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Clinical Immunology Conleth Feighery John Jackson Auto-antibodies • Often very helpful in making diagnosis • Rarely entirely specific – i.e. can occur in range of diseases • ANA, rheumatoid factor examples of this Auto-antibodies • ANA usually positive in connective tissue diseases - CTD • Sub-categories of ANA may define the type of CTD • Double stranded DNA – exclusive to SLE • Antibodies to “extractable nuclear antigens” define other types of CTD Case 6 • • • • • 32 year old bank official Dry mouth +++ Water to bedside Customer interaction difficult Fatigue + Case 6 Examination • Reduced saliva • Sub-mandibular gland swollen • Dental damage Extractable nuclear antigens • Antibodies to sub-fractions of nucleus • Ro antibodies – found in a ‘common’ CTD called Sjogren’s syndrome – in ~ 75% of pts • Also found in other CTDs including lupus – so not specific Sjogren’s syndrome Features • Inflammation of glands - lacrimal, salivary • Symptoms - dry eyes, dry mouth • Joint, muscle symptoms - sometimes • Associated CTD - RA, SLE …. • Older females Case 6 - Sjogren’s syndrome Confirming the diagnosis • History • Quantify tears, saliva production • Biopsy ? • Autoantibodies – ANA positive – Ro antibody positive Case 6 - Sjogren’s syndrome Cause • Lymphocytic infiltrate of exocrine glands • Salivary, lacrimal, genital glands affected • Monoclonal expansion of B cells can occur • Lymphoma may develop Case 6 - Sjogren’s syndrome • • • • • Associates with other diseases SLE Rheumatoid arthritis Thyroid disease Primary biliary cirrhosis • HLA genes associated Ro antibodies Can cross placenta and rarely • Cause complete congenital heart block – Damage to heart conducting system • Cause skin inflammation – ‘neonatal lupus’ ENA antibodies - valuable Help define type of CTD • Sjogren’s syndrome - Ro, La antibodies • SLE - Sm antibodies • Scleroderma - Scl 70 antibodies • Anti-RNP - mixed connective tissue disease Case 7 • • • • 44 year old female Arthralgia, myalgia Raynaud’s phenomenon Fatigue Case 7 Examination • Mild sclerodactyly • Telangiectasia, hands, face Sclerodactyly of fingers Sclero = hard Dactyly = digit Telangiectasia Case 7 diagnosis is CREST • Clinical findings • Centromere auto-antibody • • • • • C = calcinosis R = Raynaud’s E = oesophagus S = sclerodactyly T= telangiectasia Anti-centromere antibody ANA observed in dividing cells Positive in 70% of CREST patients Systemic sclerosis (scleroderma) • More severe version of CREST • Skin thickening – arms, thorax, face • GIT structures affected – oesophagus – dysphagia - small intestine – dysmotility, malabsorption • Lungs – fibrosis • Caused by deposition of collagen unexplained Systemic sclerosis (scleroderma) • Auto-antibody – to a ENA • Anti-Scl 70 - antigen is enzyme topoisomerase I Case 8 • Female, 54 years • Fatigue • Skin itch x 2 years • Mild icterus Examination • Generally healthy • Icterus confirmed • Liver, spleen size normal Liver auto-immunity • • • • Primary biliary cirrhosis Females Middle-aged Inflammatory process focused on intra-hepatic biliary tree • Liver failure – common reason for liver transplantion Case 8 auto-antibody tests 2 helpful auto-antibodies – • Anti-mitochondrial antibody Confirmatory antibody to enzyme • Anti-pyruvate dehydrogenase (PDH) Mitochrondrial antibody Kidney tubule tissue Primary biliary cirrhosis Liver granuloma – early disease Established cirrhosis Chronic active hepatitis • • • • Females Often in younger age group – 20s Less common form of liver disease Antibodies to “smooth muscle” BUT not specific for this disease Connective tissue disease Vasculitis Vasculitis • Inflammation - focus on blood vessels • Damage to blood