clinical immunology
DESCRIPTION
Clinical immunology. Conleth Feighery John Jackson Niall Conlon. Case histories. Clinical medicine - learning through a series of cases How knowledge of immunology can help Types of diseases Types of tests. Inflammatory diseases. Specialisation - Respiratory - asthma, lung infections - PowerPoint PPT PresentationTRANSCRIPT
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Clinical immunology
Conleth FeigheryJohn Jackson Niall Conlon
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Case histories
• Clinical medicine - learning through a series of cases
• How knowledge of immunology can help
• Types of diseases• Types of tests
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Inflammatory diseases
Specialisation -• Respiratory - asthma, lung infections• Bowel - peptic ulcer, Crohn’s disease• Brain - neurology - multiple sclerosis• Joints - rheumatology, RA, SLE• Allergy - immunology
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Immune deficiency disorders
• Primary immunodeficiency - rare, immunology
• Secondary - common, e.g. HIV, infectious disease specialty
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Making a diagnosis!
• Analysis of patient’s story - “the history”
• The clinical findings• Which lab tests?• Which radiology tests?• Where to go from there …….
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Patient does not wear a label !
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How doctors think
In-built biases in our thinking about likely diagnosis
Jerome Groopman
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A case history 1
• Female, 48 years• Tiredness, “slowing down”• Weight gain, 5kg• Noticing the cold - cold peripheries
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Case history 1.
• Questions you would ask ?• On examination - what you might
look for in particular ?• Tests you might initially perform ?
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Case history 1.
• Patients often use non-specific terms• Slowing down = breathlessness• Dyspnoea on exertion ?• “Systems review” - all the main body
systems - respiratory, cardiac etc.• Past history ?
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Specific terms
• Time to learn these and use them!• Impress??• Dyspnoea• Ankle oedema• Tachycardia• Bradycardia
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Case history 1.
• Examination• Pale conjunctiva, palmar creases• Mild swelling of ankles - oedema• Cold hands, white fingers• Pulse 55 beats/min• DIAGNOSIS ?
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Case history 1.
• Pale conjunctiva - anaemia ?• Oedema - possible cardiac failure• Cold hands - vascular disease ?• Pulse 55 beats/min - cardiac
disease ??• DIAGNOSIS ?
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Case history 1.
Diagnosis - Hypothyroidism• Common disorder ~ 4% pop.
affected• Need high index of suspicion• Test - thyroxine and TSH levels• Autoantibody - to “thyroid
peroxidase”• Previous hyperthyroidism !
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Clinical hypothyroidism
but often the signs are not noticeable …….
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Hypothyroidism
• Inflammatory damage to thyroid• Impaired synthesis of thyroid hormone• “Hashimoto’s thyroiditis”
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Hyperthyroidism
• Common cause - Graves’ disease• Caused by auto-antibody to TSH receptor• Antibody can transfer across placenta -
neonatal hyperthyroidism• Test - anti-TSH receptor antibody• Diagnosis - raised T4 (thyroxine) and low TSH
level
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Graves’ disease
• Autoantibody binds to cell receptor
• Excessive thyroid hormones produced
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Goitre
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Graves’ disease
Auto-immune thyroiddisease
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Patient 1 has anaemia
• What is the cause ?• Does hypothyroidism cause anaemia ?• Chronic disease - some cause anaemia• Is it due to deficiency of haematinic ?
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Anaemia in a 48 yr old female
Possible causes • Iron deficiency• Folic acid deficiency• Vit. B12 deficiency• Causes of deficiency ??
• Haemolytic anaemia
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Anaemia in a 48 yr old female
Iron deficiency• Blood loss ? From where ?• Dietary ?• Malabsorbtion ?
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Anaemia in a 48 yr old female
Folic acid, B12 deficiency ?Causes• Malabsorption !• Dietary ?• Increased folic acid requirements - pregnancy
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Case 2
• Male, 73 years• Numbness, pins and needles in feet• Unsteady gait• Breathless on exercise• QUESTIONS ?
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Case 2
• Very pale• Red tongue – glossitis• Decreased sensation in lower limbs*• Unsteady gait• Otherwise appears well
* proprioception
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B12 malabsorbtion
Pernicious anaemia• Auto-immune gastritisAuto-antibodies to• Parietal cells• Intrinsic factor
• Often subtle, sub-clinical presentation
Thomas Addison
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Pernicious anaemia - auto-immune gastritis
Diagnosis –Vitamin B12 level
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Pernicious anaemia
• Red cells enlarged = macrocytic• Atypical nuclei = megaloblastic *• Raised bilirubin – yellow
pigmentation
* seen only in bone marrow
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Text books
• Case studies in Immunology – Fred Rosen, Raif Geha
• Essentials of Clinical Immunology – Helen Chapel, Mansel Haeney et al.
• Concise Clinical Immunology for Healthcare professionals – Mary Keogan, Eleanor Wallace, Paula O’Leary
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Case 3
• Female, 33 years of age• flatulence • abdominal distension• Alternating diarrhoea, constipation• Given diagnosis “irritable bowel
synd.”
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Case 3
• More questions ?• Examination - what features might
you look for ?
