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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 - PowerPoint PPT Presentation
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Clinical Immunology
Conleth FeigheryJohn 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 = hardDactyly = 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 icterusExamination• 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 symptomsDecision 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, sinusesLower respiratory tract - lungsKidneys
• 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 testSecond 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
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