Autoimmune and Autoinflammatory Disease 3 Flashcards
What are anti-nuclear antibodies?
Group of antibodies that bind to nuclear proteins.
Test by staining of Hep-2 cells (human epidermoid cancer line).
Very common.
Low titre antibodies (<1:80) often found in normal individuals (esp older women).
Which genetic abnormalities can predispose to SLE?
Abnormalities in clearance of apoptotic cells: Polymyorphisms in genes encoding complement, MBL, CRP.
Abnormalities in cellular activation: Polymorphisms in genes encoding/controlling expression of cytokines, chemokines, co-stimulatory molecules, intracellular signalling molecules. Results in B cell hyperactivity and loss of tolerance.
What do antibodies directed particularly at intracellular proteins result in?
Debris from apoptotic cells that have not been cleared
Nuclear antigens - DNA, histones, snRNP
Cytoplasmic antigens - Ribosome, scRNP
What is the pathophysiology of SLE?
Antibodies bind to antigen to form immune complexes.
Immune complexes deposit in tissues: Skin, joints, kidney.
Immune complexes activate complement (classical pathway).
Immune complexes stimulate cells expressing Fc and complement receptors.
What is the difference between immune complex (Type III) versus antibody mediated (Type II) disease pathology?
Immune complexes deposit in basement membrane in a type III response.
How can antibody levels be quantified?
Measured by titre (the minimal dilution at which the antibody can be detected) or by concentration in standardised units.
What are the targets of an anti-nuclear antibody?
dsDNA
Ro, La, Sm, U1RNP: Ribonucleoproteins
SCL70: Topoisomerase
Centromere
How is ANA investigated?
Homogeneous staining associated with specificity for dsDNA.
Specificity investigated with ELISA based assay.
What are anti-dsDNA antibodies?
Measures antibodies against double stranded DNA:
- Are highly specific for SLE (95%)
- Occur in ~60-70% of SLE patients at some time in their disease
- Very high titres are often associated with more severe disease, including renal or central nervous system involvement.
- Useful in disease monitoring
Can increase in antibody titre is associated with disease activity and may precede disease relapse. False positive results unusual (<3%).
What are speckled antibodies?
Associated with antibodies to extractable nuclear antigens.
Specificity is for some ribonucleoproteins (Ro, La, Sm, U1RNP) – confirm with ELISA.
What are anti-ENA antibodies?
Ro, La, Sm, RNP (all are ribonucleoproteins):
- Antibodies may occur in SLE
- Anti-Ro and La are also characteristically found in Sjogren’s syndrome
- Titres not helpful in monitoring disease activity
What is the classical pathway of compliment activation?
Formation of antibody-antigen immune complexes:
- Activate complement cascade via classical pathway.
- Complement components become depleted if constantly consumed.
Quantitation of C3 and C4 acts as a surrogate marker of disease activity.
[NB we measure UNACTIVATED complement proteins, not activated forms]
What is the complement profile in inactive SLE?
C3: Normal
C4: Normal
What is the complement profile in active SLE?
C3: Normal
C4: Decreased
What is the complement profile in severe active SLE?
C3: Decreased
C4: Decreased
Which antibodies are present in anti-phospholipid syndrome?
Anti-phospholipid antibodies
- Recurrent venous or arterial thrombosis
- Recurrent miscarriage
- May be associated with livedo reticularis, cardiac valve disease
- May occur alone (primary) or in conjunction with autoimmune disease (secondary)
What are three antibody tests for anti-phospholipid syndrome?
Lupus anti-coagulant
- Prolongation of phospholipid-dependent coagulation tests
- Cannot be assessed if the patient is on anticoagulant therapy
Anti-cardiolipin antibody
- Antibody specific for negatively charged phospholipids
Anti-B2 glycoprotein 1 antibody
- Antibody specific for glycoprotein found associated with negatively charged phospholipids
Check all three antibodies in individuals presenting with unexplained thrombosis or recurrent pregnancy loss
What is Limited Cutaneous Systemic Sclerosis (CREST)?
Skin involvement does not progress beyond forearms (although it may involve peri-oral skin).
- Calcinosis
- Raynauds
- Oesophageal dysmotility
- Sclerodactyly
- Telangectasia
Primary pulmonary hypertension.
What is Diffuse Cutaneous Systemic Sclerosis?
