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מי אינו סובל מחסר חיסוני ?! פרופ' עמוס עציוני 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. 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. Science March 2003 Proinflammatory Cytokines Decrease mortality due to: 1.Hygiene understanding – Mid 19th century. 2.Vaccination – Early 20th century. 3.Antibiotics – Early-mid 20th century. No genetic changes in last 100 years. 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. Good mutations in protection against infections. •CCR5 – AIDS •DUFFY - Malaria O’Brien & Nelson, Nat.Gen 2004 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. Conventional PID classification: Cellular immune defects Humoral immune defects Complement defects Phagocyte defects etc Journal clinical investigation Nov 2005 SEVERE COMBINED IMMUNODEFICIENCY Reticulum Dysgenesis NK ADA Def. RAG1 and 1 Def. BNK + RAG 1 and 2 recombination Tcell – gamma c chain Def. NK - B+ Tcell + B NK + JAK 3 Def. IL-7R Def. NK + Omen Synd. The same RAG1 mutation (R561H) – Different clinical presentation Pt1 Symptoms CMV, EBV Erythroderma — Eosinophils 420 CD3 CD19 N Mitogen response IgG N IgE Specific ab + Diagnosis ? JCI 2005 Pt2 Staph sepsis ++ 4,550 190 — Omen Syn Pt3 Dermatitis, Candida — 0 — classical AR SCID Monocyte-chemoattractant Protein-1(MCP-1) influences the level of IL-12 which is crucial for the normal immune defense against mycobacterium tuberculosis. MCP-1 genotype G is associate with pulmonary TB Healthy control (N=176) PPD+ (N=334) Pulm. TB (N=435) P value Rantes-471 A G 26% 74% 27% 73% 27% 73% Not significant MIP-1459 C T 87% 13% 85% 15% 86% 14% Not significant MCP-1-2518 A G 49% 51% 49% 51% 28% 72% 0.0003 Allele JEM 202,2005 Neutralization of MCP-1 increases IL-12Lp40 production 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 MCP-1 and IL-12p40 levels in TB patients Genotype MCP-1 IL-12p40 AA 1108 1470 AG 1424 1348 GG 1975 1178 P value 0.0001 0.004 Flores – Villanueva et al JEM 2005 (202;1649) 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 Journal clinical investigation 1998 Rate of major chronic GI complications in patients with CGD with specific host defense molecule genotype. Molecule MPO FcR III b FcR II b IL-1R TNF - MBL JCI 1998 Association P=0.003 P=0.007 P=0.05 P=0.34 P=0.42 P=0.55 •IgA deficiency – Immunodeficient ? Dying from infection with no defect – Immunocompentent? 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. Non conventional PID classification. Host defect towards specific pathogen “Mendelian susceptibility to mycobacterial diseases” IL-2 IL-2R IFN T / NK IL-12R 18 ? IL- 15 IFNR STAT1 1 2 IL-12 NEMO AFB Sa lm . TNF NRAMP1 M CD14 TNFR TLR LPS Differential Modulation of endotoxin responsiveness by human caspare-12 polymorphisms. Saleh M et al Nature 429, 75, 2004 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. Decrease cytokine response to LPS from caspase 12L individuals Human caspase 12 Is not involved in apoptosis Caspase-12 genotype and Alzheimer or severe sepsis Casp-12S HeteroCas-12L HomoCasp-12L Total Reference group (African American) 499 (78.1%) 113 (18.1%) 11(1.8%) 623 Alzheimer 141(76.7%) 40(21.7%) 3(1.6%) 184 Sepsis 23(60.5%) 4(10.5%) 38 (p=0.002) Death from sepsis 17% 11(29%) 54% “Inborn errors of immunity are – unfortunately but inevitably - the rule rather than the exception” JL Casanova & Abel 2005