Decreased DAP12 expression in natural killer lymphocytes from patients with systemic lupus erythematosus is associated with increased transcript mutations

Toyabe, Shin-ichi; Kaneko, Utako; Uchiyama, Makoto

doi:10.1016/j.jaut.2004.09.003

Cited by 24 publications

(54 citation statements)

References 33 publications

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“…24 exhibit low NK cell activity which may be partly explained by a low expression of the adaptor protein DAP12 in SLE patients. 25 Furthermore, an association in time between disease development and low NK cell activity has been described in the lpr mouse. 26 In a mouse model of another B-cell-dependent autoimmune disease, experimental autoimmune myasthenia gravis (EAMG), Shi et al showed that depletion of NK cells during the priming phase protected from disease development by reducing IFN-c production by CD4 + T cells and increasing production of the anti-inflammatory cytokine transforming growth factor-b, while levels of pathogenic antibodies decreased.…”

Section: Discussionmentioning

confidence: 99%

Increased proportion of CD56^bright natural killer cells in active and inactive systemic lupus erythematosus

et al. 2008

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Summary Natural killer (NK) cells belong to the innate immune system but can also affect adaptive immune reactions. This immune regulatory function is often ascribed to the CD56bright subpopulation of NK cells that is prevalent in secondary lymphoid tissues and has potent cytokine‐producing ability. The NK cells have been described as affecting autoimmune disease and stimulating B‐cell production of antibodies, but their role in systemic lupus erythematosus (SLE) pathology has not been extensively studied. We have studied NK cells in SLE, a B‐cell‐driven systemic autoimmune disease, and phenotypically characterized peripheral blood NK cells in comparison to NK cells from patients with immunoglobulin A nephritis, rheumatoid arthritis and healthy individuals. We have found an increased proportion of CD56bright NK cells in SLE, regardless of disease activity. We detected a somewhat increased expression of the activating receptor NKp46/CD335 on NK cells from SLE patients, although neither the percentage of NK cells of all lymphocytes nor the expression of other NK receptors analysed (LIR‐1/CD85j, CD94, NKG2C/CD159c, NKG2D/CD314, NKp30/CD337, NKp44/CD336, CD69) differed between patient groups. We show that type I interferon, a proinflammatory cytokine known to be abundant in SLE, can cause increases of CD56bright NK cells in vitro. We confirmed that serum levels of interferon‐α were increased in active, but not in inactive, disease in the SLE patient group. In conclusion, we found an increased proportion of CD56bright NK cells in the blood of SLE patients, although it remains to be examined whether and how this relates to the disease process.

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Section: Discussionmentioning

confidence: 99%

Increased proportion of CD56^bright natural killer cells in active and inactive systemic lupus erythematosus

et al. 2008

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“…These findings appear to support the conclusion from some, but certainly not all, in vitro studies that DAP12 plays an activating or proinflammatory role in APC activities (10 -12). However, these earlier experimental observations may unlikely explain the findings from human studies where DAP12 deficiency (Nasu-Hakola syndrome) leads to severe demyelinization and brain inflammation (24) and that decreased DAP12 expression was correlated with exacerbation of systemic lupus erythematous (25). Furthermore, more recent experimental studies have suggested an inhibitory role of DAP12 signaling in macrophage or dendritic cell activation (18 -22).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies from Vivier and Lanier's laboratories have used two noninfectious models of experimental autoimmune encephalomyelitis (22) and hapten-specific contact dermatitis (23) in DAP12-deficient mice, and demonstrated diminished T cell responses due to insufficient T cell priming by APC. However, these experimental findings may not be reconciliatory with human studies where DAP12-deficient human subjects were found to suffer marked demyelination in certain brain regions accompanied by diffuse brain tissue inflammation (24) and decreased DAP12 expression was also associated with exacerbated systemic lupus erythematosus (25).…”

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confidence: 85%

Critical Negative Regulation of Type 1 T Cell Immunity and Immunopathology by Signaling Adaptor DAP12 during Intracellular Infection

