Autoinflammatory and Autoimmune Disease 2 Flashcards
What are some organ specific autoimmune diseases (6)
Graves disease. Hashimotos thyroiditis. T1DM Pernicious anaemia Myasthenia gravis Goodpastures disease
What are some organ non-specific autoimmune diseases (5)
SLE Sjorgren's syndrome Systemic sclerosis Dermato/Polymyositis ANCA-Associated vasculitis
What antibodies are present in SLE
Anti-nuclear antibody
What antibodies are present in Sjogren’s syndrome
Anti-nuclear antibody
What antibodies are present in Systemic sclerosis
Anti-nuclear antibody
What antibodies are present in rheumatoid arthritis (2)
Rheumatoid Factor.
Anti-CCP antibody
What antibodies are present in ANCA associated vasculitis
Anti-neutrophil cystoplasmic antibody
What is Graves disease
Excessive production of thyroid hormones
What is the pathophysiology of Graves disease
Mediated by IgG which stimulate the TSH receptor.
Stimulates autoantibodies against TSH-receptor bind to receptor - act as TSH agonists.
Induce uncontrolled overproduction of thyroid hormones - negative feedback cannot override antibody stimulation.
What type of reaction is Graves disease
Type II hypersensitivity
What are some symptoms of hypothyroidism (4)
Lethargic
Dry skin and hair
Constipation
Cold intolerance
Is the diagnosis of Graves disease dependant on the biochemistry
No - testing for auto-antibodies is not usually required for diagnosis
What is the commonest cause of hypothyroidism
Hashimoto’s thyroiditis is the commonest cause of hypothyroidism in iodine-repleate areas
What causes a goitre in hypothyroidism
Enlarged thyroid is infitrated by T and B cells
What is hashimoto’s thyroiditis associated with (2)
Anti-throid peroxidase antibodies
The presence of these correlates with thyroid damage and lymphocyte inflammation
Some shown to induce damage to thyrocytes.
Anti-thyroglobulin antibodies
What type of hypersensitivity reaction is hashimoto’s thyroiditis
Type 2 and 4 hypersensitivity reactions
Is detection of anti-thyroid antibodies clinically useful (3)
Not really.
Many women >65 have anti-thyroid antibodies
Some post-menopausal women with anti-thyroid antibodies have subclinical hypothyroidism
Small proportion of post-menopausal women with anti-thyroid antibodies have overt hypothyroidism
What is used to diagnose thyroid disorders
Thyroid biochemistry
What is the histology of T1DM
CD8+ T cell infiltration of pancreas which destroy beta islet cells over time.
What type of hypersensitivity reaction is T cell destruction of beta islet cells in T1DM
Type 4 hypersensitivity (CD8 mediated)
What receptors do CD8+ T cells detect and attack on the beta cells of the pancreas in T1DM (2)
Develop auto-antigens against GAD65 and IA2
When do auto-antibodies develop in T1DM
Long before disease detectable
What auto-antibodies can be generated in T1DM (4)
Anti-islet antibodies
Anti-insulin antibodies
Anti-GAD antibodies
Anti-IA2 antibodies
Individuals with 3-4 of the above are highly likely to develop T1DM
What role does auto-antobody detection play in diagnosing T1DM
No current role
What is the hallmark of pernicious anaemia
Auto-antibodies against IF, preventing absorption of B12
What are the clinical features of pernicious anaemia (4)
Vitamin B12 deficiency
Failure of vitamin B12 absorption
Macrocytic anaemia
Neurological features with subacute degeneration of cord (posterior and lateral columns), peripheral neuropathy, optic neuropathy.
What are auto-antibodies generated against in pernicious anaemia (2)
Gastric parietal cells or intrinsic factor - useful in diagnosis.
