Abnormal CD40-mediated activation pathway in B lymphocytes from patients with hyper-IgM syndrome and normal CD40 ligand expression.

The CD40-mediated activation pathway of B cells from 10 patients with hyper-IgM syndrome and normal expression of CD40 ligand was studied. In all 10 cases, B cells were found to be defective for IgG, IgA, and IgE production after stimulation by anti-CD40 mAbs and cytokines. In the patients tested, neither B cell proliferation (n = 6) nor CD23 molecule expression (n = 5) were observed in cultures stimulated with anti-CD40 mAb. These results point to an intrinsic B cell deficiency and a defect in the CD40-triggered B cell activation pathway; this conclusion was supported by a lack of detectable germinal centers in the spleen of two patients. CD40-triggered activation events, i.e., phosphatidylinositol 3 (PI3) kinase activation and induction of transcription factors NF-kappaB and AP-1, were next analyzed in B cell lines derived from five patients. Three distinct patterns were observed: an absence of detectable abnormalities (n = 1), defective PI3 kinase activation with normal induction of NF-kappaB and AP-1 (n = 3), and defects in both PI3 kinase activation and induction of NF-kappaB and AP-1 (n = 1). In three B cell lines, each exhibiting one of the CD40-mediated activation patterns, sequences of CD40 and CD40 binding protein coding regions were normal. The coding region of TNF receptor-associated factor 2 (TRAF2), which is known to interact with CD40 for NF-kappaB induction, was also found to be normal in B cell lines deficient in NF-kappaB induction. Altogether, these results suggest that CD40 ligand-positive hyper-IgM syndrome could be genetically heterogeneous, although phenotypic variability is not excluded, and that an early defect in the CD40-triggered activation cascade can account for defective Ig class switching in some patients with CD40 ligand-positive hyper-IgM syndrome.