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* Abstract Our understanding of the X-linked lymphoproliferative syndrome (XLP) has advanced significantly in the last two years. The gene that is altered in the condition (SAP/SH2D IA) has been cloned and its protein crystal structure solved. At least two sets of target molecules for this small SH2 domain-containing protein have been identified: A family of hematopoietic cell surface receptors, i.e. the SLAM family, and a second molecule, which is a phosphorylated adapter. A SAP-like protein, EAT-2, has also been found to interact with this family of surface receptors. Several lines of evidence, including structural studies and analyses of missense mutations in XLP patients, support the notion that SAP/SH2D1A is a natural inhibitor of SH2domain-dependent 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/SH2D lA gene has been disrupted suggest that EBV infection is not per se critical for the development of XLP phenotypes. It appears therefore that the SAP/SH2D1A gene controls signaling via the SLAM family of surface receptors and thus may play a fundamental role in T cell and APC interactions during viral infections.
Key Words XLP, SAP/SH2D1A, SLAM, EBV, lymphocyte
INTRODUCTION
A familial disorder affecting males with a rapidly fatal course in response to Epstein-Barr virus (EBV) infection was first reported by David Purtilo more than 25 years ago (1). Six male maternal cousins out of 18, who were born in one generation, died of fulminant infectious mononucleosis, while none of their sisters were affected. The disease was characterized by proliferation of lymphocytes and histiocytes, variable hepatic abnormalities and alterations in serum immunoglobulins ranging from agammaglobulinemia to polyclonal hypergammaglobulinemia. Two of the cousins, who were half-brothers from separate fathers, had lymphomas of the ileum and central nervous system. The disease was initially called X-linked recessive progressive combined variable immunodeficiency, or Duncan's disease after the family's name. Subsequently, the possibility of a lymphoproliferative disorder was entertained, and it was speculated that a cytotoxic effect of EBV...