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

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