CD40 LIGAND (CD40L) EXPRESSION AND B-CELL FUNCTION IN AGAMMAGLOBULINEMIA WITH NORMAL OR ELEVATED LEVELS OF IGM (HIM) - COMPARISON OF X-LINKED, AUTOSOMAL RECESSIVE, AND NON-X-LINKED FORMS OF THE DISEASE, AND OBLIGATE CARRIERS

Hyper-IgM syndrome is a rare immunodeficiency characterized by low or absent IgG, IgA, and IgE with normal or elevated levels of IgM. It can occur as an acquired or familial disorder with either X-linked or aut osomal modes of inheritance. The X-linked form (HIGM1) is a result of mutations in the CD40 ligand (CD40L) gene, but the defect in non-X-lin ked forms of the disease (HIM) has not been determined. We show here t hat CD40L expression on activated T cells from non-X-linked patients c an be detected by CD40Fc, 5c8 Mab, and anti-TRAP, whereas activated T cells from HIGM1 patients either had no detectable CD40L (Type I), or stained with anti-TRAP but not CD40Fc or 5c8 (Type II). Activated T ce lls from obligate carriers varied from low to normal expression of CD4 0L. B cells from HIGM1 and non-X-linked HIM patients proliferated in r esponse to CD40L. Costimulation of B cells from HIGM1, from sporadic H IM, or from non-X-linked HIM patients with CD40L plus IL-2 resulted in some IgM production, but no significant IgG or IgA. Costimulation wit h CD40L plus IL-10 resulted in significant IgG and/or IgA secretion by B cells from some HIGM1 patients, but consistently failed to stimulat e IgG or IgA secretion by B cells from non-X-linked patients. In addit ion, costimulation with CD40L and IL-4 failed to induce IgE secretion by B cells from one non-X-linked HIM patient, and induced a weak respo nse in another. These results suggest that patients with non-X-linked forms of HIM may have an intrinsic B cell defect preventing heavy chai n switching, which is not related to expression of CD40L.