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Immunology 2008 Lecture 25 Immunodeficiency 10 November

Immunology 2008 Lecture 25 Immunodeficiency 10 November. TODAY Immunodeficiency, Chap. 21. Immunodeficiency. Immunodeficiencies. ● Congenital/Primary genetic or developmental defect ● Acquired/Secondary result of disease or therapy. Efferent/Congenital. Chronic Granulomatous Disease.

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Immunology 2008 Lecture 25 Immunodeficiency 10 November

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  1. Immunology 2008 Lecture 25 Immunodeficiency 10 November

  2. TODAY Immunodeficiency, Chap. 21

  3. Immunodeficiency

  4. Immunodeficiencies ● Congenital/Primary genetic or developmental defect ● Acquired/Secondary result of disease or therapy

  5. Efferent/Congenital Chronic Granulomatous Disease  defect in the ability of MF and PMNs to kill phagocytosed organisms  chronic bacterial infections  several genetic defects in NADP oxidase system  antibiotics (& B.M. transplant?)

  6. Efferent/Congenital Complement Deficiencies  absence of one or another complement component  C1,4: autoimmune diseases, some infections C5-9: Neisseria infections Properdin : many pyogenic infections  maintained with antibiotics Question: Would bone marrow transplant help?

  7. Bruton’s Agammaglobulinemia DiGeorge Syndrome, Thymic Aplasia Severe Combined Immunodeficiency Central/Congenital

  8. Central/Congenital Bruton’s Agammaglobulinemia  bacterial infections starting ~4-8 months  absence of functional B-cells  X-linked recessive, gene for BTK (Bruton’s Tyrosine Kinase)  Intravenous Ig therapy

  9. ? Central/Congenital DiGeorge’s Syndrome, Thymic Hypoplasia  postnatal hypocalcemic tetany, viral and fungal infections within first few months  absence of thymus or functional T-cells  development defect of 3rd & 4th pharyngeal pouches, defective thymus & parathyroid (part of heterogenous family of Cardiovelofacial Syndrome)  sporadic deletions on chromosome 22  supportive therapy, or thymic epithelial transplant ectopic transplant

  10. Central/Congenital Severe Combined Immunodeficiency  overwhelming infections in first year of life  absence of functional T- or B-cells  several genetic defects, including ADA (adenosine deaminase), PNP (purine nucleotide phosphorylase), IL-2Rg (IL-2 receptor gamma, X-linked)  cured with successful B.M. transplant

  11. David the “Bubble Boy”, born with SCID ●Born in 1971; older brother had died of SCID (Pneumocystis infection) one year earlier. ●Potential problem was expected; 50% male, 50% diseased ●“Germ-free” birth, reverse isolation chamber. (Not truly germ-free, 35 species of microorganism identified at age 6).

  12. ● Phagocytic function, ADA & com-plement close to normal. ● IgM low, no IgG, traces of IgA, some IgD (determined with RID)

  13. ●No response to KLH, either by Ab or skin test (CMI). ●No Ab response to typhoid antigen

  14. ●Lymphocytes ~400/cmm (~10% of normal), ~1/3 sIg+, ~2/3 ERFC ●Minimal lymphocyte response to PHA, PWM, MLC. ●“Transfer Factor” given at 10-16 months; poor or no response to fungal skin tests.

  15. ●Bone marrow transplant in 1983 at age 12 (treated with mAb to reduce T-cells) from 15-year-old sister. ●Died 4 months later with a poorly understood pathology

  16. Central/Congenital New Form of Human T-Cell Deficiency Pignata, C. et al., Am. J. Med. Genet. 65, 167-170 (1996) Frank et Al., Nature. 398, 473-4 (1999)  Two sisters in southern Italy, each born with complete absence of scalp hair, eyelashes and eyebrows.  No thymic shadow visible on X-ray, striking impairment of T-cell function.  One sister died at 12 months, the other survived after receiving a B.M. transplant at 5 months  Mutation in WHN gene on chromosome 17 whn is the mutated gene responsible for nu/nu mice, encodes a transcription factor in thymus & skin

  17. Central/Congenital X-Linked Hyper-IgM Syndrome  bacterial infections in first 2 years, upper respiratory and others  low serum IgG, high IgM  X-linked recessive gene  Maintained by intravenous Ig What gene is this?

  18. Classic Three-Cell Interaction from Core Notes

  19. XHIGM - Absence of CD40L Modified to account for generation of B memory cells (IgM) (IgG…)

  20. Leukocyte Adhesion and Migration Important for all aspects of generation and execution of immune responses

  21. Efferent/Congenital Leukocyte Adhesion Deficiency, Type I  Failure to express CD18 b-2 integrin on lymphocytes, monocytes and neutrophils, part of adhesion complexes (including LFA-1) and C3b receptor  Massive bacterial infections by 2 years  Defective migration of lymphoid cells to sites of infection and inflammation  Cured by successful B.M. transplantation

  22. Acquired Immunodeficiencies Secondary to Disease ● Infectious disease (toxins, immunosuppression; HIV…) ● Malignancy (immunosuppression, depression of hematopoiesis) ● Malnutrition (T-selective deficiencies) ● Splenectomy (loss of filtration & phagocytic cells; increased bacterial infections)

  23. Acquired Iatrogenic immunodeficiencies caused by therapeutic intervention ● Cytotoxic drugs, steroids, (malignancies, autoimmune & inflammatory conditions…) ● ALG (anti-lymphocyte globulin) ● Ionizing radiation ● Cyclosporin, FK506 (tacrolimus) (organ grafts, autoimmunity…)

  24. THURSDAY Allergy, Chapter 18 Hybridomas, Appendix 10 MONDAY Exam #2, 9:00 AM Covers all material since the first exam through this week (+HLA genetics & MLR) TUESDAY Tumor Immunology, Chap. 23

  25. Fin

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