title: A transcriptional defect underlies B lymphocyte dysfunction in a patient diagnosed with non-X-linked hyper-IgM syndrome.
abstract: To establish the underlying cause of hyper-IgM syndrome in one female patient, B cell function was examined in response to CD40- and IL-4-mediated pathways. When CD40-induced functional responses were measured in unfractionated B cells, CD80 up-regulation, de novo Cmu-Cgamma recombination, and Igamma transcription were all found to be relatively unaffected. However, CD40- and IL-4-mediated CD23 up-regulation and VDJ-Cgamma transcription were clearly diminished compared to control cells. IL-4-induced CD23 expression was measurably reduced in the CD20- population as well. These results suggested that the patient's defect is positioned downstream of CD40 contact and affects both CD40- and IL-4 signal transduction pathways. Further analysis of B cell function in CD19+ B cells revealed a clear B cell defect with respect to Igamma and mature VDJ-Cgamma transcription and IgG expression. However, under the same conditions Iepsilon transcription was relatively normal. Partial restoration of B cell function occurred if PBMC or CD19+ B cells were cultured in vitro in the presence of CD154 plus IL-4. Because addition of IL-4 to cocultures containing activated T cells failed to induce B cells to undergo differentiation, the ability of the patient's B cells to acquire a responsive phenotype correlated with receiving a sustained signal through CD40. These findings support a model in which the patient expresses an intrinsic defect that is manifested in the failure of specific genes to become transcriptionally active in response to either CD154 or IL-4 and results in a functionally unresponsive B cell phenotype.
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bhushan
authors.forename: B
authors.initials: B
authors.lastname: Barnhart
authors.forename: S
authors.initials: S
authors.lastname: Shone
authors.forename: C
authors.initials: C
authors.lastname: Song
authors.forename: L R
authors.initials: LR
authors.lastname: Covey
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018122:B7-1 Antigen / Q000096:biosynthesis; D023201:CD40 Ligand; D002460:Cell Line; D002675:Child, Preschool; D018920:Coculture Techniques; D005260:Female; D008040:Genetic Linkage / Q000276:immunology; D006801:Humans; D006942:Hypergammaglobulinemia / Q000235:genetics* / Q000276:immunology; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007127:Immunoglobulin Constant Regions / Q000096:biosynthesis / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007075:Immunoglobulin M / Q000096:biosynthesis* / Q000097:blood; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007139:Immunoglobulin epsilon-Chains / Q000235:genetics; D007142:Immunoglobulin gamma-Chains / Q000096:biosynthesis / Q000235:genetics; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology; D015847:Interleukin-4 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D017455:Receptors, IgE / Q000096:biosynthesis; D013577:Syndrome; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D014960:X Chromosome
chemical_list: D018122:B7-1 Antigen; D007127:Immunoglobulin Constant Regions; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D007139:Immunoglobulin epsilon-Chains; D007142:Immunoglobulin gamma-Chains; D008562:Membrane Glycoproteins; D017455:Receptors, IgE; D023201:CD40 Ligand; D015847:Interleukin-4