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
• 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!
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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
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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.
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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
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Time to learn these and use them!
Impress??
Dyspnoea
Ankle oedema
Tachycardia
Bradycardia
Case history 1.
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Examination
Pale conjunctiva, palmar creases
Mild swelling of ankles - oedema
Cold hands, white fingers
Pulse 55 beats/min
DIAGNOSIS ?
Case history 1.
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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 thyroid
disease
Patient 1 has anaemia
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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
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Male, 73 years
Numbness, pins and needles in feet
Unsteady gait
Breathless on exercise
QUESTIONS ?
Case 2
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Very pale
Red tongue – glossitis
Decreased sensation in lower limbs*
Unsteady gait
Otherwise appears well
* proprioception
B12 malabsorbtion
Pernicious anaemia
• Auto-immune gastritis
Auto-antibodies to
• Parietal cells
• Intrinsic factor
Thomas Addison
• Often subtle, sub-clinical presentation
Pernicious anaemia - autoimmune 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
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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
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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 population
Subtle symptoms
• Often asymptomatic
• Bowel - dyspepsia, diarrhoea, bloating
• Deficiency - anaemia, osteoporosis
Cause - 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 antibody
Highly specific - only found in coeliac disease
Very sensitive + in 85% of patients
Auto-antibody detection
Immunofluorescence - tissue sections
with relevant antigen
patient serum aby
* subjective, specific
Endomysial auto-antibody
Antigen in tissue – enzyme called
tissue transglutaminase – tTG
Modifies gluten
Tissue transglutaminase auto-antibody
- ELISA
anti-IgA
patient antibody
tissue transglutaminase
IgA class antibody
Tissue transglutaminase is the antigen found in
monkey oesophagus
Tissue transglutaminase auto-antibody
anti-IgA
patient antibody
tissue transglutaminase
IgA class antibody
Very specific - in 95% patient has CD
Very sensitive + in 95% of CD patients
MOLECULAR MECHANISMS UNRAVELLED
Tissue transglutaminase
Gluten
HLA-DQ2/8
T-cells
Frits Koning, Leiden 20003
Deamidation of gliadin peptides by tTG increases their affinity for DQ2
tTG
Gliadin peptide
APC
DQ2
TCR
H2O
T Cell
Inflammation
Greg Byrne, PhD 2006
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
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23 year old female
Joint pain, stiffness
Rash on sun exposed areas
Cold peripheries
Tiredness
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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?
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
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 WCC 3.2 x 10 /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 staining
Hep2 cells used
Will stain nucleus in any cell
Not specific for systemic lupus !!!
SLE
Systemic disease - multiple areas of damage possible
Red, 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
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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
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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
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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