ABNORMAL CD4O-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. I n all 10 cases, B cells were found to be defective for IgG, IgA, and I gE production after stimulation by anti-CD40 mAbs and cytokines. In th e patients tested, neither B cell proliferation (n = 6) nor CD23 molec ule 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 conclusio n was supported by a lack of detectable germinal centers in the spleen of two patients. CD40-triggered activation events, i.e., phosphatidyl inositol 3 (PI3) kinase activation and induction of transcription fact ors NF-kappa B and AP-1, were next analyzed in B cell lines derived fr om five patients. Three distinct patterns were observed: an absence of detectable abnormalities (n = 1), defective PI3 kinase activation wit h normal induction of NF-kappa B and AP-1 (n = 3), and defects in both PI3 kinase activation and induction of NF-kappa B and AP-1 (n = 1). I n three B cell lines, each exhibiting one of the CD40-mediated activat ion patterns, sequences of CD40 and CD40 binding protein coding region s were normal. The coding region of TNF receptor-associated factor 2 ( TRAF2), which is known to interact with CD40 for NF-kappa B induction, was also found to be normal in B cell lines deficient in NF-kappa B i nduction. Altogether, these results suggest that CD40 ligand-positive hyper-IgM syndrome could be genetically heterogeneous, although phenot ypic variability is not excluded, and that an early defect in the CD40 -triggered activation cascade can account for defective Ig class switc hing in some patients with CD40 ligand-positive hyper-IgM syndrome.