X-linked lymphoproliferative disease: A progressive immunodeficiency

Our understanding of the X-Linked lymphoproliferative syndrome (XLP) has ad vanced significantly in the last two years. The gene that is altered in the condition (SAP/SH2D1A) has been cloned and its protein crystal structure s olved. At least two sets of target molecules for this small SH2 domain-cont aining protein have been identified: A family of hematopoietic cell surface receptors, i.e. the SLAM family, and a second molecule, which is a phospho rylated adapter. A SAP-like protein, EAT-2, has also been found to interact with this family of surface receptors. Several lines of evidence, includin g structural studies and analyses of missense mutations in XLP patients, su pport the notion that SAP/SH2D1A is a natural inhibitor of SH2-domain-depen dent interactions with members of the SLAM family. However, details of its role in signaling mechanisms are yet to be unravelled. Further analyses of the SAP/SH2D1A gene in XLP patients have made it clear that the development of dysgammaglobulinemia and B cell lymphoma can occur without evidence of prior EBV infection. Moreover, preliminary results of virus infections of a mouse in which the SAP/SH2D1A gene has been disrupted suggest that EBV inf ection is not per se critical for the development of XLP phenotypes. It app ears therefore that the SAP/SH2D1A gene controls signaling via the SLAM fam ily of surface receptors and thus may play a fundamental role in T cell and APC interactions during viral infections.