X-linked lymphoproliferative disease (XLP) is characterized by a selective immune deficiency to EBV. The molecular basis of XLP has been attributed to mutations of signaling lymphocytic activation molecule-associated protein, an intracellular molecule known to associate with the lymphocyte-activating surface receptors SLAM and 2B4. We have identified a single nucleotide mutation in SLAM-associated protein that affects the NK cell function of males carrying the mutated gene. In contrast to normal controls, both NK and lymphokine-activated killer cell cytotoxicity was significantly reduced in two XLP patients. In addition to decreased baseline cytotoxicity, ligation of 2B4 significantly augmented NK lytic function in normal controls but failed to enhance the cytotoxicity of NK cells from XLP patients. These findings suggest that association of SAP with 2B4 is necessary for optimal NK/lymphokine-activated killer cytotoxicity and imply that alterations in SAP/2B4 signaling contribute to the immune dysfunction observed in XLP.

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Summary:A distinct form of autosomal recessive T − B − severe combined immunodeficiency disease occurs with a high frequency among Athabascan-speaking Native Americans (SCIDA), including Navajo and Apache Indians from the southwestern US and Dene Indians from the Canadian Northwest Territories. The SCIDA gene has been linked to markers on chromosome 10p although its identity and role in the pathogenesis of this disease are unknown. We report our experience in treating 18 Navajo and Dene children with SCIDA between 1984 and 1999; 16 underwent bone marrow transplants (BMT). All children were symptomatic within 2 months of birth, had the T − B − NK + SCID phenotype and 67% presented with oral and/or genital ulcers. Three children had evidence of maternal engraftment prior to transplant. Two children died shortly after diagnosis. Three children required more than one BMT and 12 are alive with T cell reconstitution at a median followup of 7 years. Three children developed normal B cell immunity, two of whom received ablative conditioning therapy with either radiation or busulfan. Three of the four children who died received therapy with either radiation or busulfan and two of eight long-term survivors who were also recipients of cytotoxic chemotherapy have failed to develop secondary teeth. These results demonstrate the efficacy of BMT in treating infants with this distinct form of SCID, although B cell reconstitution remains a problem even with HLAmatched donors. Without conditioning, T cell engraftment is likely when closely HLA-matched donors are used. With T cell depletion of haplocompatible marrow, conditioning with immunosuppressive therapy may be necessary; however, children with SCIDA who were treated with intensive immunosuppressive and

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