CXCR4 mutations in WHIM syndrome: A misguided immune system?

Chemokines and their receptors are key molecules in the development and function of immune cell populations and the organization of lymphoid organs. Despite their central role in immunologic function, genetic studies exploring the intersection of chemokines or their receptors and human health have revealed few associations of unambiguous significance. The best-characterized examples have revealed striking selective advantage conferred by loss of receptors used as portals of entry by pathogens. Recently, mutations in the CXCR4 chemokine receptor gene were identified in a dominantly inherited immunodeficiency disease, WHIM syndrome. Genetic and biochemical evidences suggest that the loss of the receptor cytoplasmic tail domain results in aberrant signaling. Analyses of mutant cell responses to the receptor ligand CXCL12 have revealed enhanced chemotaxis, confirming the gain-of-function effect of the truncation mutations. The clinical features and potential mechanism of immunodeficiency in WHIM syndrome patients are discussed in this review.