clinical immunology conleth feighery john jackson niall conlon
TRANSCRIPT
Clinical immunology
Conleth FeigheryJohn 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• Bowel - peptic ulcer, Crohn’s disease• Brain - neurology - multiple sclerosis• Joints - rheumatology, RA, SLE• Allergy - immunology
Immune deficiency disorders
• Primary immunodeficiency - rare, immunology
• Secondary - common, e.g. HIV, infectious disease specialty
Making a diagnosis!
• Analysis of patient’s story - “the history”
• The clinical findings• Which lab tests?• Which radiology tests?• Where to go from there …….
Patient does not wear a label !
How doctors think
In-built biases in our thinking about likely diagnosis
Jerome Groopman
A case history 1
• Female, 48 years• Tiredness, “slowing down”• Weight gain, 5kg• Noticing the cold - cold peripheries
Case history 1.
• Questions you would ask ?• On examination - what you might
look for in particular ?• Tests you might initially perform ?
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 ?
Specific terms
• Time to learn these and use them!• Impress??• Dyspnoea• Ankle oedema• Tachycardia• Bradycardia
Case history 1.
• Examination• Pale conjunctiva, palmar creases• Mild swelling of ankles - oedema• Cold hands, white fingers• Pulse 55 beats/min• DIAGNOSIS ?
Case history 1.
• Pale conjunctiva - anaemia ?• Oedema - possible cardiac failure• Cold hands - vascular disease ?• Pulse 55 beats/min - cardiac
disease ??• DIAGNOSIS ?
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 !
Clinical hypothyroidism
but often the signs are not noticeable …….
Hypothyroidism
• Inflammatory damage to thyroid• Impaired synthesis of thyroid hormone• “Hashimoto’s thyroiditis”
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
Graves’ disease
• Autoantibody binds to cell receptor
• Excessive thyroid hormones produced
Goitre
Graves’ disease
Auto-immune thyroiddisease
Patient 1 has anaemia
• What is the cause ?• Does hypothyroidism cause anaemia ?• Chronic disease - some cause anaemia• Is it due to deficiency of haematinic ?
Anaemia in a 48 yr old female
Possible causes • Iron deficiency• Folic acid deficiency• Vit. B12 deficiency• Causes of deficiency ??
• Haemolytic anaemia
Anaemia in a 48 yr old female
Iron deficiency• Blood loss ? From where ?• Dietary ?• Malabsorbtion ?
Anaemia in a 48 yr old female
Folic acid, B12 deficiency ?Causes• Malabsorption !• Dietary ?• Increased folic acid requirements - pregnancy
Case 2
• Male, 73 years• Numbness, pins and needles in feet• Unsteady gait• Breathless on exercise• QUESTIONS ?
Case 2
• Very pale• Red tongue – glossitis• Decreased sensation in lower limbs*• Unsteady gait• Otherwise appears well
* proprioception
B12 malabsorbtion
Pernicious anaemia• Auto-immune gastritisAuto-antibodies to• Parietal cells• Intrinsic factor
• Often subtle, sub-clinical presentation
Thomas Addison
Pernicious anaemia - auto-immune gastritis
Diagnosis –Vitamin B12 level
Pernicious anaemia
• Red cells enlarged = macrocytic• Atypical nuclei = megaloblastic *• Raised bilirubin – yellow
pigmentation
* seen only in bone marrow
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
Case 3
• Female, 33 years of age• flatulence • abdominal distension• Alternating diarrhoea, constipation• Given diagnosis “irritable bowel
synd.”
Case 3
• More questions ?• Examination - what features might
you look for ?
Case 3
• Hgb – 10g/dl• MCV – 73• Ferritin – 8ug/L (low)• Folic acid – 3ug/L (low)
• DIAGNOSIS ?
Iron, folic acid deficiency
• Malabsorption !• Coeliac disease
Iron, folic acid deficiency
• Malabsorption !• Coeliac disease
Coeliac disease
Destruction of villi - “atrophy”
Coeliac disease
• Common ~ 1% of populationSubtle symptoms• Often asymptomatic• Bowel - dyspepsia, diarrhoea, bloating• Deficiency - anaemia, osteoporosisCause - eating gluten !
Gluten - essential for disease
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 !
Essential genetic factors
Endomysial auto-antibody
IgA class antibodyHighly specific - only found in coeliac diseaseVery sensitive + in 85% of patients
Auto-antibody detection
Immunofluorescence - tissue sections with relevant antigen
* subjective, specific
patient serum aby
Endomysial auto-antibody
Antigen in tissue – enzyme called tissue transglutaminase – tTGModifies gluten
Tissue transglutaminase auto-antibody - ELISA
IgA class antibodyTissue transglutaminase is the antigen found in monkey oesophagus
anti-IgApatient antibody
tissue transglutaminase
Tissue transglutaminase auto-antibody
IgA class antibodyVery specific - in 95% patient has CDVery sensitive + in 95% of CD patients
anti-IgApatient antibody
tissue transglutaminase
Gluten
HLA-DQ2/8
T-cells
Tissue transglutaminase
Frits Koning, Leiden 20003
MOLECULAR MECHANISMS UNRAVELLED
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
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
Endocrine auto-immunity
Case history 4 23 year old female Joint pain, stiffness Rash on sun exposed areas Cold peripheries Tiredness
DIAGNOSIS ?
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?
Case history 4
Diagnosis - “Connective tissue disease”
Possibilities include - Rheumatoid arthritis Systemic lupus erythematosus
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
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
Anti-nuclear antibody positive stainingHep2 cells usedWill stain nucleus in any cellNot specific for systemic lupus !!!
SLE
Systemic disease - multiple areas of damage possibleRed, white cells and platelets often affected
Case history 4
Diagnosis Findings suggestive of systemic lupus
erythematosus Additional tests ? Antibody to double stranded DNA ?
Anti-dsDNA
Crithidia lucilea
ds DNA antibodies
SLE - synovial inflammation
SLE synovial inflammation
“butterfly” rash on “malar’” region of face photo-sensitive
SLE - classic butterfly rash
Rheumatoid arthritis
• Commonest form of connective tissue disease• No diagnostic blood test !!
Rheumatoid arthritis
Joint deformity in established disease
Rheumatoid arthritis
• X-ray findings very helpful in diagnosis
Lytic lesions on X-ray
Rheumatoid arthritis
Rheumatoid arthritis
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
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
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
Sjogren’s syndrome
• Dry eyes, dry mouth• Inflammation in salivary, lacrimal glands• ENA antibodies – anti-Ro, anti-La*
• Ro and La named after patients
Scleroderma
• Condition in which skin thickening develops• Caused by deposition of collagen in skin and
internal organs• ENA antibody – anti-Scl-70
Tightening of skin in some types of CTD
“Scleroderma”
End of lecture 1