1. מי אינו סובל מחסר חיסוני ?! פרופ' עמוס עציוני

2. Patient 1 Lihi – 1y 4 month, parents not related. Normal development + immunization. No previous infections. 3 days high fever + Meningeal signs. Purulent meningitis due to Step. Pneumonia Full recovery with antibiotics.

3. Patient 2 2 healthy siblings. Parents not related. 6 month of age-pneumococcal meningitis. 1y osteomyelitis. From 1y up to now 8 years old- normal development no infections. Normal CBC. Humoral immunity: IgG+A+M serum levels and specific antibody response (including polysaccharides + anti pneumococcal antibodies) – normal. Cellular Immunity: T cell subsets and mitogen response - normal.

4. Science March 2003

5. Proinflammatory Cytokines

7. Decrease mortality due to: 1.Hygiene understanding – Mid 19 th century. 2.Vaccination – Early 20 th century. 3.Antibiotics – Early-mid 20 th century. No genetic changes in last 100 years.

8. Genetic and environmental influences on premature death in adult adoptee. Sorensen T et al. NEJM 1988 1003 adoptee born between 1924-1926 in Denmark. The study compared causes of death in the adoptee and the biological or adoptive parents. Cause of death: 1) Infections – biological parents 2) Vascular – both biological and adoptive parents. 3) Cancer – Adoptive parents.

10. Good mutations in protection against infections. CCR5 – AIDS DUFFY - Malaria

12. O’Brien & Nelson, Nat.Gen 2004

13. Nat Med. 2005 Nov;11(11):1170-2. Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1.

14. Conventional PID classification: Cellular immune defects Humoral immune defects Complement defects Phagocyte defects etc

15. Journal clinical investigation Nov 2005

16. SEVERE COMBINED IMMUNODEFICIENCY Reticulum Dysgenesis NK - ADA Def. B - RAG1 and 1 Def. NK + RAG 1 and 2 recombination Tcell – gamma c chain Def. NK - B + JAK 3 Def. NK + IL-7R Def. Tcell + B NK + Omen Synd.

17. The same RAG1 mutation (R561H) – Different clinical presentation Pt1 Pt2 Pt3 Symptoms CMV, EBVStaph sepsis Dermatitis, Candida Erythroderma — ++ — Eosinophils 420 4,550 0 CD3 CD19 N Mitogen response IgG N IgE 190 Specific ab + — — Diagnosis ? Omen Syn classical AR SCID JCI 2005

19. Monocyte-chemoattractant Protein-1(MCP-1) influences the level of IL-12 which is crucial for the normal immune defense against mycobacterium tuberculosis.

20. P valuePulm. TB (N=435) PPD + (N=334) Healthy control (N=176) Allele Not significant 27% 73% 27% 73% 26% 74% Rantes-471 A G Not significant 86% 14% 85% 15% 87% 13% MIP-1  459 C T 0.000328% 72% 49% 51% 49% 51% MCP-1-2518 A G MCP-1 genotype G is associate with pulmonary TB JEM 202,2005

22. Monocytes from MCP-1 homozygous AA: No antibody (ab) Control Isotype ab Control Anti-MCP-1 neutralizing ab Monocytes from MCP-1 homozygous GG: No antibody (ab) Control Isotype ab Control Anti-MCP-1 meutralizing ab Neutralization of MCP-1 increases IL-12Lp40 production

23. MCP-1 and IL-12p40 levels in TB patients IL-12p40 MCP-1 Genotype 14701108A 13481424A G 11781975G 0.0040.0001P value Flores – Villanueva et al JEM 2005 (202;1649)

24. Conclusion: “MCP-1 2518G has a dose effect on the of progression of TB infection to disease in Mexicans and Koreans” Flores-Villanueva, JEM, 202, 2005

25. Journal clinical investigation 1998

26. Rate of major chronic GI complications in patients with CGD with specific host defense molecule genotype. Molecule Association MPOP=0.003 F c  R III bP=0.007 F c  R II bP=0.05 IL-1RP=0.34 TNF -  P=0.42 MBLP=0.55 JCI 1998

27. IgA deficiency – Immunodeficient ? Dying from infection with no defect – Immunocompentent?

28. Immunocompetant – The ability to mount a normal immune response to a pathogen. Immunodeficiency – classical definition – A patient with a known defect in the immune system. – proposed definition – A patient who does not survive on infectious episode.

29. Non conventional PID classification. Host defect towards specific pathogen “Mendelian susceptibility to mycobacterial diseases”

30. STAT1 NEMO TLR

31. Differential Modulation of endotoxin responsiveness by human caspare-12 polymorphisms. Saleh M et al Nature 429, 75, 2004

32. Caspases mediate essential key proteolytic events in the inflammatory cascades (cytokine maturation -1-4-5) and in the apoptotic cell pathway (-2-3-6-7-8 -9-10). Caspase 12 may therefore be important in the host response to infections or in the pathogenesis of Alzheimer’s disease.

35. Decrease cytokine response to LPS from caspase 12L individuals

36. Human caspase 12 Is not involved in apoptosis

37. Caspase-12 genotype and Alzheimer or severe sepsis TotalHomo- Casp-12L Hetero- Cas-12L Casp-12S 62311(1.8%)113 (18.1%)499 (78.1%) Reference group (African American) 1843(1.6%)40(21.7%)141(76.7%) Alzheimer 384(10.5%) (p=0.002) 11(29%)23(60.5%) Sepsis 54%17% Death from sepsis

38. “Inborn errors of immunity are – unfortunately but inevitably - the rule rather than the exception” JL Casanova & Abel 2005