Skin involvement does progress beyond forearms.
CREST features
- More extensive gastrointestinal disease
- Interstitial pulmonary disease
- Scleroderma kidney/renal crisis
Which antibodies are associated with limited cutaenous systemic sclerosis?
Anti-centromere antibodies
Which antibodies are associated with diffuse cutaneous systemic sclerosis?
Nucleolar pattern
Anti-topoisomerase antibodies (Scl70)
RNA polymerase
Fibrillarin
What is the pathophysiology of dermomyositis?
Within muscle – perivascular CD4 T cells and B cells.
Immune complex mediated vasculitis.
What is the pathophysiology of polymyositis?
Within muscle – CD8 T cells surround HLA Class I expressing myofibres.
CD8 T cells kill myofibres via perforin/granzymes.
What are appropriate investigations for myositis?
Positive ANA (in some patients): Extended myositis panel
Anti-aminoacyl transfer RNA synthetase antibody eg Jo-1 (cytoplasmic)
Anti-signal recognition peptide antibody (nuclear and cytoplasmic) (PM)
Anti-Mi2 (nuclear) (DM>PM)
Which diseases are dsDNA +ve?
SLE
Which diseases are ENA+ve?
Ro, La, Sm, RNP: SLE (any), Sjogrens (Ro, La)
SCL70: Diffuse cutaneous systemic sclerosis
Centromere: Limited cutaneous systemic sclerosis (CREST)
Which diseases are cytoplasmic?
t-RNA synthetase (Jo1): Myositis
Which diseases are associated with the following autoantibodies?
a) Anti-CCP Anti-cyclic citrullinated protein antibody
b) RF Rheumatoid factor (anti-IgG Fc antibody)
c) ANA Anti-nuclear antibody
d) Anti-dsDNA
e) Anti-Sm
f) Anti-RNP
g) Anti-Ro, anti-La
h) Anti-centromere
i) Anti-SCL70
j) Anti-Jo-1 (anti-histidyl tRNA synthetase) and other anti-tRNA synthetase antibodies
k) Anti-cardiolipin, anti-B2GPI, lupus anticoagulant
a) Rheumatoid arthritis
b) Rheumatoid arthritis, Primary Sjogrens
c) Connective tissue disease (screening)
d) Systemic lupus erythematosus
e) Systemic lupus erythematosus
f) Systemic lupus erythematosus or mixed connective tissue disease
g) Primary Sjogren’s or SLE
h) Limited cutaneous systemic sclerosis
i) Diffuse cutaneous systemic sclerosis
j) Idiopathic inflammatory myositis
k) Anti-phospholipid syndrome
What are large vessel systemic vasculitis?
Takayasu’s arteritis
Giant cell arteritis/polymyalgia rheumatica
What are medium vessel systemic vasculitis?
Polyarteritis nodosa
Kawasaki disease
What are small vessel (ANCA associated) systemic vasculitis?
Microscopic polyangiitis
Granulomatosis with polyangiitis
Eosinophilic granulomatosis with polyangiitis
What are small vessel (immune complex) systemic vasculitis?
Anti-GBM disease
IgA disease
Cryoglobulinaemia
What is a mixed vessel systemic vasculitis?
Behcet’s
What is c-ANCA?
Cytoplasmic fluorescence
Associated with antibodies to enzyme proteinase 3
Occurs in > 90% of patients with granulomatous polyangiitis with renal involvement
What is p-ANCA?
Perinuclear staining pattern.
Associated with antibodies to myeloperoxidase.
Less sensitive and specific than cANCA.
Associated with microscopic polyangiitis and eosinophilic granulomatous polyangiitis.
Investigations show:
- Positive antinuclear antibodies (ANA)
- Anti-dsDNA+ve
- Low C3 and C4
- High ESR
Negative results for:
- Ro, La, Sm, RNP
- SCL70
- Centromere
- Jo-1
- Anti-neutrophil cytoplasmic antibodies (ANCA)
What is the diagnosis?
Systemic lupus erythematosus
Investigations show:
Positive anti-neutrophil cytoplasmic antibodies (ANCA)
Negative results for:
- Anti-nuclear antibody (ANA)
- Normal complement
- Raised ESR and CRP
What is the diagnosis?
ANCA associated vasculitis
