EBV and Systemic Lupus Erythematosus: A New Perspective

Gross, Andrew J.; Hochberg, Donna; Rand, William; Thorley‐Lawson, David A.

doi:10.4049/jimmunol.174.11.6599

Cited by 196 publications

(191 citation statements)

References 54 publications

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“…We determined the fractionated non-B-cell populations to be ∼97% pure, suggesting a maximum of ∼3% contaminating B cells. B-cell contamination therefore is unlikely to be the reason we detected BART miRNAs in the non-B-cell fractions, first because infection frequencies are very low, even in immune-suppressed patients with elevated EBV levels (29,30), and second because the viral genome was undetectable in the non-B cells. Overall, our data suggest that in asymptomatic patients BART miRNAs are expressed by latently infected circulating B cells but also are present in noninfected non-B cells, suggesting miRNA transfer in vivo.…”

Section: Ebv Bart Mirnas Are Present In Peripheral B Lymphocytes and mentioning

confidence: 97%

Functional delivery of viral miRNAs via exosomes

Pegtel

Cosmopoulos

Thorley‐Lawson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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1,424

1,227

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Noncoding regulatory microRNAs (miRNAs) of cellular and viral origin control gene expression by repressing the translation of mRNAs into protein. Interestingly, miRNAs are secreted actively through small vesicles called "exosomes" that protect them from degradation by RNases, suggesting that these miRNAs may function outside the cell in which they were produced. Here we demonstrate that miRNAs secreted by EBV-infected cells are transferred to and act in uninfected recipient cells. Using a quantitative RT-PCR approach, we demonstrate that mature EBV-encoded miRNAs are secreted by EBV-infected B cells through exosomes. These EBV-miRNAs are functional because internalization of exosomes by MoDC results in a dose-dependent, miRNAmediated repression of confirmed EBV target genes, including CXCL11/ ITAC, an immunoregulatory gene down-regulated in primary EBVassociated lymphomas. We demonstrate that throughout coculture of EBV-infected B cells EBV-miRNAs accumulate in noninfected neighboring MoDC and show that this accumulation is mediated by transfer of exosomes. Thus, the exogenous EBV-miRNAs transferred through exosomes are delivered to subcellular sites of gene repression in recipient cells. Finally, we show in peripheral blood mononuclear cells from patients with increased EBV load that, although EBV DNA is restricted to the circulating B-cell population, EBV BART miRNAs are present in both B-cell and non-B-cell fractions, suggestive of miRNA transfer. Taken together our findings are consistent with miRNA-mediated gene silencing as a potential mechanism of intercellular communication between cells of the immune system that may be exploited by the persistent human γ-herpesvirus EBV.

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Section: Ebv Bart Mirnas Are Present In Peripheral B Lymphocytes and mentioning

confidence: 97%

Functional delivery of viral miRNAs via exosomes

Pegtel

Cosmopoulos

Thorley‐Lawson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

1,424

1,227

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“…Although resting, these cells may retain the ability to release exosomes that have incorporated EBER1. However, latency III cells have been detected in circulation of individuals under immune suppression (44), and may represent an additional source of EBER1 + exosomes. Although chronic sensing of latent EBV may lead to disease in predisposed individuals, EBER1 recognition during early stages of EBV infection is possibly protective for the host, as at this time adaptive immune responses are not yet functional.…”

Section: Discussionmentioning

confidence: 99%

“…To evaluate whether EBER1 molecules are taken up by pDCs in vivo, we studied pDC-infiltrated skin lesions of lupus erythematosus (LE) patients that suffer from chronically elevated EBV loads (44). We examined paraffin sections of skin biopsies by immunofluorescent staining.…”

Section: Exosomes From Latent Ebv-infected Cells Target Primary Tonsimentioning

confidence: 99%

Sensing of latent EBV infection through exosomal transfer of 5′pppRNA

Baglio¹,

Eijndhoven²,

Koppers-Lalić

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

137

145

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Complex interactions between DNA herpesviruses and host factors determine the establishment of a life-long asymptomatic latent infection. The lymphotropic Epstein-Barr virus (EBV) seems to avoid recognition by innate sensors despite massive transcription of immunostimulatory small RNAs (EBV-EBERs). Here we demonstrate that in latently infected B cells, EBER1 transcripts interact with the lupus antigen (La) ribonucleoprotein, avoiding cytoplasmic RNA sensors. However, in coculture experiments we observed that latent-infected cells trigger antiviral immunity in dendritic cells (DCs) through selective release and transfer of RNA via exosomes. In ex vivo tonsillar cultures, we observed that EBER1-loaded exosomes are preferentially captured and internalized by human plasmacytoid DCs (pDCs) that express the TIM1 phosphatidylserine receptor, a known viraland exosomal target. Using an EBER-deficient EBV strain, enzymatic removal of 5′ppp, in vitro transcripts, and coculture experiments, we established that 5′pppEBER1 transfer via exosomes drives antiviral immunity in nonpermissive DCs. Lupus erythematosus patients suffer from elevated EBV load and activated antiviral immunity, in particular in skin lesions that are infiltrated with pDCs. We detected high levels of EBER1 RNA in such skin lesions, as well as EBV-microRNAs, but no intact EBV-DNA, linking non-cell-autonomous EBER1 presence with skin inflammation in predisposed individuals. Collectively, our studies indicate that virus-modified exosomes have a physiological role in the host-pathogen stand-off and may promote inflammatory disease.exosomes | EBV-EBER1 | innate sensing | dendritic cells | skin inflammation

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“…Although no single pathogen (except for a putative role for Epstein-Barr virus and parvovirus B19 (61,62)) has yet been associated with SLE immunopathogenesis, recent data seem to point towards the fact that chronic inflammation in SLE could arise from chronic immune system activation towards unknown infections (60).…”

Section: Infections Inflammation and Autoimmunity In Cvidmentioning

confidence: 99%