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YEAR 5: Immunology SM > Immuno: Autoinflammatory and Autoimmune diseases 2 > Flashcards

Immuno: Autoinflammatory and Autoimmune diseases 2 Flashcards

1
Q

Describe the pathophysiology of Graves’ disease

A

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

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2
Q

Which antibodies is Hashimoto’s thyroiditis associated with?

A

Anti-TPO antibodies

Anti-thyroglobulin antibodies

NOTE: there can be present in normal people

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3
Q

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

A

CD8+ T cell infiltration of the pancreas

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

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4
Q

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

A
  • 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

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5
Q

Outline the pathophysiology of pernicious anaemia.

A

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

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6
Q

What is a major complication of vitamin B12 deficiency?

A

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

NOTE: other neurological features include peripheral neuropathy and optic neuropathy

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7
Q

Which antibodies are useful in the diagnosis of pernicious anaemia?

A

Anti-parietal cell antibodies

Anti-intrinsic factor antibodies

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8
Q

Outline the pathophysiology of myasthenia gravis.

A

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

Myasthenia gravis is characterised by fluctuating weakness

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

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9
Q

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

A

EMG studies are usually abnormal

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

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10
Q

Which antibodies may be present in myasthenia gravis?

A

Anti-acetylcholine receptor antibodies

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11
Q

What type of hypersensitivity reaction is myasthenia gravis?

A

Type II hypersensitivity

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12
Q

Outline the pathophysiology of Goodpasture’s syndrome.

A

Caused by anti-glomerular basement membrane antibodies

Leads to lung and kidney damage

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

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13
Q

List some genetic polymorphisms that predispose to rheumatoid arthritis.

A
  • HLA DR1
  • HLA DR4
  • PTPN22
  • PAD 2 and PAD 4 polymorphisms
  • Polymorphisms affecting TNF, IL1, IL6 and IL10
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14
Q

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

A

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)

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15
Q

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

A

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

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16
Q

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

A
  • 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
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17
Q

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

A
  • 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

NOTE: there are IgA and IgG variants of RF

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18
Q

Describe B cell involvement in the pathophysiology of rheumatoid arthritis.

A
  • 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
19
Q

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

A

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

20
Q

What happens to joints affected by rheumatoid arthritis?

A
  • The synovium becomes inflamed forming a pannus
  • This invades the articular cartilage and adjacent bone
  • There is also an increased synovial fluid volume
21
Q

What are antinuclear antibodies and how are they tested?

A

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

22
Q

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

A
  • 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)
23
Q

Which type of hypersensitivity reaction is SLE?

A

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

24
Q

Describe Antibody dilutions meaning

A

By how much the dilution needs before the antibodies are at a certain level,

ie. higher = more antibodies; 1in x

25
Q

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

A
  • 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))
26
Q

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

A

Sjogren’s syndrome

NOTE: these antibodies are not helpful in monitoring disease activity

27
Q

List some other autoantibodies that are implicated in autoimmune disease

A
  • Scl70, RNA polymerase, fibrrilarin - diffuse cutaneous systemic sclerosis
  • Mi2, SRP - idiopathic inflammatory myopathies
28
Q

Which antibodies are tested for in antiphospholipid syndrome?

A
  • Anti-cardiolipid 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 (in vitro phenomenon), if put in phospholipids, time decrease

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

29
Q

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

A

C3 and C4 - C4 will decrease before C3

C3 down - severe

NOTE: we measure unactivated complement proteins

ESR CRP

CRP can be normal, if high?infection

Screen for Anti phospholipid antibodies

30
Q

What triad defines antiphospholipid syndrome?

A

Recurrent venous or arterial thrombosis

Recurrent miscarriage

Thrombocytopenia

NOTE: this can occur alone or in conjunction with autoimmune disease

31
Q

Pregnant with Systemic sclerosis

A

Anti Ro and anti La can cross the placenta

and influence foetal cardiac conduction = Heartblock

32
Q

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

A

Th2 and Th17

33
Q

Outline the pathophysiology of systemic sclerosis.

A

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

34
Q

What are the main features of limited cutaneous systemic sclerosis?

A

Skin involvement does not extend beyond forearms

Calcinosis

Raynaud’s phenomenon

Esophageal dysmotility

Sclerodactyly

Telangiectasia

NOTE: also pulmonary hypertension

35
Q

What are the main features of diffuse cutaneous systemic sclerosis?

A
  • Skin involvement extends beyond the forearms
  • CREST features
  • More extensive gastrointestinal disease
  • Interstitial pulmonary disease
  • Renal cysts / failure
36
Q

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

A

Limited - anti-centromere

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

37
Q

Describe the differences between the histology of dermatomyositis and polymyositis.

A
  • Dermatomyositis - Skin involvement - heliotrope rash
    wihtin muscle- 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)
38
Q

Which antibodies are seen in dermatomyositis and polymyositis?

A
  • ANA positive (in some patients) - ask for extended myositis panel
  • Dermatomyositis: anti-aminoacyl tRNA synthetase (e.g. Jo-1), anti-Mi2
  • Polymyositis: anti-aminoacyl tRNA synthetase antibody is cytoplasmic
39
Q

ANA positive, how to differentiate between Connective tissue diseases?

A
40
Q

Which classification system is used for systemic vasculitides?

A

Chapel Hill

41
Q

Which small vessel vasculitides are associated with ANCA?

A
  • Microscopic polyangiitis (pANCA)
  • Eosinophililc Granulomatosis with polyangiitis (pANCA)
    aka Churg-Strauss syndrome
  • Granulomatosis with polyangiitis (cANCA)
42
Q

Outlie the pathophysiology of ANCA.

A
  • 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

43
Q

Describe the key difference between cANCA and pANCA.

A

cANCA

  • Cytoplasmic fluorescence
  • Associated with antibodies against proteinase 3
    Occurs in >90% of GPA patients with renal involvement (wegeners)

pANCA

  • Perinuclear staining pattern
  • Associated with antibodies to myeloperoxidase
  • Associated with MPA and EGPA (Churg-Strauss syndrome)
  • Less sensitive and specific than cANCA

YEAR 5: Immunology SM (12 decks)

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