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Case 3
• Hgb – 10g/dl• MCV – 73• Ferritin – 8ug/L (low)• Folic acid – 3ug/L (low)
• DIAGNOSIS ?
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Iron, folic acid deficiency
• Malabsorption !• Coeliac disease
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Iron, folic acid deficiency
• Malabsorption !• Coeliac disease
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Coeliac disease
Destruction of villi - “atrophy”
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Coeliac disease
• Common ~ 1% of populationSubtle symptoms• Often asymptomatic• Bowel - dyspepsia, diarrhoea, bloating• Deficiency - anaemia, osteoporosisCause - eating gluten !
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Gluten - essential for disease
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Coeliac disease
An auto-immune disease ?• Strong association with MHC class II allotypes
- HLA-DQ2, HLA-DQ8• MHC genes ~ 40% of genetic component• Auto-antibodies - very specific !
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Essential genetic factors
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Endomysial auto-antibody
IgA class antibodyHighly specific - only found in coeliac diseaseVery sensitive + in 85% of patients
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Auto-antibody detection
Immunofluorescence - tissue sections with relevant antigen
* subjective, specific
patient serum aby
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Endomysial auto-antibody
Antigen in tissue – enzyme called tissue transglutaminase – tTGModifies gluten
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Tissue transglutaminase auto-antibody - ELISA
IgA class antibodyTissue transglutaminase is the antigen found in monkey oesophagus
anti-IgApatient antibody
tissue transglutaminase
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Tissue transglutaminase auto-antibody
IgA class antibodyVery specific - in 95% patient has CDVery sensitive + in 95% of CD patients
anti-IgApatient antibody
tissue transglutaminase
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Gluten
HLA-DQ2/8
T-cells
Tissue transglutaminase
Frits Koning, Leiden 20003
MOLECULAR MECHANISMS UNRAVELLED
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Deamidation of gliadin peptides by tTG increases their affinity for DQ2
Gliadin peptide
tTG
H2O
PQ
PE
LP
YP
PQ
APC DQ2 T CellTCR
Greg Byrne, PhD 2006
Inflammation
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Auto-immune diseases
• Co-associate• Thyroid disease, pernicious anaemia, coeliac
disease co-exist• Also diabetes mellitus• More common in females• Auto-antibody - often diagnostic• Linked to MHC class II genes
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Endocrine auto-immunity
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Case history 4 23 year old female Joint pain, stiffness Rash on sun exposed areas Cold peripheries Tiredness
DIAGNOSIS ?
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Case history 4
Questions - Swelling of joints ? Stiffness - when during day, how long ? Rash - permanent, comes and goes ? Cold - Raynaud’s phenomenon ? Tiredness - sleep pattern,
concentration?
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Case history 4
Diagnosis - “Connective tissue disease”
Possibilities include - Rheumatoid arthritis Systemic lupus erythematosus
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Case history 4
Investigations - Blood tests FBC Hgb 9 g/l low WCC 3.2 x 109 /L - low Lymphocytes - 0.7 x 109 /L - low Platelets – 100 x 109 /L - low
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Case history 4
More tests - ESR - 55mm/hr high C-reactive protein – 5 mg/L - normal Rheumatoid factor - negative Anti-nuclear antibody - positive, 1280 titre
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Anti-nuclear antibody positive stainingHep2 cells usedWill stain nucleus in any cellNot specific for systemic lupus !!!
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SLE
Systemic disease - multiple areas of damage possibleRed, white cells and platelets often affected
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Case history 4
Diagnosis Findings suggestive of systemic lupus
erythematosus Additional tests ? Antibody to double stranded DNA ?
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Anti-dsDNA
Crithidia lucilea
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ds DNA antibodies
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SLE - synovial inflammation
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SLE synovial inflammation
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“butterfly” rash on “malar’” region of face photo-sensitive
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SLE - classic butterfly rash
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Rheumatoid arthritis
• Commonest form of connective tissue disease• No diagnostic blood test !!
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Rheumatoid arthritis
Joint deformity in established disease
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Rheumatoid arthritis
• X-ray findings very helpful in diagnosis
Lytic lesions on X-ray
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Rheumatoid arthritis
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Rheumatoid arthritis
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Rheumatoid arthritis
• Common - 1-2% of population
• Female > male
• Older age group - 50s +
• Chronic, destructive arthritis in some pts
• Reduced life expectancy
• Anti-TNF drugs beneficial
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Rheumatoid arthritis
• Rheumatoid factor positive = “RF”• RF = IgM antibody to IgG• NOT specific for RA• New antibody test – antibody to “cyclic
citrullinated peptide” – more specific for RA
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Other connective tissue diseases
• Some have features similar to lupus• Commonly ANA positive but ……• Also have antibodies to other specific antigens• These are antibodies to so-called “extractable
nuclear antigens” = ENA
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Sjogren’s syndrome
• Dry eyes, dry mouth• Inflammation in salivary, lacrimal glands• ENA antibodies – anti-Ro, anti-La*
• Ro and La named after patients
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Scleroderma
• Condition in which skin thickening develops• Caused by deposition of collagen in skin and
internal organs• ENA antibody – anti-Scl-70
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Tightening of skin in some types of CTD
“Scleroderma”
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End of lecture 1