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Clinical Immunology

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

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Clinical Immunology

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  1. Clinical Immunology Conleth Feighery John Jackson

  2. 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

  3. 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

  4. Case 6 • 32 year old bank official • Dry mouth +++ • Water to bedside • Customer interaction difficult • Fatigue +

  5. Case 6 Examination - • Reduced saliva • Sub-mandibular gland swollen • Dental damage

  6. 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

  7. Sjogren’s syndrome Features • Inflammation of glands - lacrimal, salivary • Symptoms - dry eyes, dry mouth • Joint, muscle symptoms - sometimes • Associated CTD - RA, SLE …. • Older females

  8. Case 6 - Sjogren’s syndrome Confirming the diagnosis - • History • Quantify tears, saliva production • Biopsy ? • Autoantibodies • ANA positive • Ro antibody positive

  9. 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

  10. Case 6 - Sjogren’s syndrome • Associates with other diseases • SLE • Rheumatoid arthritis • Thyroid disease • Primary biliary cirrhosis • HLA genes associated

  11. Ro antibodies Can cross placenta and rarely - • Cause complete congenital heart block • Damage to heart conducting system • Cause skin inflammation – ‘neonatal lupus’

  12. 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

  13. Case 7 • 44 year old female • Arthralgia, myalgia • Raynaud’s phenomenon • Fatigue

  14. Case 7 Examination - • Mild sclerodactyly • Telangiectasia, hands, face

  15. Sclerodactyly of fingers Sclero = hard Dactyly = digit

  16. Telangiectasia

  17. Case 7 diagnosis is CREST • Clinical findings • Centromere auto-antibody • C = calcinosis • R = Raynaud’s • E = oesophagus • S = sclerodactyly • T= telangiectasia

  18. Anti-centromere antibody -ANA observed in dividing cells Positive in 70% of CREST patients

  19. 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

  20. Systemic sclerosis (scleroderma) • Auto-antibody – to a ENA • Anti-Scl 70 - antigen is enzyme topoisomerase I

  21. Case 8 • Female, 54 years • Fatigue • Skin itch x 2 years • Mild icterus Examination • Generally healthy • Icterus confirmed • Liver, spleen size normal

  22. Liver auto-immunity • Primary biliary cirrhosis • Females • Middle-aged • Inflammatory process focused on intra-hepatic biliary tree • Liver failure – common reason for liver transplantion

  23. Case 8 auto-antibody tests 2 helpful auto-antibodies – • Anti-mitochondrial antibody Confirmatory antibody to enzyme - • Anti-pyruvate dehydrogenase (PDH)

  24. Mitochrondrial antibody Kidney tubule tissue

  25. Primary biliary cirrhosis Liver granuloma – early disease Established cirrhosis

  26. 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

  27. Connective tissue disease Vasculitis

  28. Vasculitis • Inflammation - focus on blood vessels • Damage to blood vessel - • local thrombosis, • haemorrhage • damage to tissue it supplies

  29. Vasculitic lesions in vasculitis

  30. WG – case No other systemic symptoms Decision to treat with cyclophosphamide, steroids

  31. Blood vessel size in vasculitis

  32. Vasculitis • Clinical presentation can be obscure • Systemic inflammatory disease - ? cause • Pyrexia of unknown origin • Infection ?? • Malignancy ??

  33. 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

  34. Wegener’s granulomatosis • Bleeding is often the clue! • Nasal – epistaxis • Lungs – haemoptysis • Kidney – haematuria • PUO – pyrexia of unknown origin • Systemic symptoms – joint, muscle pain

  35. Wegener’s - clinical features Episcleritis Saddle nose deformity

  36. 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

  37. 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

  38. WG – case • Rapid deterioration - in 1 week • Temp 38 • Synovitis of small joints • Episcleritis • Blistering necrotic skin rash • Haemoptysis +++

  39. WG - case 1 Differential diagnosis - • Tuberculosis ? • Carcinoma of lung ? • Bacterial infection ? • Auto-immune disease – vasculitis ?

  40. WG - case 1 • WCC - 25 x 109/L • Urine - haematuria, proteinuria • Lung biopsy - alveolitis (ICU) • Auto-antibody screen + C-ANCA • DIAGNOSIS - Wegener’s

  41. C-ANCA PR3+

  42. Wegener’s auto-antibodies First step - • Anti-neutrophil cytoplasmic antibody = ANCA • Immunofluorescence test Second step - • Anti-PR3 • ELISA

  43. 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

  44. Wegener’s granulomatosis • Treatment • Immunosuppressive drugs – cyclophosphamide • Steroids • Good response usually – mortality of disease reduced +++

  45. Wegener’s granulomatosis However - • Relapse is very common ~ 50% • Further organs may become involved • Chronic renal damage may develop – dialysis, transplant

  46. Another case …… • Another example of connective tissue disease • Auto-antibodies help “dissect” the condition

  47. 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

  48. Case 8. • Tests - v.low platelet count 7 x 109 • WCC count 3 x 109 • Haemoglobin 10g • ANA positive, titre 640 • Diagnosis ??

  49. Case 8. • Further auto-antibody tests • Anti-cardiolipin antibody ++ • Anti-beta2-glycoprotein antibody ++ • Diagnosis ?? • Anti-phospholipid syndrome

  50. Anti-phospholipid syndrome • Classic features • Thrombosis - recurrent • Thrombocytopaenia • Miscarriages - recurrent

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