B cell differentiation defects in common variable immunodeficiency are ameliorated after stimulation with anti-CD40 antibody and IL-10.
In these studies we show that although purified B cells of patients with common variable immunodeficiency (CVI) have a normal capacity to proliferate, they manifest differentiation defects at multiple levels. Compared with controls, circulating CVI B cell populations contain reduced numbers of sIgG+ and sIgA+ cells with a commensurate increase in sIgM+ B cells, suggesting an in vivo defect in isotype switch. In addition, CVI B cells manifest Ig secretion defects on stimulation with either anti-CD40 and IL-10 or SAC and IL-2 and IL-10, which are of increasing severity for IgM, IgG, and IgA, respectively. These Ig secretion defects are not overcome by addition of a variety of cytokines, including TGF-beta, to anti-CD40-driven cultures. In further studies we show that despite the above abnormalities, CVI B cells are induced to express normal or near-normal levels of C mu, C gamma, and C alpha mRNA after 7 days of stimulation with anti-CD40 and IL-10. That this CH mRNA expression represents a recovery of CVI B cell differentiation is supported by studies of Ig secretion in which CVI B cells that are first stimulated for 7 days with anti-CD40 and IL-10 and then restimulated in coculture with activated normal allogeneic T cells and IL-10, secrete substantial levels of IgM and IgG and increased amounts of IgA. Overall, therefore, CVI B cell function can be significantly improved by maintenance in culture. These data suggest the abnormalities of B cell differentiation in CVI are reversible and that the defect is a form of B cell anergy.
Eisenstein
E M
EM
Mucosal Immunity Section, National Institute of Allergy and Infectious Disease, Bethesda, MD 20892.
Chua
K
K
Strober
W
W
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D001483:Base Sequence; D019013:CD40 Antigens; D002454:Cell Differentiation; D017074:Common Variable Immunodeficiency / Q000097:blood / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood / Q000235:genetics; D007074:Immunoglobulin G / Q000097:blood / Q000235:genetics; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000494:pharmacology; D008213:Lymphocyte Activation; D008875:Middle Aged; D008969:Molecular Sequence Data; D011947:Receptors, Antigen, B-Cell / Q000097:blood / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; D017931:DNA Primers; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D011947:Receptors, Antigen, B-Cell; D016753:Interleukin-10