What auto-antiboides are generated in myaesthenia gravis
Antibodies against ACh receptors on postsynaptic muscle membranes
What are the clinical feature of myaesthenia gravis (4)
Fluctuating weakness
Extra-ocular weakness or ptosis is very common
EMG studies are abnormal
Tensilon test is positive (inject edrophonium (an anti-cholinesterase) to prolong life of acetylcholine and allow it to act on residual receptors)
What is useful in the diagnosis of myaesthenia gravis
Anti-acetylcholine receptor antibodies are present in 75% of patients - diagnostically useful
What type of hypersensitivity reaction is myaesthenia gravis
Type 2 hypersensitivity reaction
What can occur to the offspring of mothers with myaesthenia gravis
May experience transient neonatal maesthenia
What type of disease is Goodpasture’s disease
An anti-glomerular basement membrane disease
What is useful in the diagnosis of Goodpasture’s disease
Antibodies specific for glomerular basement membrane disease underpin the pathology and are useful in the diagnosis of anti-glomerular basement membrane disease
What type fo hypersensitivity reaction is Goodpasture’s disease
Type 2 hypersensitivity reaction
What is the pathological hallmark of Goodpasture’s disease on biopsy
Crescentic nephritis
How are auto-antibodies detected in the kidney
Flourescein conjugated polyclonal anti-human immunoglobulin detects auto-antibodies.
How do flourescent auto-antibody markers appear in Goodpasture’s disease
Smooth linear deposition of antibody along the glomerular basement membrane
Anti-GAD antibody is seen in _____
Diabetes mellitus (Type 1)
Anti-thyroglobulin antibody is seen in ____
Hashimotos thyroiditis
Anti-basement membrane antibody is seen in ____
Goodpasture’s disease
Anti-intrinsic factor antibody is seen in ____
Pernicious anaemia
Anti-acetylcholine receptor antibody is seen in _____
Myaesthenia gravis
Anti-TSH receptor antibody is seen in ___
Grave’s disease
Symptoms: nervous, palpitations, heat intolerant, diarrhoea
Grave’s disease
Symptoms: lethargic, dry skin and hair, constipation, cold intolerant
Hashimotos thyroiditis
8 Year old boy.
Thirsty, polyuria, malaise.
Urine dipstick confirms glycosuria
T1DM
Symptoms: tired, pale, mild numbness of feet. Anaemic (Hb 8.4) Macrocytosis MCV 108 Urine dipstick negative Folate normal Vitamin B12 very low
Pernicious anaemia
Drooping eyelids.
Weakness, particularly on repetitive activity. Symptoms worse at the end of the day
Myaesthenia gravis
48 year old man. haemoptysis with widespread crackles in the lungs. Swelling of legs, reduced urine output.
Creatinine 472
Microscopic haematuria and proteinuria.
CXR - widespread shadowing
Elevated TLCO suggesting pulmonary haemorrhage.
Anti-neutrophic cytoplasmic antibody negative.
Anti-basement membrane positive
Crescentic nephritis on biopsy
Goodpasture’s syndrome.
Pain, stiffness and swelling of multiple small joints within hands.
Normochromic anaemia. High ESR and CRP
Grossely deformed hands.
Rheumatoid arthritis.
What polymorphisms are assocaited with a genetic predisposition to Rheumatoid arthritis (4)
HLA DR4 (DRB1, 0401, 0404, 0405) and HLA DR1.
PTPN22 polymorphisms.
Polymorphisms affecting TNF, IL1, IL6, IL10.
PAD2 nad PAD4 polymorphisms.
What do the HLA DR4 and HLA DR1 alleles predispose to developing rheumatoid arthritis
Susceptible alleles share a sequence at positions 70-74 of the HLA DR beta chain (shared epitope)
These alleles may bind ‘arthritogenic peptides’ and have been shown to bind to citrullinated peptides with high affinity
What do the PAD2 and PAD4 alleles predispose to developing rheumatoid arthritis
They are enzymes involved in deimination of arginine to create citrulline.
Polymorphisms are associated with increased citrullination - creating a high load of citrullinated proteins.
Peptides from these citrullinated proteins may be presented by HLA DR4 and DR1 molecules to T cells to stimulate Th cells which will promote development of an antibody response to the citrullinated proteins
What environmental factors are associated with the development of rheumatoid arthritis (2)
Smoking
Gum infection with porphyromonas gingivalis
What antibodies are present in RA (2)
Antibodies to cyclic citrullinated peptide (Anti-CCP)
Antibodies against rheumatoid factor
How sensitive is anti-CCP for the diagnosis of RA
60-70% sensitivity
How specific is anti-CCP for the diagnosis of RA
95% specificity
What is rheumatoid factor
An IgM anti-IgG antibody directed against the common (Fc) region of human IgG
How specific/sensitive is rheumatoid factor for the detection of RA
60-70% specific and sensitive
What two B cell immune responses occur in RA (2)
Type 2 response - antibody binding to citrullinated proteins may lead to: activation of complement, activation fo macrophages via Fc R and complement receptors, NK cell activation with ADCC
Type 3 response - immune complex formation (RF and anti-CCP) and deposition with complement activation.
