| Summary: | X-linked Lymphoproliferative Disease (XLP) is a primary immune deficiency
characterized by a profound susceptibility to Epstein-Barr Virus (EBV). The clinical
phenotypes ascribed to XLP implicate a gene involved in the regulation of cell-mediated
immunity. Recently, the molecular basis for disease has been attributed to mutations of
SH2D1A, or SLAM-associated protein (SAP), an intracellular signal transduction
molecule known to associate with the co-stimulatory receptors SLAM and 2B4.
Molecular evidence now suggests that SAP may modulate the activation of T
lymphocytes and natural killer (NK) cells through association with the cytoplasmic
regions of SLAM and 2B4 respectively. However, precisely how SAP participates in
immune signaling remains unknown. Because NK cells are critical in anti-tumour and
anti-viral immune responses, and because reduced NK cytotoxicity has previously been
demonstrated in this disease, we sought to assess the role of mutant SAP (Arg55Leu) in
NK cells derived from XLP patients. Reverse transcription-PCR analysis ascertained that
SAP mRNA is expressed in primary NK and lymphokine-activated killer (LAK) cells.
Functional assays indicated that the cytotoxic activity of both NK and LAK cell subsets
were significantly deficient in two XLP patients relative to normal controls. Furthermore,
ligation of 2B4 failed to augment cytotoxicity and secretion of gamma-interferon (IFN-y)
by NK cells derived from XLP patients, while enhancing these functions in NK cells
obtained from healthy controls. In conclusion, these findings suggest that the association
of SAP with 2B4 is necessary for effective NK / LAK immune functions and moreover,
imply that alterations in SAP/2B4 signaling may contribute to the immune deficiency
observed in XLP. === Medicine, Faculty of === Pathology and Laboratory Medicine, Department of === Graduate
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