Immuno 11: Autoinflammatory and AI disease 2 Flashcards
Name the autoantigen in the following diseases: Goodpastures disease Pemphigus vulgaris Graves Myasthenia gravis
Goodpasture’s disease
Non-collagenous domain of basement membrane collagen IV
Pemphigus vulgaris
Epidermal cadherin
Graves’ disease
TSH receptor
Myasthenia gravis
Nicotinic acetylcholine receptor
What is the autoantigen in:
SLE
Rheumatoid arthritis
SLE:
DNA
Histones
RNP
Rheumatoid arthritis:
Fc portion of IgG
Describe the pathophysiology of Graves’ disease
Excessive production of thyroid hormones mediated by IgG antibodies that stimulate the TSH receptor
What type of reaction is seen in T1DM + what antibodies?
T1DM - type II and IV
Anti-GAD (glutamic acid decarboxylase) = MOST IMPORTANT
Anti-islet cell
Anti-insulin
Anti-IA2
What type of reaction is seen in pernicious anaemia + what antibodies?
Pernicious anaemia – type II
Anti-gastric parietal cell – most sensitive
Anti-intrinsic factor – most specific
What type of reaction is seen in Myasthenia gravis + what antibodies?
Myasthenia gravis – type II
Anti-nAChR (MAIN)
Anti-MuSK (muscle-specific kinase )
Anti-VGCC (Voltage gated calcium channel) – Lambert-Eaton
What type of reaction is seen in Goodpastures disease + what antibodies?
Goodpasture’s syndrome – type II
Anti-basement membrane type IV collagen
List some genetic polymorphisms that predispose to rheumatoid arthritis.
PAD 2 and PAD 4 polymorphisms - MOST IMPORTANT
HLA DR1
HLA DR4
PTPN22
Polymorphisms affecting TNF, IL1, IL6 and IL10
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
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
T cell involvement in the pathophysiology of rheumatoid arthritis
CD4 activation -> IFNg and IL17 production -> fibroblast and macrophage activation -> MMPs, IL-1, TNFa
CD8 infiltrate synovium -> inflammation -> pannus formation -> invades cartilage and bone
What Gell and Coombs classification is myasthenia gravis?
Type I
Type II
Type III
Type IV
Type II – anti-nAChR antibodies
What are antinuclear antibodies and how are they tested?
Group of antibodies against nuclear proteins
Tested by staining Hep-2 (human epidermoid cancer line) cells
NOTE: these are very common and are often present in healthy individuals
What are the two different types of antinuclear antibodies + what conditions are they seen in?
Anti-dsDNA (looks homogenous) - V. specifc for SLE
Anti-ENA (looks speckled) - there are different types:
- Ro, La, Sm, RNP – SLE, Sjogrens (Ro and La)
- Centromere – limited cutaneous systemic sclerosis
- Scl70 – diffuse cutaneous systemic sclerosis
- Jo1 – dermatomyositis
- SRP – polymyositis
Other than dsDNA, which other quantifiable component can be measured as a surrogate marker for disease activity in SLE? what to use in sle flare ups?
C3 and C4 – C4 will decrease before C3
Classical pathway affected
nb in flares ESR is better than CRP
What is the triad of antiphospholipid syndrome?
Recurrent venous or arterial thrombosis
Recurrent miscarriage
Thrombocytopaenia
What antibodies are present in antiphospholipid sydrome?
Anti-cardiolipin antibody – immunoglobulins directed against phospholipids and β2 glycoprotein-1
Lupus anticoagulant – prolongation of phospholipid-dependent coagulation tests (aPTT)
NOTE: cannot be assessed if the patient is on anticoagulant therapy
NOTE: both tests should be performed as 40% of patients have disconcordant antibodies
What test maybe be falsely raised in antiphospholipid syndrome?
APTT
What is the mechanism of systemic sclerosis?
Systemic sclerosis aka scleroderma:
Th2 and Th17 mediated inflammation
Cytokines activate fibroblasts -> fibrosis
Endothelial cell activation -> microvascular disease
What are the two different types of systemic sclerosis?
