Auto-inflammatory and Auto-Immune Disease 3 Flashcards
What are anti-nuclear antibodies? How are they detected?
Group of antibodies that bind to nuclear proteins
Test: staining of Hep-2 cells (nucleus stains green)
V common to have low titres esp. old women
Which diseases are characterised by anti-nuclear antibodies?
SLE
Sjogrens syndrome
Systemic sclerosis
Dermatomyositis
Polymyositis
Describe the abnormalities causing genetic predisposition to SLE
Clearance of apoptotic cells- nuclear antigens exposed + accumulate
Cellular activation: cytokine expression, co-stimulatory molecules, intracellular signalling molecules leads to B cell hyper-reactivity + loss of tolerance
-> Production of antibodies directed at intracellular proteins: nuclear + cytoplasmic antigens
Describe the formation of complexes and subsequent consequences in SLE
Ab’s bind to Ag to form immune complexes
Complexes deposit in tissues: Skin, Joints, Kidney
Complexes activate Complement (classical)
Complexes stimulate cells expressing Fc + complement receptors
List 11 features of SLE
Serositis
Oral or Nasal ulcers
Arthritis in >2 joints
Photosensitivity
Blood disorders
Renal involvement
ANA+
Immunologic
Neurologic Sx
Malar rash
Discoid rash
Compare the staining of the glomerular basment membrane in SLE nephritis against Goodpasture’s disease
SLE: “Lumpy bumpy”, as complexes deposit
Goodpasture’s: Smooth, as Ab’s to BM
CRP or ESR… which is more sensitive in SLE flares?
ESR is MORE sensitive
How is measurement of unactivated complement proteins a surrogate marker of disease activity in SLE?
Ab-Ag complexes activate classical complement pathway
Components deplete if constantly consumed
Quantification of C3 + C4: less complement = more active disease
C4 decreases first, then C3 if very severe
How do you determine the type of ANA?
Staining:
Homogenous: anti-dsDNA
Speckled: anti-extractable nuclear antigens, confirm with ELIZA
What are anti-dsDNA antibodies associated with?
SLE (specificity 95%)
Occur in 60-70%
High titres a/w severe disease acitvity
What test can give definitive confirmation of SLE after detection of anti-dsDNA antibodies?
Crithidia Luciliae staining
List 4 ribonucleoproteins
Ro
La
Sm
RNP
In which diseases may anti-Ro and La be present?
Sjogren’s (+SLE)
The following extractable nuclear antigens are associated with which diseases:
anti-Scl70 (topoisomerase)
anti-Centromere
anti-Mi2, SRP, Jo1
Scl70 (topoisomerase): Diffuse Scleroderma
Centromere: Limited Scleroderma
Mi2, SRP, Jo1: Idiopathic inflammatory myopathies
What acts as a surrogate marker of disease activity?
Quantification of C3 + C4
Abs binding to Ag consuming complement, will get low C3 + C4
Tend to deplete C4 first, then if v severe will deplete C3 as well
C3 low: very unwell
How is complement quantified?
Measure unactivated compliment proteins, not activated forms
What is the triad characterising anti-phospholipid syndrome?
- Recurrent venous or arterial thrombosis
- Recurrent miscarriage
- (slight) Thrombocytopenia: Livedo reticularis
How may anti-phospholipid syndrome present?
Alone (primary) e.g. patients with recurrent miscarriage of unexplained cause or unexplained thrombosis
or
in conjunction with AI disease (secondary) e.g. consider if dx of SLE
What is the most common treatable cause of miscarriage?
Anti-phospholipid syndrome
Which 3 antibodies may be present in anti-phospholipid syndrome?
Lupus anti-coagulant
Anti-cardiolipin
Anti-B2 glycoprotein 1
What happens in the presence of lupus anti-coagulant?
Prolongs phospholipid dependent coagulation tests- APTT
Why take caution with APTT in patients with lupus anticoagulant?
Prolonged APTT- normally would indicate prone to bleeding but phospholipids are low because of antibodies
APTT is distorted, they are procoagulant
Clotting time can be corrected by adding phospholipids to saturate antibodies (though not if on anti-coagulant)
What disordered haemostatic state are those with anti-phospholipid syndrome in?
Paradoxically pro-coagulant
Low platelets, but v prone to clots due to antibodies
Anti-cardiolipin + Lupus anticoagulant promote coagulation
What characterises primary Sjogren’s syndrome?
Inflammatory infiltration + destruction of exocrine glands
Particular involvement of lacrimal + salivary glands
Give 5 features of primary Sjogren’s syndrome
Dry eyes
Dry mouth
Arthralgias
Fatigue
Increased risk of certain lymphomas e.g. MALT
What lab results would be seen in a patient with primary sjogrens syndrome?
