CD40 : CD40L interactions in X-linked and non-X-linked hyper-IgM syndromes

Hyper-IgM (HIM) syndrome is a rare immunodeficiency characterized by low or absent IgG, IgA, and IgE with normal or elevated levels of IgM. This disor der can be acquired or familial with either X-linked or autosomal patterns of inheritance. The X-linked form of the disease is a consequence of mutati ons in the CD40 ligand (CD40L) gene that encodes a protein expressed primar ily on activated CD4(+) T cells. The cognate interaction between CD40L on T cells and CD40 on antigen-stimulated B cells, macrophage, and dendritic ce lls is critical for the development of a comprehensive immune response. The non-X-linked form of HIM syndrome is heterogeneous and appears in some cas es to be a consequence of mutations in the AID gene which encodes a B cell specific protein required for class switch recombination, somatic mutation, and germinal center formation. However, mutations in other unidentified ge nes are clearly the basis of the disease in a subset of patients. In this a rticle, we review the essential features of the X-linked and non-X-linked f orms of HIM syndrome and discuss the critical role the CD40:CD40L receptor- ligand pair plays in the pathogenesis of these immune deficiencies.