Divangahi

Yang

Kugathasan

et al. 2007

The Journal of Immunology

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Transmembrane signaling adaptor DAP12 has increasingly been recognized for its important role in innate responses. However, its role in the regulation of antimicrobial T cell responses has remained unknown. In our current study, we have examined host defense, T cell responses, and tissue immunopathology in models of intracellular infection established in wild-type and DAP12-deficient mice. During mycobacterial infection, lack of DAP12 leads to pronounced proinflammatory and Th1 cytokine responses, overactivation of Ag-specific CD4 and CD8 T cells of type 1 phenotype, and heightened immunopathology both in the lung and lymphoid organs. DAP12-deficient airway APC display enhanced NF-κB activation and cytokine responses upon TLR stimulation or mycobacterial infection in vitro. Of importance, adoptive transfer of Ag-loaded DAP12-deficient APC alone could lead to overactivation of transferred transgenic or endogenous wild-type T cells in vivo. We have further found that the immune regulatory role by DAP12 is not restricted only to intracellular bacterial infection, since lack of this molecule also leads to uncontrolled type 1 T cell activation and severe immunopathology and tissue injury during intracellular viral infection. Our study thus identifies DAP12 as an important novel immune regulatory molecule that acts, via APC, to control the level of antimicrobial type 1 T cell activation and immunopathology.

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“…Foremost among these concerns is the confounding effect of transcript variation, mainly alternative splice variants, on the effectiveness of RNAi with the shRNA that we used. Numerous RNA splice variants of human NKG2D, DAP10, and DAP12 have been described (12,48,49), and a query of the public nucleotide sequence databases revealed many more that have not been fully characterized. We have not excluded the possibility that alternative expression of these variants between NK cells vs activated and expanded CD8 ϩ T cells or from one normal donor compared with another may influence the extent of gene knockdown with our RNAi.…”

Section: Discussionmentioning

confidence: 99%

“…That cytolysis can also be inhibited by DAP12 RNAi was unexpected and raises questions about whether there are key DAP12-binding receptor partners expressed by activated and expanded CD8 ϩ T cells influencing cytolysis. Of clinical relevance, DAP12 loss-of-function mutations have been identified (49,54), and it would be important to understand whether CD8 ϩ T cells activated and expanded from such individuals would be impaired with regard to tumor killing.…”

Section: Discussionmentioning

confidence: 99%

Silencing Human NKG2D, DAP10, and DAP12 Reduces Cytotoxicity of Activated CD8+ T Cells and NK Cells

Karimi

Cao²,

Baker³

et al. 2005

The Journal of Immunology

111

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Human CD8+ T cells activated and expanded by TCR cross-linking and high-dose IL-2 acquire potent cytolytic ability against tumors and are a promising approach for immunotherapy of malignant diseases. We have recently reported that in vitro killing by these activated cells, which share phenotypic and functional characteristics with NK cells, is mediated principally by NKG2D. NKG2D is a surface receptor that is expressed by all NK cells and transmits an activating signal via the DAP10 adaptor molecule. Using stable RNA interference induced by lentiviral transduction, we show that NKG2D is required for cytolysis of tumor cells, including autologous tumor cells from patients with ovarian cancer. We also demonstrated that NKG2D is required for in vivo antitumor activity. Furthermore, both activated and expanded CD8+ T cells and NK cells use DAP10. In addition, direct killing was partially dependent on the DAP12 signaling pathway. This requirement by activated and expanded CD8+ T cells for DAP12, and hence stimulus from a putative DAP12-partnered activating surface receptor, persisted when assayed by anti-NKG2D Ab-mediated redirected cytolysis. These studies demonstrated the importance of NKG2D, DAP10, and DAP12 in human effector cell function.

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Decreased DAP12 expression in natural killer lymphocytes from patients with systemic lupus erythematosus is associated with increased transcript mutations

Cited by 24 publications

References 33 publications

Increased proportion of CD56^bright natural killer cells in active and inactive systemic lupus erythematosus

Increased proportion of CD56^bright natural killer cells in active and inactive systemic lupus erythematosus

Critical Negative Regulation of Type 1 T Cell Immunity and Immunopathology by Signaling Adaptor DAP12 during Intracellular Infection

Silencing Human NKG2D, DAP10, and DAP12 Reduces Cytotoxicity of Activated CD8+ T Cells and NK Cells

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Decreased DAP12 expression in natural killer lymphocytes from patients with systemic lupus erythematosus is associated with increased transcript mutations

Cited by 24 publications

References 33 publications

Increased proportion of CD56bright natural killer cells in active and inactive systemic lupus erythematosus

Increased proportion of CD56bright natural killer cells in active and inactive systemic lupus erythematosus

Critical Negative Regulation of Type 1 T Cell Immunity and Immunopathology by Signaling Adaptor DAP12 during Intracellular Infection

Silencing Human NKG2D, DAP10, and DAP12 Reduces Cytotoxicity of Activated CD8+ T Cells and NK Cells

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Increased proportion of CD56^bright natural killer cells in active and inactive systemic lupus erythematosus

Increased proportion of CD56^bright natural killer cells in active and inactive systemic lupus erythematosus