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 Cμ-Cγ recombination, and Iγ transcription were all found to be relatively unaffected. However, CD40- and IL-4-mediated CD23 up-regulation and VDJ-Cγ 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 Iγ and mature VDJ-Cγ transcription and IgG expression. However, under the same conditions Iε 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.