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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Agammaglobulinemia / genetics
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Agammaglobulinemia / immunology
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Agammaglobulinemia / pathology
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Antigens, Differentiation, T-Lymphocyte / genetics*
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Antigens, Differentiation, T-Lymphocyte / immunology
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B-Lymphocytes / immunology
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B-Lymphocytes / pathology
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Bacterial Infections / immunology
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Bacterial Infections / pathology
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Carcinoma / genetics
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Carcinoma / immunology
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Carcinoma / pathology
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Child, Preschool
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Common Variable Immunodeficiency / genetics*
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Common Variable Immunodeficiency / immunology
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Common Variable Immunodeficiency / pathology*
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Female
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Germinal Center / immunology
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Germinal Center / pathology
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Homozygote
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Humans
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Immunologic Memory / genetics
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Immunologic Memory / immunology
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Inducible T-Cell Co-Stimulator Protein
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Interleukin-10 / immunology
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology
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Male
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Middle Aged
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Models, Immunological
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Neutropenia / genetics
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Neutropenia / immunology
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Neutropenia / pathology
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Pedigree
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T-Lymphocytes / immunology
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T-Lymphocytes / pathology
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Vulvar Neoplasms / genetics
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Vulvar Neoplasms / immunology
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Vulvar Neoplasms / pathology
Substances
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Antigens, Differentiation, T-Lymphocyte
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ICOS protein, human
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Inducible T-Cell Co-Stimulator Protein
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Interleukin-10