vessel – local thrombosis, – haemorrhage – damage to tissue it supplies Vasculitic lesions in vasculitis WG – case No other systemic symptoms Decision to treat with cyclophosphamide, steroids Blood vessel size in vasculitis Vasculitis • • • • • Clinical presentation can be obscure Systemic inflammatory disease - ? cause Pyrexia of unknown origin Infection ?? Malignancy ?? Wegener’s granulomatosis • Small vessel vasculitis • Classically affects Upper respiratory tract – nose, ears, sinuses Lower respiratory tract - lungs Kidneys • But can affect any organ, including skin • GIT sometimes, but less common Wegener’s granulomatosis • • • • Bleeding is often the clue! Nasal – epistaxis Lungs – haemoptysis Kidney – haematuria • PUO – pyrexia of unknown origin • Systemic symptoms – joint, muscle pain Wegener’s - clinical features Episcleritis Saddle nose deformity Wegener’s granulomatosis • Diagnosis often missed in past • Not uncommon disorder – but many medics have not seen a case • 100+ cases diagnosed in 15 years, SJH • Clinical features can be atypical • Auto-antibody – specific, sensitive – use leading to increased diagnosis WG – case , 1992 • • • • • RE - 26 year old Australian, on world tour 3 week history of haemoptysis Possible weight loss of 6kg Arthralgia - large joints Rash - macular, erythematous WG – case • • • • • • Rapid deterioration - in 1 week Temp 38 Synovitis of small joints Episcleritis Blistering necrotic skin rash Haemoptysis +++ WG - case 1 Differential diagnosis • Tuberculosis ? • Carcinoma of lung ? • Bacterial infection ? • Auto-immune disease – vasculitis ? WG - case 1 • • • • • WCC - 25 x 109/L Urine - haematuria, proteinuria Lung biopsy - alveolitis (ICU) Auto-antibody screen + C-ANCA DIAGNOSIS - Wegener’s C-ANCA PR3+ Wegener’s auto-antibodies First step • Anti-neutrophil cytoplasmic antibody = ANCA • Immunofluorescence test Second step • Anti-PR3 • ELISA Wegener’s granulomatosis • Why is the diagnosis missed ? • Limited Wegener’s – upper airways alone – Sinusitis – Rhinitis – Deafness • Skin or other organ alone • Diagnosis not considered Wegener’s granulomatosis • Treatment • Immunosuppressive drugs – cyclophosphamide • Steroids • Good response usually – mortality of disease reduced +++ Wegener’s granulomatosis However • Relapse is very common ~ 50% • Further organs may become involved • Chronic renal damage may develop – dialysis, transplant Another case …… • Another example of connective tissue disease • Auto-antibodies help “dissect” the condition Case 8. • 24 year old female parachutist • Presented with marked ecchymosis - sites of parachute strap marks • Mild arthralgia, fatigue • DVT in calf 1 year previously Case 8. • • • • • Tests - v.low platelet count 7 x 109 WCC count 3 x 109 Haemoglobin 10g ANA positive, titre 640 Diagnosis ?? Case 8. • Further auto-antibody tests – Anti-cardiolipin antibody ++ – Anti-beta2-glycoprotein antibody ++ • Diagnosis ?? • Anti-phospholipid syndrome Anti-phospholipid syndrome • • • • Classic features Thrombosis - recurrent Thrombocytopaenia Miscarriages - recurrent Anti-phospholipid syndrome • Associated with connective tissue disease especially SLE • Overlaps with • ITP - idiopathic thrombocytopenic purpura • May have clinical features like TTP - thrombotic thrombocytopenic purpura ?? Case 8 - 2006 • Remained well for 10 years • Developed mild arthritis • dsDNA antibody positive Case 8 - January 2006 • • • • Dyspnoea on exertion Anaemia, low WCC, low platelets Hypertension Marked lower limb oedema Case 8 - 2006 • Casts - red cells in urine • Marked proteinuria - nephrotic • Renal biopsy - diffuse proliferative glomerulonephritis (class IV) • Diagnosis - SLE The end Next term Immunodeficiency disorders Allergy