Defective natural killing activity but retention of lymphocyte-mediated antibody-dependent cellular cytotoxicity in patients with the X-linked lymphoproliferative syndrome

Argov, Shmuel; Johnson, Donald R.; Collins, Michaeleen; Koren, Hillel S.; Lipscomb, Helen; Purtilo, David T.

doi:10.1016/0008-8749(86)90001-8

Cited by 37 publications

(22 citation statements)

References 22 publications

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“…The role of ADCC in the clinical phenotype of XLP is unclear. Some investigators report normal ADCC function in XLP patients (8), whereas others suggest that ADCC may be abnormal (6). We are currently investigating the ADCC function of NK cells obtained from these affected boys to determine whether the defect in 2B4 FIGURE 4.…”

Section: Discussionmentioning

confidence: 99%

“…In XLP patients, severe illness, including fulminant and fatal infectious mononucleosis, manifests following primary infection with EBV, and the overall disease prognosis is extremely poor. The specific immune defects, which manifest following exposure to EBV, include an inability to generate EBV-specific Abs (3), defective Ig class switching (4), and abnormal NK and T cellmediated cytotoxicity (5)(6)(7)(8)(9). The nature of these defects suggests a global dysfunction in cell-mediated immunity.…”

Section: -Linked Lymphoproliferative Disease (Xlp)mentioning

confidence: 99%

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Cutting Edge: Defective NK Cell Activation in X-Linked Lymphoproliferative Disease

Benoît

Wang

Pabst

et al. 2000

The Journal of Immunology

142

108

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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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Section: Discussionmentioning

confidence: 99%

Section: -Linked Lymphoproliferative Disease (Xlp)mentioning

confidence: 99%

Cutting Edge: Defective NK Cell Activation in X-Linked Lymphoproliferative Disease

Benoît

Wang

Pabst

et al. 2000

The Journal of Immunology

142

108

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“…Indeed, a number of reports, all originating from Purtilo's group, have also documented defective NK and CTL activity in patients with XLP. [29][30][31][32] Similarly, male patients in our kindred have defective NK cell function. 33 An important function of NK cells is to rapidly secrete IFN-␥ in response to viral infection and in addition to cytotoxicity defects, NK cells from patients with XLP have been shown to have deficient IFN-␥ production.…”

Section: Vasculitis Inmentioning

confidence: 99%

Lymphocytic vasculitis in X-linked lymphoproliferative disease

Dutz

Benoît

Wang

et al. 2001

Blood

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IntroductionX-linked lymphoproliferative syndrome (XLP) or Duncan disease is a fascinating disease that presents as an Epstein-Barr virus (EBV)-specific immune defect. The original case, described by David Purtilo in 1975 1 involved an 8-year-old boy who died of fulminant hepatitis and bone marrow failure 1 month after the onset of acute infectious mononucleosis (IM). A few years later, it was noted that 2 brothers had also died of illnesses resembling fulminant IM, and it was learned that 3 maternally related male cousins had also died as a result of complications of an EBV infection. Purtilo correctly deduced that a novel X-linked disease was present in this family -a disease that resulted in substantial mortality and morbidity after primary exposure to EBV. By 1978, an XLP registry was established to facilitate the study of the disease, and 3 main clinical presentations were ascribed 2 : (I) fulminant infectious mononucleosis and death, (ii) dysgammaglobulinemia with elevated levels of IgM and IgA and decreased levels of IgG, and (iii) extranodal lymphomas of either B-or T-cell origin. Other less common expressions of the disease have been reported, including aplastic anemia, virus-associated hemophagocytosis (VAHS), and pulmonary vasculitis. Many XLP kindred have been studied extensively in an effort to characterize the nature of the immune defect, leading to a specific susceptibility to EBV. Interest in these cases continues as EBV infection is ubiquitous and has been implicated in the genesis of both lymphoid and mesenchymal tumors. It has been hoped that a better understanding of patients with XLP and their immunologic defects may shed light on the unique nature of the relationship between EBV and human infection.The molecular basis for XLP has recently been ascribed to mutations affecting the SLAM-associated protein (SAP). 3-5 SAP is a Src-homology 2 (SH2) domain-containing protein. Expression of SAP protein has been detected in both murine thymus and human peripheral blood lymphocytes. 3 SAP RNA has been detected primarily in T cells, T-cell lines, and in both T-and B-cell neoplasms. 5 Expression of RNA has been detected in lymphoid germinal centers and natural killer (NK) cells by some 4 but not others. 3 The SAP gene contains 4 exons and encodes a protein of 128 amino acids with a single SH2 domain. This SH2 domain has been shown to interact with the costimulatory surface molecule termed signaling lymphocyte activation molecule (SLAM)/ CDw150 in lymphocytes 3 and the costimulatory molecule 2B4 present in NK cells and some T cells. 6 The binding of SAP to 2B4 or SLAM has been proposed to regulate cell signaling through these molecules. How the described mutations in SAP produce an XLP phenotype is still unclear.We describe a patient who died as a result of chronic systemic vasculitis and fulfilled clinical criteria for the diagnosis of XLP. Sequencing of this patient's SAP gene revealed a novel mutation affecting the SH2 domain. Immunohistochemical analysis using antibodies to CD45RO and CD8 revealed t...