Anti-nuclear antibody +ve
Speckled staining
ENA +ve: Ro +/- La
Why should those with anti-Ro or La that are pregnant be monitored?
IgG Abs (monomers)
Can cross placenta, may cross react with foetal cardiac conduction tissue + cause neonatal heart block/ rash
Need specialist foetal cardiac monitoring
Give 5 features of limited cutaneous systemic sclerosis
CREST
Calcinosis
Raynauds- vascular disease (+ in lungs- primary pulmonary HTN)
Oesophageal dysmotility
Sclerodactlyly
Telangectasia
Describe the skin involvement in limited cutaneous systemic sclerosis
Does not progress beyond forearms
(may involve peri-oral skin)
Describe skin involvement in diffuse cutaneous systemic sclerosis
Progresses beyond forearms e.g. often chest + abdomen
What characterises diffuse cutaneous systemic sclerosis?
CREST features
More extensive GI disease
Interstitial pulmonary disease
Scleroderma kidney/ renal crisis
Describe the pathophysiology in systemic sclerosis
Type IV: Th2 + Th17 mediated inflammation
Cytokines activate fibroblasts: fibrosis
Endothelial cell activation: microvascular disease
Extractable nuclear antibodies also present
Which antibodies are present in systemic sclerosis?
Limited: Anti-centromere
Diffuse: Anti-Scl70 (topoisomerase)
What are idiopathic inflammatory myopathies? What can they be associated with?
Connective tissue disorders characterised by muscle weakness:
Dermatomyositis + Polymyositis
Malignancy
Describe the pathophysiology of dermatomyositis
Type III: immune complexes deposit in vasculature + irritate skin
In muscle: perivascular CD4 T cells + B cells
+/-Anti-Jo1 + Anti-Mi2 antibodies
Describe the pathophysiology of polymyositis
Type IV
In muscle, CD8 T cells surround HLA I expressing myofibres
CD8 T cells kill myofibres via perforin/ granzymes
+/-Anti-SRP
What investigations should be requested in idiopathic inflammatory myopathies?
Extended Myositis panel
+ Screen for malignancy
Give 7 features of dermatomyositis
Heliotrope rash (peri-orbital)
Mechanics hands: dry, scaly, cracked
Proximal muscle weakness
Gottron’s papules (on extensors of fingers)
Respiratory muscle weakness
Interstitial lung disease (fibrotic)
Raynauds
Give 4 features of polymyositis
Proximal muscle weakness
Respiratory muscle weakness
Interstitial lung disease (fibrotic)
Raynauds
What autoantibody can be used to screen for connective tissue disease?
Anti-nuclear antibody
What disease is associated with anti-CCP?
Rheumatoid Arthritis
What disease is associated with Rheumatoid factor?
Rheumatoid arthritis
Primary Sjogren’s
What disease is associated with anti-dsDNA?
SLE
What disease is associated with anti-Sm?
SLE
What disease is associated with anti-RNP?
SLE
Mixed connective tissue disease
What disease is associated with anti-Ro and anti-La?
Primary Sjogren’s
SLE
What disease is associated with anti-centromere?
Limited cutaneous systemic sclerosis
What disease is associated with anti-SCL70?
Diffuse cutaneous systemic sclerosis
What disease is associated with anti-Jo-1 and other anti-tRNA synthetase antibodies?
Idiopathic inflammatory myositis
What disease is associated with anti-cardiolipin, anti-B2GPI and lupus anticoagulant?
Anti-phospholipid syndrome
What are Anti-neutrophil cytoplasmic antibodies? How do they cause disease?
Against antigens in granules in neutrophil cytoplasm
Inflammation can lead to expression of the Ags on neutrophil cell surface
Ab-Ag binding can activate neutrophils (Type II/ V reaction)
Neutrophils interact with endothelial cells + damage vessels- vasculitis
Which small vessel vasculitides are ANCA associated?
Microscopic polyangitis
Granulomatosis with polyangitis (Wegners)
Eosinophillic granulomatosis with polyangitis (Churg-Strauss)
What are cANCAs? What are they associated with?
Cytoplasmic fluorescence staining ANCAs
A/w Abs to enzyme Proteinase 3
In >90% of GPA patients with renal involvement
What are pANCAs? What are they associated with?
Perinuclear staining pattern ANCAs
A/w Abs to myeloperoxidase
Less sensitive + specific than cANCA
A/w MPA + eGPA
A/w UC + PSC + AI hepatitis
