Intrinsic defect in B cells of patients with hyper-immunoglobulin M syndrome.
We challenge the theory that the CD40-CD40 ligand is the only explanation for X-linked immunodeficiency in patients with hyper-immunoglobulin M (IgM) syndrome (HIGM1), and we demonstrate an intrinsic defect in the patients' B cells. Patients with HIGM1 have a defective CD40 ligand on their activated T-helper cells; therefore, they cannot receive signals for isotype switching when the cells are activated by T cell-dependent antigens. We activated mononuclear cells from three patients with HIGM1 and from three healthy blood donors with T cell-independent mitogens and studied their proliferative responses and Ig secretion. Normal murine plasma membrane fragments were implanted into peripheral blood mononuclear cells, and the cells were activated with Staphylococcus aureus Cowan I, pokeweed mitogen, and lipopolysaccharide. This implantation significantly augmented the proliferative responses to the mitogens in two patients. However, it augmented IGM secretion in response to B-cell mitogens in only one patient. No IgG or IgA response could be detected in the implanted mononuclear cells that originated from patients with HIGM1, unlike implanted mononuclear cells from healthy donors, which responded by IgM, IgG, and IgA antibody secretion following their stimulation with B-cell mitogens. The data suggest that the B cells of patients with HIGM1 possess an additional defect which prevents Ig isotype switching in response to T cell-independent mitogens. This defect is not located in the membrane receptors or within the membrane enzymes.
Porat
Y B
YB
Department of Human Microbiology, Sackler School of Medicine, Tel-Aviv University, Israel.
Levy
D
D
Levy
J
J
Zan-Bar
I
I
D000293:Adolescent; D000328:Adult; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D023201:CD40 Ligand; D002462:Cell Membrane / Q000276:immunology / Q000637:transplantation; D002648:Child; D005260:Female; D006801:Humans; D006942:Hypergammaglobulinemia / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D007070:Immunoglobulin A / Q000096:biosynthesis; D017578:Immunoglobulin Class Switching / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000494:pharmacology; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008934:Mitogens / Q000502:physiology
D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; D008934:Mitogens; D023201:CD40 Ligand; D015847:Interleukin-4