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Clinical immunology

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

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Clinical immunology

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  1. Clinical immunology Conleth Feighery John Jackson Niall Conlon

  2. Case histories Clinical medicine - learning through a series of cases How knowledge of immunology can help Types of diseases Types of tests

  3. Inflammatory diseases Specialisation - • Respiratory - asthma, lung infections • Bowel - peptic ulcer, Crohn’s disease • Brain - neurology - multiple sclerosis • Joints - rheumatology, RA, SLE • Allergy - immunology

  4. Immune deficiency disorders Primary immunodeficiency - rare, immunology Secondary - common, e.g. HIV, infectious disease specialty

  5. Making a diagnosis! Analysis of patient’s story - “the history” The clinical findings Which lab tests? Which radiology tests? Where to go from there …….

  6. Patient does not wear a label !

  7. How doctors think In-built biases in our thinking about likely diagnosis Jerome Groopman

  8. A case history 1 Female, 48 years Tiredness, “slowing down” Weight gain, 5kg Noticing the cold - cold peripheries

  9. Case history 1. Questions you would ask ? On examination - what you might look for in particular ? Tests you might initially perform ?

  10. 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 ?

  11. Specific terms • Time to learn these and use them! • Impress?? • Dyspnoea • Ankle oedema • Tachycardia • Bradycardia

  12. Case history 1. Examination Pale conjunctiva, palmar creases Mild swelling of ankles - oedema Cold hands, white fingers Pulse 55 beats/min DIAGNOSIS ?

  13. Case history 1. • Pale conjunctiva - anaemia ? • Oedema - possible cardiac failure • Cold hands - vascular disease ? • Pulse 55 beats/min - cardiac disease ?? • DIAGNOSIS ?

  14. 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 !

  15. Clinical hypothyroidism but often the signs are not noticeable …….

  16. Hypothyroidism • Inflammatory damage to thyroid • Impaired synthesis of thyroid hormone • “Hashimoto’s thyroiditis”

  17. 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

  18. Graves’ disease • Autoantibody binds to cell receptor • Excessive thyroid hormones produced

  19. Goitre

  20. Graves’ disease Auto-immune thyroid disease

  21. Patient 1 has anaemia • What is the cause ? • Does hypothyroidism cause anaemia ? • Chronic disease - some cause anaemia • Is it due to deficiency of haematinic ?

  22. Anaemia in a 48 yr old female Possible causes • Iron deficiency • Folic acid deficiency • Vit. B12 deficiency • Causes of deficiency ?? • Haemolytic anaemia

  23. Anaemia in a 48 yr old female Iron deficiency • Blood loss ? From where ? • Dietary ? • Malabsorbtion ?

  24. Anaemia in a 48 yr old female Folic acid, B12 deficiency ? Causes • Malabsorption ! • Dietary ? • Increased folic acid requirements - pregnancy

  25. Case 2 • Male, 73 years • Numbness, pins and needles in feet • Unsteady gait • Breathless on exercise • QUESTIONS ?

  26. Case 2 • Very pale • Red tongue – glossitis • Decreased sensation in lower limbs* • Unsteady gait • Otherwise appears well * proprioception

  27. B12 malabsorbtion Pernicious anaemia • Auto-immune gastritis Auto-antibodies to • Parietal cells • Intrinsic factor • Often subtle, sub-clinical presentation Thomas Addison

  28. Pernicious anaemia - auto-immune gastritis Diagnosis – Vitamin B12 level

  29. Pernicious anaemia Red cells enlarged = macrocytic Atypical nuclei = megaloblastic * Raised bilirubin – yellow pigmentation * seen only in bone marrow

  30. 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

  31. Case 3 Female, 33 years of age flatulence abdominal distension Alternating diarrhoea, constipation Given diagnosis “irritable bowel synd.”

  32. Case 3 More questions ? Examination - what features might you look for ?

  33. Case 3 Hgb – 10g/dl MCV – 73 Ferritin – 8ug/L (low) Folic acid – 3ug/L (low) DIAGNOSIS ?

  34. Iron, folic acid deficiency • Malabsorption ! • Coeliac disease

  35. Iron, folic acid deficiency • Malabsorption ! • Coeliac disease

  36. Coeliac disease Destruction of villi - “atrophy”

  37. Coeliac disease • Common ~ 1% of population Subtle symptoms • Often asymptomatic • Bowel - dyspepsia, diarrhoea, bloating • Deficiency - anaemia, osteoporosis Cause - eating gluten !

  38. Gluten - essential for disease

  39. 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 !

  40. Essential genetic factors

  41. Endomysial auto-antibody IgA class antibody Highly specific - only found in coeliac disease Very sensitive + in 85% of patients

  42. Auto-antibody detection Immunofluorescence - tissue sections with relevant antigen patient serum aby * subjective, specific

  43. Endomysial auto-antibody Antigen in tissue – enzyme called tissue transglutaminase – tTG Modifies gluten

  44. Tissue transglutaminase auto-antibody - ELISA anti-IgA patient antibody tissue transglutaminase IgA class antibody Tissue transglutaminase is the antigen found in monkey oesophagus

  45. 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

  46. MOLECULAR MECHANISMS UNRAVELLED Tissue transglutaminase Gluten HLA-DQ2/8 T-cells Frits Koning, Leiden 20003

  47. P T Cell Q P E L DQ2 TCR APC P Y P Q P Deamidation of gliadin peptides by tTG increases their affinity for DQ2 tTG PQPQLPYPQP PQPELPYPQP Gliadin peptide H2O Inflammation Greg Byrne, PhD 2006

  48. 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

  49. Endocrine auto-immunity

  50. Case history 4 • 23 year old female • Joint pain, stiffness • Rash on sun exposed areas • Cold peripheries • Tiredness • DIAGNOSIS ?

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