title: Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency.
abstract: The homozygous deletion of the inducible costimulator (ICOS), an activation-induced member of the CD28 family on T cells, causes an antibody deficiency syndrome in affected humans. The identification of a total of 9 ICOS-deficient patients revealed that this monogenic disease comprises the full clinical phenotype described for common variable immunodeficiency (CVID), including recurrent bacterial infections, adult as well as childhood onset, splenomegaly, autoimmune phenomena (autoimmune neutropenia), intestinal lymphoid hyperplasia, and malignancy (carcinoma of the vulva). All patients exhibited a profound hypogammaglobulinemia and a disturbed B-cell homeostasis. The severe reduction of class-switched memory B cells resulted from poor germinal center formation in the absence of ICOS. The additional decrease of naive B cells was associated with a partial inhibition of the early B-cell development at the pre-B-I stage. T-cell homeostasis seemed not to be affected, but low IL-10 production by ICOS-deficient T cells may contribute to the disturbed germinal center reaction. Human ICOS deficiency is indistinguishable from CVID and thus serves as a monogenic model for this complex syndrome.
authors.affiliation: Division of Rheumatology and Clinical Immunology, University Hospital, Freiburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Warnatz
authors.forename: Lukas
authors.initials: L
authors.lastname: Bossaller
authors.forename: Ulrich
authors.initials: U
authors.lastname: Salzer
authors.forename: Andrea
authors.initials: A
authors.lastname: Skrabl-Baumgartner
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schwinger
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
authors.forename: Marzena
authors.initials: M
authors.lastname: Orlowska-Volk
authors.forename: Rolf
authors.initials: R
authors.lastname: Knoth
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.forename: Ruth
authors.initials: R
authors.lastname: Draeger
authors.forename: Michael
authors.initials: M
authors.lastname: Schlesier
authors.forename: Hans Hartmut
authors.initials: HH
authors.lastname: Peter
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
mesh_terms: D000328:Adult; D000361:Agammaglobulinemia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics* / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D001424:Bacterial Infections / Q000276:immunology / Q000473:pathology; D002277:Carcinoma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002675:Child, Preschool; D017074:Common Variable Immunodeficiency / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D005260:Female; D018858:Germinal Center / Q000276:immunology / Q000473:pathology; D006720:Homozygote; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology; D060889:Inducible T-Cell Co-Stimulator Protein; D016753:Interleukin-10 / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D018448:Models, Immunological; D009503:Neutropenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D010375:Pedigree; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014846:Vulvar Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D016753:Interleukin-10