CD40 LIGAND EXPRESSION IS DEFECTIVE IN A SUBSET OF PATIENTS WITH COMMON VARIABLE IMMUNODEFICIENCY

Common variable immunodeficiency (CVI) is characterized by hypogammagl obulinemia and recurrent bacterial infections due to failure of CVI B cells to differentiate in vivo into immunoglobulin-secreting plasma ce lls. We hypothesized that T-cell dysfunction resulting in abnormal con tact-mediated B-cell activation may play a prominent role in the failu re of CVI B cells to produce specific antibody. We have previously sho wn that B-cell proliferation and IgE production after stimulation with anti-CD40 and interleukin (IL) 4 were normal in 22 CVI patients evalu ated, indicating that CVI B cells respond to signals delivered via CD4 0. Here we report that CD40 ligand (gp39) mRNA expression by activated lymphocytes from CVI patients (n = 31) as a group was significantly d epressed (P < 0.0001) compared with normal controls (n = 32). gp39 mRN A expression by activated lymphocytes from 13 CVI patients fell below the normal control range. T-cell surface expression of functional gp39 protein was correspondingly low in those patients with gp39 mRNA leve ls below normal control range and normal in patients with gp39 mRNA le vels within normal control range. In CVI patients as a group, gp39 mRN A levels correlated with IL-2 mRNA levels (P < 0.002, r = 0.6) and pro duction (P < 0.001, r = 0.7) but not with gene expression or productio n of other lymphokines evaluated, suggesting an as-yet-undetermined as sociation between gp39 and IL-2 gene regulation. Of the 13 patients wh ose activated T cells exhibited gp39 mRNA expression below the normal control range, 2 had normal T-cell-derived lymphokine production, wher eas the remaining 11 exhibited broader T-cell dysfunction, resulting i n IL-2 deficiency, and in some patients deficient production of other lymphokines as well, reflecting a heterogeneity in the underlying mech anisms leading to depressed gp39 expression in these patients. The obs ervation that both gene and surface expression of gp39 by activated T cells is depressed in a subgroup of CVI patients suggests that ineffic ient signaling via CD40 may be responsible, in part, for failure of B- cell differentiation in these patients.