 38

* Microscopic polyangiitis (pANCA) * Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) (pANCA) * Granulomatosis with polyangiitis (cANCA)

Question 39

Outlie the pathophysiology of ANCA.

Answer 39

* These antibodies are specific to antigens located within primary granules within the cytoplasm of neutrophils * Inflammation may lead to expression of these antigens on the surface of neutrophils * Antibody engagement with these antigens may lead to neutrophil activation (type II hypersensitivity) NOTE: these are different from anti-nuclear antibodies

Question 40

Describe the key difference between cANCA and pANCA.

Answer 40

**pANCA** * Perinuclear staining pattern * Associated with antibodies to myeloperoxidase * Less sensitive and specific than cANCA * Associated with microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis **cANCA** * Cytoplasmic fluorescence * Associated with antibodies against proteinase 3 * Occurs in \>90% of Granulomatosis with polyangiitis patients with renal involvement