Limited cutaneous systemic sclerosis (CREST Syndrome)
Diffuse cutaneous systemic sclerosis
What antibody for:
Limited cutaneous systemic sclerosis
Anti-centromere antibodies
Anti-Scl70 (topoisomerase) antibodies
What are the features of limited cutaneous systemic sclerosis
CREST:
Skin involvement of hands, forearms, feet and face
Calcinosis Raynaud’s phenomenon Esophageal dysmotility Sclerodactyly Telangiectasia (can also get pulmonary hypertension)
Features of diffuse cutaneous systemic sclerosis?
More extensive skin involvement
Gastrointestinal disease
Interstitial pulmonary disease/fibrosis
Scleroderma renal crisis – endothelial cells proliferate leading to a small lumen and poor renal blood supply –> severe hypertension (like renal artery stenosis)
Which pts are likley to have the following ANA antibodies raised:
Anti-Jo1
Anti- Mi2
Anti-SRP
Anti-Jo1 – dermatomyositis, associated with lung involvement
Anti-Mi2 – more commonly found in dermatomyositis (but can be found in polymyositis)
Anti-SRP – polymyositis
Features of dermatomyositis v 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)
Features of Polymyositis?
Within the muscle, you will see CD8 T cells surrounding myofibres that express HLA class I
CD8 T cells kill myofibres via perforin/granzyme (type IV)
Which classification system is used for systemic vasculitides?
Chapel Hill
What are ANCA (anti-neutrophil cytoplasmic antibody) associated vasculitidies?
Small vessel vasculitidies
How does ANCA cause vasculitis?
Anti-neutrophil cytoplasmic antibody – antigens located in granules within neutrophil cytoplasm
Inflammation can lead to expression of these antigens on neutrophil cell surface – antibody binding can activate neutrophils (type II hypersensitivity)
Neutrophils then interact with endothelial cells –> vasculitis
Which small vessel vasculitides are associated with ANCA?
Microscopic polyangiitis (pANCA) Churg-Strauss syndrome (pANCA)
Granulomatosis with polyangiitis (cANCA) - aka wegners disease
What condition shows:
Glomeruloephritis
Epitaxis
Necrosis of nasal cartilage -> saddle nose
Granulomatosis with polyangiitis (cANCA) - aka wegners disease
Describe the key difference between cANCA and pANCA
cANCA - CYTO
Cytoplasmic fluorescence
Associated with antibodies against proteinase 3
Occurs in > 90% of Wegener’s patients with renal involvement
pANCA - PERINUC
Perinuclear staining pattern
Associated with antibodies to myeloperoxidase
Less sensitive and specific than cANCA
Associated with MPA and Churg-Strauss syndrome
Link the following antibodies to the disease they are most associated with.
Anti-IgG antibody Anti-Sm cANCA pANCA Anti-centromere
Anti-IgG antibody - Rheumatoid arthritis
Anti-Sm - form of ANA associated w SLE
cANCA - GPA
pANCA - MPA
Anti-centromere - Limited cutaneous systemic sclerosis
A patient presents with lesions over their knuckles and shortness of breath. He is slow to take a seat in your clinic. Which of the follow antibodies is most likely to be positive in this patient?
Anti-Jo1
Anti-dsDNA
Anti-Ro
Anti-Scl70
Anti-Jo1 – associated with Mechanic’s hands and pulmonary involvement (Dermatomyositis)
Which of the following antibodies is most sensitive for rheumatoid arthritis?
Rheumatoid factor
Anti-SRP
Anti-CCP
Anti-RNP
Anti-CCP – more sensitive for RA than rheumatoid factor
What are the following associated w/ antibodies against?
cANCA
pANCA
cANCA = proteinase 3
pANCA = myeloperoxidase
What ANAs are found in the following diseases:
SLE Sjorgens Limited Cutaneous Systemic Sclerosis Diffuse Cutaneous Systemic Sclerosis Dermatomyositis Polymyositis
SLE = Anti-dsDNA (MAIN), anti-Ro, anti-La, anti-RNP, anti-RNP
Sjorgens = Anti-Ro and Anti-La
Limited Cutaneous Systemic Sclerosis = Anti-centromere
Diffuse Cutaneous Systemic Sclerosis = Anti-scl70 (topoisomerase)
Dermatomyositis = Anti-Jo1
Polymyositis = Anti-SRP
