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Lethal infectious diseases of childhood: Single-gene inborn errors of immunity ?

Lethal infectious diseases of childhood: Single-gene inborn errors of immunity ? Jean-Laurent Casanova. Head, St. Giles Laboratory of Human Genetics of Infectious Diseases Pediatrician, Necker Hospital for Sick Children, Paris, France Professor, The Rockefeller University, New York, USA.

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Lethal infectious diseases of childhood: Single-gene inborn errors of immunity ?

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  1. Lethal infectious diseases of childhood: Single-gene inborn errors of immunity ? Jean-Laurent Casanova Head, St. Giles Laboratory of Human Genetics of Infectious Diseases Pediatrician, Necker Hospital for Sick Children, Paris, France Professor, The Rockefeller University, New York, USA

  2. 1911-1917: The discovery of inapparent infections Only 10-7 to 10-1 infected individuals develop clinical disease Microbes are necessary but not sufficient to cause disease Even in the course of primary infections … What accounts for inter-individual variability ? What is the pathogenesis of infectious diseases ?...

  3. Life-threatening infections of childhood: Single-gene inborn errors of immunity? Genetic cases of life-threatening infections 100% Single-gene defects Polygenic/Complex predisposition Age Puberty Primary infection Secondary infection/Reactivation

  4. Tuberculosis and other mycobacterialdiseases Mycobacteria IL-12R1 IL-12 p35 CYBB p40 IL-12R2 NEMO IRF8 CD40 CD40L IFN-gR1 IFN-gR2 STAT-1 (GAF) IFN-g Monocyte/Dendritic Cell T Lymphocyte

  5. Invasive pneumococcaldisease TLRs IL-1Rs 1 18 33 1 2 4 5 6 10 UNC-93B MyD88 TLR3 7 8 9 IRAK-4 TRIF Invasive pneumococcal disease ?

  6. Herpes simplex encephalitis TLRs IL-1Rs 1 18 33 1 2 4 5 6 10 UNC-93B MyD88 TLR3 7 8 9 IRAK-4 TRIF TRAF3 Herpes simplex encephalitis Invasive pneumococcal disease

  7. Mucocutaneouscandidiasis

  8. Conclusions and perspectives • Pioneers and leaders in the field of human inborn errors of immunity • Aim: dissecting the molecular basis of host defense in natura • The genetic theory: the new frontier in infectious diseases Aim: understanding the pathogenesis of infectious diseases (at last) Selected references: Altare et al., Science 1998; de Jong et al., Science 1998; Dupuis et al., Science 2001; Picard et al., Science 2003; Casrouge et al., Science 2006; Casanova and Abel, Science 2007; Zhang et al., Science 2007; von Bernuth et al., Science 2008; Puel et al., Science 2011. • New targets: fulminant viral hepatitis, acute viral myocarditis, etc. • New technologies: deep sequencing, stem cells, etc.

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