Deficient Natural Killer Cell Activity in X-Linked Lymphoproliferative Syndrome

Sullivan, John L.; Byron, Kevin; Brewster, Frank; Purtilo, David T.

doi:10.1126/science.6158759

Cited by 218 publications

(74 citation statements)

References 24 publications

(7 reference statements)

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“…NK cell activity was decreased in three of the four cases each effector-to-target cell ratio (13). Interferon treatment of effector cells resulted in small increases in cytotoxicity, but normal activity was never achieved.…”

Section: Resultsmentioning

confidence: 89%

“…Target cells consisted of cell lines 8392 and 8402 for EBV-specific cytolysis (11). NK cell targets consisted of cell line K562, Daudi, and herpes simplex virus-infected fibroblasts (13,14). In selected experiments, target cells consisted of spontaneous and/or B95-8 EBV-induced B LCL.…”

Section: Cytotoxicity Studiesmentioning

confidence: 99%

“…Cell-mediated cytotoxicity was determined against EBVinfected and NK-sensitive target cells (12,13). Target cells consisted of cell lines 8392 and 8402 for EBV-specific cytolysis (11).…”

Section: Cytotoxicity Studiesmentioning

confidence: 99%

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X-linked lymphoproliferative syndrome. Natural history of the immunodeficiency.

Sullivan¹,

Byron²,

Brewster³

et al. 1983

J. Clin. Invest.

118

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A B S T R A C T The X-linked lymphoproliferative syndrome is characterized by immunodeficiency to Epstein-Barr virus (EBV) manifested by severe or fatal infectious mononucleosis and acquired immunodeficiency. We studied immune responses in six males of a well-characterized kindred with the X-linked lymphoproliferative syndrome. Two males were studied before and during acute fatal EBV infection. Both individuals demonstrated normal cellular and humoral immunity before EBV infection. During acute EBV infection, both individuals developed vigorous cytotoxic cellular responses against EBV-infected and -iipinfected target cells. Anomalous killer and natural killer T cell activity was demonstrated against a va'-riety of lymphoid cell lines, autologous fibroblasts and autologous hepatocytes. Effector cells responsible for anomalous killing reacted with a pan-T cell monoclonal antibody, and belonged to the OKT.8 T cell subset. Death in each case was caused by liver failure, but one patient developed extensive liver necrosis, whereas the other developed a massive infiltration of the liver with EBV-infected immunoblasts after aggressive immunosuppressive therapy. Immunological studies were performed on four males who had survived EBV infection years previously. They demonstrated global cellular immune defects with deficiencies of lymphocyte proliferative responses to mitogens and antigens, humoral immune deficiencies, abnormalities of regulatory T cell subsets and deficient natural killer cell activity. We propose that an aberrant immune response triggered by acute EBV infection results in unregulated anomalous killer and natural killer cell activity against EBV infected and uninfected cells. These studies suggest that global immune defects appearing in males with X-linked lymphopro-

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Section: Resultsmentioning

confidence: 89%

Section: Cytotoxicity Studiesmentioning

confidence: 99%

See 1 more Smart Citation

X-linked lymphoproliferative syndrome. Natural history of the immunodeficiency.

Sullivan¹,

Byron²,

Brewster³

et al. 1983

J. Clin. Invest.

118

View full text Add to dashboard Cite

show abstract

“…When bound to these ligands, death receptors on target cells (for example, FAS) can activate the caspase enzymatic cascade that 14 . The bestcharacterized cytokine produced by NK cells is IFNγ, but they can also secrete numerous interleukins (for example, IL-10), TNF, growth factors (for example, granulocyte-macrophage colony-stimulating factor (GM-CSF)) 37 and chemokines (for example, chemokine (C-C motif) ligand 3 (CCL3), CCL4 and CCL5) Tumour surveillance by NK cells NK cells were first implicated in tumour immunosurveillance in the 1980s, when several studies reported a higher incidence of cancers in individuals with defective NK cell function caused by genetic disorders such as Chédiak-Higashi syndrome and X-linked lymphoproliferative syndrome 40,41 . During the same period, increased tumour growth and metastasis were described in mutant mice with impaired NK cell activity 42 and in mice treated with an NK cell-depleting antibody 43 .…”

Section: Nk Cell Functionsmentioning

confidence: 99%

NK cells and cancer: you can teach innate cells new tricks

2015

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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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Deficient Natural Killer Cell Activity in X-Linked Lymphoproliferative Syndrome

Cited by 218 publications

References 24 publications

X-linked lymphoproliferative syndrome. Natural history of the immunodeficiency.

X-linked lymphoproliferative syndrome. Natural history of the immunodeficiency.

NK cells and cancer: you can teach innate cells new tricks

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

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