A transcriptional defect underlies B lymphocyte dysfunction in a patient diagnosed with non-X-linked hyper-IgM syndrome

To establish the underlying cause of hyper-IgM syndrome in one female patie nt, B cell function was examined in response to CD40-and IL-4-mediated path ways. When CD40-induced functional responses were measured in unfractionate d B cells, CD80 upregulation, de novo C mu-C gamma recombination, and I gam ma transcription were all found to be relatively unaffected. However, CD40- and IL-4-mediated CD23 up-regulation and VDJ-C gamma transcription were cl early diminished compared to control cells. IL-4-induced CD23 expression wa s measurably reduced in the CD20(-) population as well. These results sugge sted that the patient's defect is positioned downstream of CD40 contact and affects both CD40(-) and IL-4 signal transduction pathways. Further analys is of B cell function in CD19(+) B cells revealed a clear B cell defect wit h respect to I gamma and mature VDJ-C gamma transcription and IgG expressio n. However, under the same conditions I epsilon transcription was relativel y 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, Becaus e addition of IL-4 to cocultures containing activated T cells failed to ind uce B cells to undergo differentiation, the ability of the patient's B cell s to acquire a responsive phenotype correlated with receiving a sustained s ignal through CD40, These findings support a model in which the patient exp resses an intrinsic defect that is manifested in the failure of specific ge nes to become transcriptionally active in response to either CD154 or IL-4 and results in a functionally unresponsive B cell phenotype.