title: B cells from subjects with CVI can be driven to Ig production in response to CD40 stimulation.
abstract: The majority of patients with common variable immunodeficiency (CVI) have low to normal numbers of membrane Ig-bearing B cells; yet these cells fail to differentiate in vivo resulting in hypogammaglobulinemia. We have suggested that the differentiation failure of CVI B cells is related to a failure to respond appropriately to signals involved in terminal B cell differentiation as most CVI subjects' cells undergo activation and proliferation normally. Whether this failure relates to a direct "intrinsic" defect in the B cells or is secondary to a lack of appropriate T cell or other influences in vivo is uncertain. We have previously reported that the majority of patients with CVI have elevated circulating levels of IL-6. We now show that the IL-6 produced by these patients is functionally normal. Additionally, the display of IL-6 receptors on in vitro stimulated CVI B cells is normal. However, we found that the patients' cells do not make IgE in response to an IL-6/T-cell-dependent differentiation pathway employing exogenous interleukin-4 (IL-4). The failure to respond in the IL-6-dependent system could not be overcome by exogenous IL-6 or varying doses of IL-4. In contrast, when stimulated by CD40 plus IL-4 in a differentiation pathway that does not require IL-6, B cells from CVI patients were stimulated to produce IgE. These findings, along with our earlier data showing that 13-cis-retinoic acid can drive maturation in CVI patients, strengthen the concept that B cells in patients with CVI have the potential for terminal differentiation but do not appear to achieve this in vitro or in vivo through a polyclonal Ig differentiation pathway that employs IL-6 as one of its maturation signals.
authors.affiliation: Hart and Louise Lyon Laboratory, Department of Medicine, UCLA School of Medicine 90024-1680.
authors.forename: A
authors.initials: A
authors.lastname: Saxon
authors.forename: N
authors.initials: N
authors.lastname: Sidell
authors.forename: K
authors.initials: K
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000276:immunology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D019013:CD40 Antigens; D002454:Cell Differentiation; D004357:Drug Synergism; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis*; D007153:Immunologic Deficiency Syndromes / Q000276:immunology*; D015847:Interleukin-4 / Q000494:pharmacology; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D011971:Receptors, Immunologic / Q000032:analysis; D019947:Receptors, Interleukin-6
chemical_list: D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; D015850:Interleukin-6; D011971:Receptors, Immunologic; D019947:Receptors, Interleukin-6; D015847:Interleukin-4; D007073:Immunoglobulin E