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An introduction to clinical immunology

An introduction to clinical immunology. Kevin Dooms, MD Bellingham Asthma, Allergy & Immunology Clinic February 25, 2011. Disclosures. No conflicts of interest for this talk Dr. Prody did by me a cup of coffee. So your immune system is broken?. Increased susceptibility to infection

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An introduction to clinical immunology

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  1. An introduction to clinical immunology Kevin Dooms, MD Bellingham Asthma, Allergy & Immunology Clinic February 25, 2011

  2. Disclosures • No conflicts of interest for this talk • Dr. Prody did by me a cup of coffee

  3. So your immune system is broken? • Increased susceptibility to infection • Increased autoimmunity • e.g. lupus, MS, psoriasis • decreased immune autoregulation • Increased cancersusceptibility • oncogenic viruses (e.g. EBV) • decreased immune surveillance

  4. Immune deficiency: Primary vs. Acquired • Primary deficiency • heritable or spontaneous mutations • “experiments of nature”, -Robert Good, MD, PhD • Acquired deficiency • protein-calorie malnutrition • infection (HIV) • iatrogenic: radiation, chemo

  5. Primary immune deficiency syndromes (IDS) • Defects in innate immune response • phagocytic killing (e.g. neutrophils) • complement cascade, TLRs • Defects in stages of T/B/NK lymphocyte maturation • mutations in enzymes/transcription factors • Defect in adaptive lymphocyte response toantigenic stimulation • defective Ig production/function

  6. Roadmap: congenital defects in immune cell ontogeny

  7. Common lab studies • Complete blood count (CBC) • absolute lymphocyte count (ALC) • IgG, IgA, IgM (+/- IgG subclasses) • C3, C4, CH50 (+/-MBL) • IgG protein vaccine titers (Tetanus, Diphtheria) • IgG polysaccharide vaccine titers (S. Pneumoniae) • Delayed-type hypersensitivity • Special studies: flow cytometry, lymphoproliferation/mitogen stimulation, FISH, etc.

  8. Case 1 • 6-week-old female with a generalized seizure • Birth history: term gestation, smallish baby, slow growth, a little “funny looking” • Exam: low-set ears, heart murmur • Labs: critically low calcium, low WBC count • Other: ventriculoseptal defect (heart), misshapen kidneys

  9. DiGeorge Anomaly • Defect:microdeletion in 22q11 • field defect in embryogenesis • 1:4,000, AD?, also spontaneous • Findings: • malformed thymus, parathyroid • malformed heart, kidney • abnormal facies, MR • immune defects • Lab findings: • +/- low calcium, +/- low T cells • Treatments:depends on involved systems • Natural history:proportional to microdeletion

  10. DiGeorge anomaly

  11. DGA: defect in 3rd and 4th pharyngeal arches

  12. DGA appearance: • - low-set, downturned ears • bulbous nose • “fish”mouth

  13. Chest X-ray in DGA Normal Absent thymus

  14. Multi-system IDS . .

  15. FYI: other multisystem disorders with immune deficiency • Ataxia-telangiectasia • ATM mutation, defective DNA repair humoral defects (IgA, IgG2 def) • abnormal gait (ataxia) • vascular malformations, tumors • autoimmune disease • Chédiak-Higashi • pyogenic bacterial infections • oculocutaneous albinism, organ infiltrates • Wiskott-Aldrich • defective WAS protein • infections, eczema, microthrombocytopenia (small platelets)

  16. Case 2 • 3-year-old boy presents with chronic diarrhea, “swollen lymph nodes”, and skin infections • Birth history: term gestation, smallish baby, slow growth • Exam: skin/perirectal abscesses • Labs: • normal T & B cells • normal Ig and complement levels • Other: Mom is pregnant. It’s a boy.

  17. Chronic Granulomatous Disease • Defect: 1:250,000 • usually XL, also AR forms • defective superoxide anion formation (reactive O2 species) • Findings: numerous skin and organ abscesses • Lab findings: abnormal oxidative burst • Treatments: • Bactrim, IFN-g, itraconazole • HSCT, ?gene therapy • Natural history: • frequent serious bacterial (catalase +) infections • death in teens or twenties

  18. Chronic granulomatous disease (CGD)

  19. Abscesses in Chronic Granulomatous Disease (CGD) Lymphadenitis Purulent liver abscess Classic “granuloma” Lung abscess

  20. Mom’s pregnant: chances of another affected child? Bonus: can her daughters be affected? X chromosome

  21. Disorders of innate immunity . ..

  22. Other disorders of innate immunity

  23. You will never meet anyone with LAD

  24. Case 3 • 68 year old gentleman with non-stop sinus infections, 3 serious pneumonias, bacterial meningitis twice • Past history: infections as above, juvenile arthritis • Exam: no lymphoid tissue, nasal voice • Labs: • absent immune globulins (Ig) • no response to polysaccharide antigens • no B cells

  25.  sinus infection since 1979 Normal tonsils  No tonsils (or lymph nodes)

  26. (Bruton’s) X-linked agammaglobulinemia • Defect: • X-linked recessive, 1:200,000 • Btkmutation; failure at pre-B receptor • AR forms: IgM HC (µ), λ5 surrogate LC; Igα • Clinical findings: • frequent sinopulmonary infection • no lymphoid tissue • Lab findings: • no B cells (CD19), no IgGAM, no protective antibodies • Treatments: • lots and lots of antibiotics • IVIG (intravenous IgG) • Natural history: • infections, but relatively normal life span

  27. X-linked agammaglobulinemia

  28. B cell disorders (adaptive immunity) ..

  29. T vs B cell Immunodeficiency

  30. Case 4 • JP is a 4-month-old boy with failure to thrive, diarrhea, thrush, pneumonia, skin infections • Birth history: • small, but now infections • “normal” newborn screen • Exam: cachectic infant • Labs: • low lymphocytes (ALC) • low Ig, no response to vaccines

  31. Severe combined immune deficiency (SCID) • Multiple defects: • <1:100,000 (XL, common gamma chain) • 1:2,500 Navajo/Apache (Artemis) • Findings: • minimal thymus/lymphoid tissue, s-i-c-k baby • low lymphocytes, normal IgG (passive transfer) • Treatments: • antimicrobials, stem cell transplant, ?gene therapy • Natural history: • usually fatal in 1-2 years (viruses, intracellular pathogens)

  32. Severe combined immune deficiency (SCID)

  33. Failure to thrive in SCID Erythroderma in Omenn Syndrome

  34. Common gamma chain (ϒc) SCID IL-2RG: shared by receptors for IL-2,4,7,9,15

  35. Combined T and B cell disorders .. .

  36. Therapeutic approaches to IDS • Prophylactic antibiotics • Passive immunization • IVIG, Subcutaneous IgG • Stem cell transplantation • SCID, CGD, WAS, LAD, bare lymphocyte • Enzyme replacement • attempted in ADA, PNP

  37. Most common IDS in the community? • Selective antibody disorder (SAD) • recurring sino-broncho-pulmonary infections • increased risk of autoimmunity • rare to have serious infections • +/- IVIG, usually outgrow the problem • Common variable immune disorder (CVID) • though worse infections (e.g. bronchiectasis) • significant cancer risk: NHL, gastric carcinoma • need IVIG, never outgrow • HIV/AIDS

  38. IDS we didn’t touch on • Innate disorders: • Complement, MBL, and TLR defects • disorders of NK cells • disorders in T-independent pathways • Disorders of immune dysregulation • Autoinflammatory disorders • HIV/AIDS • and many more….

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