Transcript 2nd-Med-immunol-Feighery

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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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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Immunodeficiency disorders
Allergy