The X-linked hyperimmunoglobulin M syndrome.

X-linked hyperimmunoglobulin M (X-HIM) is a rare inherited immune deficiency disease that was first described in 1961. Affected patients suffer recurrent pyogenic and opportunistic infections, neutropenia, and an increased susceptibility to cancer. In 1993, five groups independently showed that this disease results from defects in the CD40 ligand gene. CD40 ligand is a 39-kDa protein expressed on the surface of activated CD4+ T cells that delivers contact-dependent signals to CD40-expressing cells: B cells, monocytes, dendritic cells, epithelial cells, endothelial cells, and fibroblasts. The loss of interaction between CD40 and its ligand results in an impairment of T-cell function, of B-cell differentiation, and of monocyte function. Identification of the genetic defect in X-HIM has provided a definitive diagnosis of the disease, a better description of the clinical manifestations, and the capacity for genetic screening. Studies of the role of CD40 and its ligand in the immune response from many laboratories around the world have provided a better understanding of the pathogenesis of the disease. Further research may lead to novel and definitive therapeutic options for patients with X-HIM.