Immuno: Autoinflammatory and Autoimmune diseases 2 Flashcards
Describe the pathophysiology of Graves’ disease
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
Which antibodies is Hashimoto’s thyroiditis associated with?
Anti-TPO antibodies
Anti-thyroglobulin antibodies
NOTE: there can be present in normal people
What histological feature have been observed in the pancreas of non-obese diabetic mice?
CD8+ T cell infiltration of the pancreas
The CD8+ T cells bind to peptides presented by MHC Class I
List some autoantibodies that are found in type I diabetes mellitus.
- 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
Outline the pathophysiology of pernicious anaemia.
Patients develop antibodies against intrinsic factor which leads to failure of absorption of vitamin B12
What is a major complication of vitamin B12 deficiency?
Subacute degeneration of the spinal cord (involving the posteroir and lateral columns)
NOTE: other neurological features include peripheral neuropathy and optic neuropathy
Which antibodies are useful in the diagnosis of pernicious anaemia?
Anti-parietal cell antibodies
Anti-intrinsic factor antibodies
Outline the pathophysiology of myasthenia gravis.
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
Which investigations may be used in the diagnosis of myasthenia gravis?
EMG studies are usually abnormal
Tensilon test - administer very short-acting acetylcholinesterase inhibitor (e.g. edrophonium bromide) which causes a rapid improvement in symptoms.
Which antibodies may be present in myasthenia gravis?
Anti-acetylcholine receptor antibodies
What type of hypersensitivity reaction is myasthenia gravis?
Type II hypersensitivity
Outline the pathophysiology of Goodpasture’s syndrome.
Caused by anti-glomerular basement membrane antibodies
Leads to lung and kidney damage
NOTE: antibodies can be detected using fluorescein conjugated anti-human immunoglobulin
List some genetic polymorphisms that predispose to rheumatoid arthritis.
- HLA DR1
- HLA DR4
- PTPN22
- PAD 2 and PAD 4 polymorphisms
- Polymorphisms affecting TNF, IL1, IL6 and IL10
What is a key common feature amongst HLA alleles that are associated with rheumatoid arthritis?
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)
Describe the role of PAD in the pathogenesis of rheumatoid arthritis.
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
List some environmental factors that contribute to the pathogenesis of rheumatoid arthritis
- 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
Name and describe the antibodies that are often detected in the diagnosis of rheumatoid arthritis.
- 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
Describe B cell involvement in the pathophysiology of rheumatoid arthritis.
- 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
Outline the roles of T cells in the pathophysiology of rheumatoid arthritis.
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
What happens to joints affected by rheumatoid arthritis?
- The synovium becomes inflamed forming a pannus
- This invades the articular cartilage and adjacent bone
- There is also an increased synovial fluid volume
What are antinuclear antibodies and how are they tested?
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
List some genetic defects that may predispose to the development of SLE.
- 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)
Which type of hypersensitivity reaction is SLE?
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
What are the two types of ANA and how can they be distinguished?
- 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))
Which disease are anti-Ro and anti-La antibodies characteristically found in?
Sjogren’s syndrome
NOTE: these antibodies are not helpful in monitoring disease activity
List some other autoantibodies that are implicated in autoimmune disease
Diffuse cutaneous scleroderma
Idiopathic inflammatory myopathies
- Scl70, RNA polymerase, fibrrilarin - diffuse cutaneous systemic sclerosis
- Mi2, SRP - idiopathic inflammatory myopathies
Other than anti-dsDNA titre, which other quantifiable component can be measure as a surrogate marker for disease activity in SLE?
C3 and C4 - C4 will decrease before C3
NOTE: we measure unactivated complement proteins
What triad defines antiphospholipid syndrome?
Recurrent venous or arterial thrombosis
Recurrent miscarriage
Thrombocytopenia
NOTE: this can occur alone or in conjunction with autoimmune disease
Which antibodies are tested for in antiphospholipid syndrome?
- 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
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
Which cells are particularly important in the pathophysiology of systemic sclerosis?
Th2 and Th17
Outline the pathophysiology of systemic sclerosis.
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
What are the main features of limited cutaneous systemic sclerosis?
Skin involvement does not extend beyond forearms
Calcinosis
Raynaud’s phenomenon
Esophageal dysmotility
Sclerodactyly
Telangiectasia
NOTE: also pulmonary hypertension
What are the main features of diffuse cutaneous systemic sclerosis?
- Skin involvement extends beyond the forearms
- CREST features
- More extensive gastrointestinal disease
- Interstitial pulmonary disease
- Renal cysts
Which antibodies are seen in limited and diffuse cutaneous systemic sclerosis?
Limited - anti-centromere
Diffuse - anti-topoisomerase 2 (aka anti-Scl70)
Describe the differences between the histology of dermatomyositis and polymyositis.
- 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)
Which antibodies are seen in dermatomyositis and polymyositis?
- Dermatomyositis: anti-aminoacyl tRNA synthetase (e.g. Jo-1), anti-Mi2
- Polymyositis: anti-aminoacyl tRNA synthetase antibody is cytoplasmic
Which classification system is used for systemic vasculitides?
Chapel Hill
Which small vessel vasculitides are associated with ANCA?
- Microscopic polyangiitis (pANCA)
- Churg-Strauss syndrome (pANCA)
- Granulomatosis with polyangiitis (cANCA)
Outlie the pathophysiology of ANCA.
- 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
Describe the key difference between cANCA and pANCA.
cANCA
- Cytoplasmic fluorescence
- Associated with antibodies against proteinase 3
- Occurs in >90% of Wegener’s patients with renal involvement
pANCA
- Perinuclear staining pattern
- Associated with antibodies to myeloperoxidase
- Less sensitive and specific than cANCA
- Associated with MPA and Churg-Strauss syndrome