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“…It has been suggested that the inability of the immune system of XLP patients to control EBV-infected B lymphocytes is likely due to defects of Th cells, CTLs, and NK cells (15)(16)(17). The gene defective in XLP has recently been identified, both by positional cloning and functional cloning approaches, and has been designated src homology 2 (SH2) domain protein 1A, Duncan's disease SH2 protein, or signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) (18 -20).…”

mentioning

confidence: 99%

Abnormal T Cell Receptor Signal Transduction of CD4 Th Cells in X-Linked Lymphoproliferative Syndrome

Nakamura

Zarycki

Sullivan

et al. 2001

The Journal of Immunology

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The molecular basis of X-linked lymphoproliferative (XLP) disease has been attributed to mutations in the signaling lymphocytic activation molecule-associated protein (SAP), an src homology 2 domain-containing intracellular signaling molecule known to interact with the lymphocyte-activating surface receptors signaling lymphocytic activation molecule and 2B4. To investigate the effect of SAP defects on TCR signal transduction, herpesvirus saimiri-immortalized CD4 Th cells from XLP patients and normal healthy individuals were examined for their response to TCR stimulation. CD4 T cells of XLP patients displayed elevated levels of tyrosine phosphorylation compared with CD4 T cells from healthy individuals. In addition, downstream serine/threonine kinases are constitutively active in CD4 T cells of XLP patients. In contrast, TCR-mediated activation of Akt, c-Jun-NH2-terminal kinases, and extracellular signal-regulated kinases in XLP CD4 T cells was transient and rapidly diminished when compared with that in control CD4 T cells. Consequently, XLP CD4 T cells exhibited severe defects in up-regulation of IL-2 and IFN-γ cytokine production upon TCR stimulation and in MLRs. Finally, SAP specifically interacted with a 75-kDa tyrosine-phosphorylated protein upon TCR stimulation. These results demonstrate that CD4 T cells from XLP patients exhibit aberrant TCR signal transduction and that the defect in SAP function is likely responsible for this phenotype.

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Defective natural killing activity but retention of lymphocyte-mediated antibody-dependent cellular cytotoxicity in patients with the X-linked lymphoproliferative syndrome

Cited by 37 publications

References 22 publications

Cutting Edge: Defective NK Cell Activation in X-Linked Lymphoproliferative Disease

Cutting Edge: Defective NK Cell Activation in X-Linked Lymphoproliferative Disease

Lymphocytic vasculitis in X-linked lymphoproliferative disease

Abnormal T Cell Receptor Signal Transduction of CD4 Th Cells in X-Linked Lymphoproliferative Syndrome

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