Clinical immunology Conleth Feighery John Jackson Niall Conlon

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