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XLP (X-linked lymphoproliferative disease)

X-linked lymphoproliferative (XLP) disease is a fatal immunological disorder that renders the immune system unable to respond effectively to Epstein-Barr virus (EBV) infection. Other typical clinical phenotypes of XLP include malignant lymphoma, dysgammaglobulinemia, nasopharyngeal carcinomas, aplastic anemia, and vasculitis and pulmonary lymphomatoid granulomatosis.

The gene that is affected in XLP patients was cloned through its association with a cell surface structure termed SLAM and was therefore termed SLAM-associated protein or SAP. Simultaneously, the XLP gene was cloned by positional cloning and was subsequently called SH2D1A. The gene that encodes the SAP/SH2D1A protein is either deleted or mutated in XLP patients, resulting in uncontrolled B- and T-cell proliferation upon EBV infection. Human SAP, which is primarily expressed in T cells comprises a single SH2 domain followed by a short tail of 26 residues. The SH2 domain binds to a specific segment around the residue Tyr281 of the cytoplasmic domain of T- and B-lymphocyte surface receptor SLAM. Since binding of SAP to SLAM prevents recruitment of the tyrosine phosphatase SHP-2, SAP is thought to act as a regulator of the SLAM signal transduction pathway in T cells.

The mouse SAP gene is localized on the X chromosome and comprises four exons spanning approximately 25 kb [1]. Its expression appears to be restricted to T lymphocytes. Whereas a high level of SAP expression is observed in Th1 cells, only small amounts are detectable in Th2 cells. Moreover, SAP expression is down-regulated upon in vitro activation of T cells, including CD4+, CD8+ single-positive T cells, and Th1 and Th2 cells.

Like human SAP, mouse SAP binds to the cytoplasmic domain of the T- and B-lymphocyte surface receptor SLAM, supporting the notion that SAP is a regulator of SLAM signal transduction pathways.

[1] Wu, C. et al. Immunogenetics 51, 805-815 (2000).