What is the pathophysiology of X-linked lymphoproliferative (XLP) syndrome?

Updated: Jan 27, 2019
  • Author: Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Answer

X-linked lymphoproliferative (XLP) syndrome is characterized by a high susceptibility to severe infection with EBV. Hemophagocytic lymphohistiocytosis is the most common presenting feature. Other patients develop fulminant infectious mononucleosis following infection with EBV. Most succumb to hepatic necrosis and/or bone marrow failure. Those that survive manifest chronic hypogammaglobulinemia and are at risk for lymphoma and aplastic anemia.

In 1998, the gene for classic XLP syndrome was isolated on the long arm of the X chromosome at Xq25. This locus encodes a 128-amino acid src homology2 (SH2) domain-containing protein and was named SH2D1A. Codiscovery by other groups led to the other designations, DSHP and SAP (signaling lymphocytic activation molecule [SLAM]–associated protein). The latter is based on the encoded protein's association with SLAM.

Deficiency of SAP results in sustained T-cell proliferation in response to EBV infection due to reduced ability to kill EBV-infected B cells. In the absence of SAP, interaction of CD48 on EBV-infected cells with 2B4 (a receptor belonging to the immunoglobulin superfamily that is found on natural killer [NK] cells as well as a small subset of T cells) on NK cells inhibits their ability to kill the EBV-infected cell. In addition, in the absence of SAP, SLAM molecules interact with SHP-2, resulting in an inhibitory effect on T-cell function. Therefore the defect in XLP converts normally activating signals into inhibitory signals. [7, 8, 9, 10]

An XLP syndrome caused by mutations in the inhibitor-of-apoptosis gene XIAP has also been reported. [11, 12]


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