Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency.
No genetic defect is known to cause common variable immunodeficiency (CVID), a heterogeneous human disorder leading to adult-onset panhypogammaglobulinemia. In a search for CVID candidate proteins, we found four of 32 patients to lack ICOS, the "inducible costimulator" on activated T cells, due to an inherited homozygous deletion in the ICOS gene. T cells from these individuals were normal with regard to subset distribution, activation, cytokine production and proliferation. In contrast, naive, switched and memory B cells were reduced. The phenotype of human ICOS deficiency, which differs in key aspects from that of the ICOS-/- mouse, suggests a critical involvement of ICOS in T cell help for late B cell differentiation, class-switching and memory B cell generation.
Grimbacher
Bodo
B
Division of Rheumatology and Clinical Immunology, Medical School, University of Freiburg, Hugstetterstr. 55, 79106 Freiburg, Germany.
Hutloff
Andreas
A
Schlesier
Michael
M
Glocker
Erik
E
Warnatz
Klaus
K
Dräger
Ruth
R
Eibel
Hermann
H
Fischer
Beate
B
Schäffer
Alejandro A
AA
Mages
Hans W
HW
Kroczek
Richard A
RA
Peter
Hans H
HH
D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics*; D001402:B-Lymphocytes / Q000502:physiology; D018106:CD28 Antigens / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D017074:Common Variable Immunodeficiency / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007156:Immunologic Memory / Q000276:immunology; D060889:Inducible T-Cell Co-Stimulator Protein; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000502:physiology
D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; C556692:ICOS protein, human; C556694:Icos protein, mouse; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D060889:Inducible T-Cell Co-Stimulator Protein; D011948:Receptors, Antigen, T-Cell