The molecular basis of X-linked hyper-IgM immunodeficiency

Abstract

The interaction between the CD40 ligand (gp39), expressed by activated T cells, and CD40, constitutively expressed by B cells, is critical for an effective antibody response to T cell dependent antigens. Patients with X-linked hyper IgM (HIM) syndrome fail to express a functional CD40 ligand due to a mutation within the gene for gp39. As a direct consequence, HIM patients, when immunized with T dependent antigens, produce only small amounts of IgM antibody without the development of immunologic memory, amplification and switch from IgM to IgG. Mutations affecting the gene for the HIM syndrome are localized throughout the coding region of gp39 and consist predominantly of point mutations. The resulting amino acid substitutions interfere directly with the receptor binding site or lead to stop codons or deletions secondary to splice site mutations. Expression of gp39 by activated T cells from patients with common variable immunodeficiency (CVI) is low in approximately half of the patients and is associated with depressed expression of IL-2. These findings suggest that inefficient signaling via CD40 may be responsible in part for failure of B cell differentiation in CVI.