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Pathogenesis IgE atopy & anaphylaxis J van Schalkwyk Perioperative Physician Auckland City Hospital Major Players • Mast Cell • Basophil • IgE • • • • B cell Plasma cell T cell Dendritic cell A complex drama! A. How IgE forms B. Mast cell and basophil C. Control A. IgE formation 1. Antigen meets B cell Ag A. IgE formation 1. Antigen meets B cell 2. B cell packages & presents Ag to helper T cell A. IgE formation 1. Antigen meets B cell 2. B cell packages & presents Ag to helper T cell 3. B cell proliferates A. IgE formation 1. Antigen meets B cell 2. B cell packages & presents Ag to helper T cell 3. B cell proliferates 4. A switch to IgE A. IgE production 1. Antigen meets B cell 2. B cell packages & presents Ag to helper T cell 3. B cell proliferates 4. A switch to IgE CD40L IL4 “class switch recombination” A. IgE production 1. Antigen meets B cell 2. B cell packages & presents Ag to helper T cell 3. B cell proliferates 4. Plasma cells & memory cells Memory cell B. Basophil & Mast cell IgE binds to the mast cell HOW? B. Mast Cell IgE binds to the mast cell HOW? FceRI B. Mast Cell FceRI • High affinity • 200 000/cell • 10% occupancy works fully! B. Mast Cell Ag B. Mast Cell Ag B. Mast Cell Ag B. Mast Cell Ag PI3 kinase B. Mast Cell Degranulation • • • • • Serotonin Pg, leukotrienes Proteases Chemokines Cytokines Histamine (H1, H2, H3) B. Mast Cell Target organs • • • • Lungs Heart Vasculature Cutaneous ANAPHYLAXIS Cardiovascular collapse Urticaria Bronchospasm B. The Basophil Role still unclear! • < 1% of white cells • No tryptase • Lots of histamine • Rich in FceRI Late phase? C. Control Massively complex • Th1 versus Th2 • • • • Genetic factors The dendritic cell FceRII Innate Immunity! C. Control Th2 phenotype • A particular Th1 pattern in CD4+ phenotype helper cells… Gamma interferon production! IL12 IL4 C. Control Th2 phenotype • A particular pattern of cytokine production in CD4+ helper cells… ATOPY IL4 C. Control Why Th2? • • • • • Genetics Allergens The basophil Histamine! Innate immunity! Polymorphic Toll-like receptors FceRII (CD23) inhibits soluble CD23 promotes alternate IgE switches IgE V genes and atopy Implications Diagnostic • Tryptase • Histamine • Newer tests of basophils in anaphylaxis Therapeutic Exciting but expensive prospects for immune modulation • omalizumab • GE2 cross links FceRI to FcgRII The End