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review Im > 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-thyroid peroxidase (TPO) antibodies

Anti-thyroglobulin antibodies

NOTE: there can be present in normal people

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3
Q

Which Gel and Coombs class is T1DM

A

Type IV hypersensitivity - CD8 T cell mediated destruction of pancreatic islet cells

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4
Q

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

A
  • Anti-glutamic acid dehydrogenase (GAD)
  • Anti-islet antigen (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

Autoimmune destruction of gastric parietal cells leading to vitamin B12 deficiency

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6
Q

What is a major complication of vitamin B12 deficiency?

A
  • Subacute degeneration of the spinal cord (involving the posterior and lateral columns)
  • Megaloblastic anaemia

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

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9
Q

What are some characteristic symptoms of myasthenia gravis?

A

Progessive muscle weakness following repetitive activity

  • Drooping eyelids, double vision
  • Dysarthria, dysphasia
  • Proximal muscle weakness

Symptoms worse at the end of the day

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10
Q

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

A
  • Anti-nAchR antibodies in blood
  • EMG studies are usually abnormal
  • Tensilon test - administer very short-acting acetylcholinesterase inhibitor which causes a rapid improvement in symptoms (rarely used)
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11
Q

Outline the pathophysiology of Goodpasture’s syndrome.

A

Caused by anti-glomerular basement membrane antibodies (specifically binidng to collagen type IV)

Leads to lung and kidney damage

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12
Q

What are typical symptoms of Goodpasture disease

A
  • Lungs - SoB, haemotypsis, widespread crackes
  • Kidneys - haematuria, oedema, reduced urine output, hypertension
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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 peptidylarginine deiminases (PAD) in the pathogenesis of rheumatoid arthritis.

A

Peptidylarginine deiminases (2 and 4) are involved in the deimination 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 - expresses PAD thus increasing 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
    • Best diagnostic test
  • 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

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
19
Q

What are antinuclear antibodies and how are they tested?

A

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

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

20
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)
    • Leads to antigen persistance
  • Abnormalities in cellular activation (polymorphisms in genes encoding cytokines, chemokines, co-stimulatory molecules and intracellular signalling molecules)
    • Leads to B cell hyperactivity and loss of tolerance

Both of the above promote the creation of antibodies directed against particular intracellular proteins (could bind to nuclear or cytoplasmic antigens)

21
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

22
Q

What is antibody titre?

A

The titre value represents the highest dilution of the patient’s serum at which the antibodies can still be detected. For example, if a person has an antibody titer of 1:320, it means that their blood can be diluted 320 times and still show a measurable level of antibodies.

minimal dilution at which the antibody can be detected

23
Q

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

A
  • Anti-dsDNA - highly specific for SLE (used diagnostically and for disease monitoring)
  • Anti-ENA (extractable nuclear antigens) - ribonucleoproteins (e.g. Ro, La, Sm), Scl-70, centromere
24
Q

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

A
  • Complement proteins C3 and C4 (will be low)
  • ESR, CRP
25
Q

Describe the difference in immunofluorescence patterns between dsDNA and ENA antigens

A
  • anti-dsDNA creates homogenous
  • anti-ENA creates speckled patterns
26
Q

What are some clincial features of anti-phospholipid syndrome

A

Triad

  • recurrent arterial or venous thrombosis
  • recurrent miscarriages
  • thrombocytopenia

Livedo reticularis on skin

Can occur alone or secondary to SLE

27
Q

Which antibodies are tested for in antiphospholipid syndrome?

A
  • Anti-cardiolipin - immunoglobulins directed against phospholipids (also positive in syphilis)
  • Anti-beta2 glycoprotein-1 - antibody specific for glycoprotein found associated with negatively charged phospholipids
  • Lupus anticoagulant - prolongation of phospholipid-dependent coagulation tests (in vitro phenomenon)

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

28
Q

What is the pathophysiology of Sjorgren’s syndrome?

A

Autoimmune destruction of exocrine glands

29
Q

What autoantibodies are positive in Sjogren’s?

A

Anti-Ro and Anti-La

30
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

31
Q

What are the main features of limited cutaneous systemic sclerosis?

A

Calcinosis

Raynaud’s phenomenon

Esophageal dysmotility

Sclerodactyly

Telangiectasia

NOTE: also pulmonary hypertension

32
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
33
Q

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

A

Limited - anti-centromere

Diffuse - anti-topoisomerase (aka anti-Scl70)

34
Q

Describe the differences between the histology of dermatomyositis and polymyositis.

A
  • 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)
35
Q

What are some cutaneous features of dermatomyositis

A
  • Heliotrope rash
  • Gottron papules
  • Photosensitivity
36
Q

What are some diagnostic investigations in inflammatory myopathies

A
  • Bloods
    • Raised CK
    • ANA
  • EMG
  • Muscle biopsy (gold standard)
37
Q

What key symptoms differentiates inflammatory myopathies from PMR

A

Muscle weakness only present in inflammatory myopathies not PMR

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

If ANA is positive, which ANA subtypes indicate which type of disease

A
40
Q

Which classification system is used for systemic vasculitides?

A

Chapel Hill

41
Q

What does ANCA stand for

A

Anti-neutrophil cytoplasmic antibodies

42
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)
43
Q

Outlie the pathophysiology of ANCA.

A
  • These antibodies are specific to antigens located 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

44
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

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