What T cell reaction is involved in RA
Type 4 response = T cell activation.
How does a RA joint differ to a normal joint (2)
Increased synovial fluid volume
Inflamed synovial tissue forms a ‘pannus’ overlaying and invading articular cartilage and adjacent bone tissues
What are anti-nuclear antibodies
Group of antibodies that bind to nuclear proteins
How are anti-nuclear antibodies detected
Test by staining of Hep-2 cells
How specific are anti-nuclear antibodies in disease detection
Low titre antibodies (<1:80) often found in normal individuals (especially in older women)
19 year old female.
4 month history of fatigue, generalised arthralgia, particularly of small joints of hands. Hall fall, mouth ulcers, butterfly rash.
SLE
What are the clinical features of SLE (8)
CNS: seizures. Skin: butterfly rash, discoid lupus. Heart: endocarditis, myocarditis. Glomerulonephritis. Lungs: serositis, pleuritis, pericarditis. Blood: haemolytic anaemia, leukopenia, thrombocytopenia Arthritis Lymphadenopathy
What are the genetic predispositions of SLE (4)
Abnormalities in clearance of apoptotic cells (polymorphisms in genes encoding complement, MBL, CRP)
Abnormalities in cellular activation (polymorphisms in genes encoding/controlled expression of cytokines, chemokines, co-stimulatory molecules, intracellular signalling molecules)
B cell hyperactivity and loss of tolerance.
Antibodies directed particularly at intracellular proteins (nuclear antigens - DNA, histones, snRNP; cytoplasmic antigens - ribosome, cRNP)
What is the pathogenesis of SLE
Antibodies bind to antigen to form immune complexes.
Immune complexes deposit in tissues (skin, joints, kidneys)
Immune complexes activate complement (classical pathway)
Immune complexes stimulate cells expressing Fc and complement receptors
What type of hypersensitivity reaction is involved in SLE
Type 3 hypersensitivity
How do type 3 immune complexes deposit on the basement membrane (SLE)
Immune complex deposition - detection of granular ‘lumpy-bumpy’ pattern with flouroscein
How are antibody levels quantified
Measured by titre (the minimal dilution at which the antibody can be detected) or by concentration in standardised units
What are the two targets of anti-nuclear antibody (ANA)
dsDNA
Extractable nuclear antigens (ENAs) - ribonucleoproteins, enzymes (e.g. RNA polymerase or topoisomerase)
In ANA detection, what does a homogenous staining associated with
dsDNA
What type of antibody detected is most specific for SLE
dsDNA
They are highly specific for SLE (95%)
Occur in 60-70% of SLE patients at some point in time of their disease.
Very high titres are often associated with more severe disease - including renal or CNS involvement
Useful in disease monitoring - an increase in antibody titre is associated with disease activity and may precede disease relapse
In ANA detection, what is a speckled staining associated with
ENA 4
What are the anti-ENA antibodies (4)
Ribonucleoproteins (Ro, La, Sm, RNP)
Titres are not helpful in monitoring disease activity
What condition are anti-Ro and La characteristically found in
Sjogren’s syndrome
What anti-ENA antibodies are associated with diffuse cutaneous systemic sclerosis (3)
Scl70
RNA polymerase
Fibrillarin
What anti-ENA antibodies are associated with idiopathic inflammatory myopathies (2)
Mi2
SRP
What parts of the complement pathway are associated with disease activity in SLE
C3 and C4
Important to measure unactivated complement proteins, not activated forms
What will happen to C3 and C4 in severe active SLE
Reduced C3 and C4
What will happen to C3 and C4 in active SLE
Normal C3
Reduced C4
What is anti-phsopholipid syndrome associated with (2)
Recurrent venous or arterial thrombosis
Recurrent miscarriage
What auto-antibodies are present in anti-phsopholipid syndrome
Anti-phospholipid antibodies
What is measured in anti-phospholipid syndrome (2)
Anti-cardiolipin antibody (immunoglobulins directed against phospholipids, and beta2 glycoprotein-1)
Lupus anti-coagulant (prolongation of phospholipid-dependent coagulation tests, cannot be assessed if the patient is on anticoagulant therapy)
What are the pathological features of systemic sclerosis (4)
