title: Dependence of immunoglobulin class switch recombination in B cells on vesicular release of ATP and CD73 ectonucleotidase activity.
abstract: Immunoglobulin (Ig) isotype diversification by class switch recombination (CSR) is an essential process for mounting a protective humoral immune response. Ig CSR deficiencies in humans can result from an intrinsic B cell defect; however, most of these deficiencies are still molecularly undefined and diagnosed as common variable immunodeficiency (CVID). Here, we show that extracellular adenosine critically contributes to CSR in human naive and IgM memory B cells. In these cells, coordinate stimulation of B cell receptor and toll-like receptors results in the release of ATP stored in Ca(2+)-sensitive secretory vesicles. Plasma membrane ectonucleoside triphosphate diphosphohydrolase 1 CD39 and ecto-5'-nucleotidase CD73 hydrolyze ATP to adenosine, which induces CSR in B cells in an autonomous fashion. Notably, CVID patients with impaired class-switched antibody responses are selectively deficient in CD73 expression in B cells, suggesting that CD73-dependent adenosine generation contributes to the pathogenesis of this disease.
authors.affiliation: Department of Pediatrics, University of Genova and Pediatria II, Institute G Gaslini, 16148 Genova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Schena
authors.forename: Stefano
authors.initials: S
authors.lastname: Volpi
authors.forename: Caterina Elisa
authors.initials: CE
authors.lastname: Faliti
authors.forename: Federica
authors.initials: F
authors.lastname: Penco
authors.forename: Spartaco
authors.initials: S
authors.lastname: Santi
authors.forename: Michele
authors.initials: M
authors.lastname: Proietti
authors.forename: Ursula
authors.initials: U
authors.lastname: Schenk
authors.forename: Gianluca
authors.initials: G
authors.lastname: Damonte
authors.forename: Annalisa
authors.initials: A
authors.lastname: Salis
authors.forename: Marta
authors.initials: M
authors.lastname: Bellotti
authors.forename: Franco
authors.initials: F
authors.lastname: Fais
authors.forename: Claudya
authors.initials: C
authors.lastname: Tenca
authors.forename: Marco
authors.initials: M
authors.lastname: Gattorno
authors.forename: Hermann
authors.initials: H
authors.lastname: Eibel
authors.forename: Marta
authors.initials: M
authors.lastname: Rizzi
authors.forename: Klaus
authors.initials: K
authors.lastname: Warnatz
authors.forename: Marco
authors.initials: M
authors.lastname: Idzko
authors.forename: Cemil Korcan
authors.initials: CK
authors.lastname: Ayata
authors.forename: Mirzokhid
authors.initials: M
authors.lastname: Rakhmanov
authors.forename: Thierry
authors.initials: T
authors.lastname: Galli
authors.forename: Alberto
authors.initials: A
authors.lastname: Martini
authors.forename: Marco
authors.initials: M
authors.lastname: Canossa
authors.forename: Fabio
authors.initials: F
authors.lastname: Grassi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Traggiai
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000917:Antibody Formation / Q000235:genetics / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D001081:Apyrase / Q000276:immunology / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D017074:Common Variable Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D011995:Recombination, Genetic
chemical_list: D015703:Antigens, CD; D000255:Adenosine Triphosphate; D015720:5'-Nucleotidase; D001081:Apyrase; C067869:CD39 antigen