Inflammation with Th17 and Th2 cells dominating
Cytokines lead to activation of fibroblasts and the development of fibrosis (polymorphisms within type 1 collagen alpha 2 chains and fibrillin 1 may be important, polymorphisms in TGF-beta have also been described)
Cytokines lead to activation of endothelial cells and contribute to microvascular disease
Loss of B cell tolerance to nuclear antigens
What occurs in limited cutaneous systemic sclerosis (CREST)
Skin involvement does not progress beyond forearms (although it may involve peri-oral skin)
What are the hallmarks of CREST syndrome (6)
Calcinosis Raynauds Oesophageal dysmotility Sclerodactyly Telangectasia
(also primary pulmonary hypertension)
What occurs in diffuse cutaneous systemic sclerosis
Skin involvement does progress beyond forearms
What CREST features are present in diffuse cutaneous systemic sclerosis (3)
More extensive gastrointestinal disease
Interstitial pulmonary disease
Scleroderma kidney/renal crisis
What is an important prognostic indicator in systemic sclerosis
ANA staining
What ANA staining is characteristic of diffuse systemic sclerosis (4)
Nucleolar pattern
Anti-topoisomerase antibodies (Scl70)
RNA polymerase
Fibrillarin
What ANA staining is characteristic of limited cutaneous systemic sclerosis
Anti-centromere antibodies
Weakness, malaise, rash
Idiopathic inflammatory myopathy
What are the main two idiopathic inflammatory myopathies
Dermatomyositis
Polymyositis
What are the pathological features of dermatomyositis (2)
Within muscle - perivascualr CD4 T cells and B cells
Immune complex mediated vasculitis - type 3 response
What are the pathological features of polymyositis (2)
Within muscle - CD8 T cells surround HLA class 1 expressing myofibres CD8 T cells kill myofibres via perforin/granzymes - type 4 response
What ANA can sometimes be detected in dermatomyositis (2)
Anti-aminoacyl transfer RNA synthetase antibody eg Jo-1 (cytoplasmic)
Maybe: Anti-Mi2 (nuclear)
What ANA can sometimes be detected in polymyositis
Anti-signal recognition peptide antibody (nuclear and cytoplasmic)
What condition is characterised by ANA+ve dsDNA +ve
SLE
What conditions are characterised by ANA+ve, ENA+ve: Ro, La, Sm, RNP +ve (2)
SLE (any)
Sjogrens (Ro, La)
What condition is characterised by ANA+ve, ENA+ve:SCL70 +ve
Diffuse cutaneous systemic sclerosis
What condition is characterised by ANA+ve ENA+ve:Centromere +ve
Limited cutaneous systemic sclerosis (CREST)
What condition is characterised by ANA+ve, cytoplasmic +vve t-RNA synthetase (jo1) +ve
Myositis
What are the large vessel vasculitis (2)
Takayasu’s arteritis
Giant cell arteritis/polymyalgia rheumatica
What are the medium vessel vasculitis (2)
Polyarteritis nodosa
Kawasaki disease
What are the small vessel vasculitis (ANCA associated) (3)
Microscopic polyangiitis (MPA_
Granulomatosis with polyangiitis (GPA)
Eosinophilic granulomatosis with polyangiitis (eGPA)
What are the small vessel vasculitis (immune complex) (3)
Anti-GBM disease
IgA disease
Cryoglobinaemia
What are ANCA
Anti-neutrophil cytoplasmic antibodies - different from anti-nuclear antibodies
Antibodies specific for antigens located in primary granules within
cytoplasm of neutrophils
Inflammation may lead to expression of these antigens on cell surface of neutrophils
Antibody engagement with cell surface antigens may lead to neutrophil activation (type II hypersensitivity)
Activated neutrophils interact with endothelial cells causing damage to vessels - vasculitis
What are the two types of ANCA antibodies
cANCA
pANCA
What are cANCA antibodies (3)
Cytoplasmic fourenscence
Associated with antibodies to enzyme proteinase 3
Occurs in >90% of patients with granulomatous polyangitis with renal involvement
What are pANCA antibodies (4)
Perinuclear staining pattern
Associated with antibodies to myeloperoxidase
Less sensitive and specific than cANCA
Associated with microscopic polyangiitis and eosinophilic granulomatous polyangiitis
What is ANA (anti-nuclear antibody) for
Screening test for a connective tissue disease
What is ANCA (anti neutrophil cystoplasmic antibody) for
Associated with a subset of small vessel vasculitides including MPA< GPA and eGPA
