Detection of Epstein–Barr virus-encoded small RNA-expressed myofibroblasts and IgG4-producing plasma cells in sclerosing angiomatoid nodular transformation of the spleen

Epstein-Barr virus (EBV), in addition to its transforming properties, contributes to the pathogenesis of several inflammatory diseases. Here, we investigated its involvement in oral lichen planus (OLP), a common autoimmune-like disease of unknown etiopathogenesis that can display a malignant potential. EBV-infected cells (EBV+ cells) were sought in a large series of clinically representative OLPs ( n = 99) through in situ hybridization to detect small noncoding EBV-encoded RNAs. Overall, our results demonstrated that EBV was commonly found in OLP (74%), with significantly higher frequency (83%) in the erosive form than in the reticular/keratinized type mild form (58%). Strikingly, many erosive OLPs were massively infiltrated by large numbers of EBV+ cells, which could represent a large part of the inflammatory infiltrate. Moreover, the number of EBV+ cells in each OLP section significantly correlated with local inflammatory parameters (OLP activity, infiltrate depth, infiltrate density), suggesting a direct relationship between EBV infection and inflammatory status. Finally, we characterized the nature of the infiltrated EBV+ cells by performing detailed immunohistochemistry profiles ( n = 21). Surprisingly, nearly all EBV+ cells detected in OLP lesions were CD138+ plasma cells (PCs) and more rarely CD20+ B cells. The presence of EBV+ PCs in erosive OLP was associated with profound changes in cytokine expression profile; notably, the expression of key inflammatory factors, such as IL1-β and IL8, were specifically increased in OLP heavily infiltrated with EBV+ PCs. Moreover, electron microscopy–based experiments showed that EBV+ PCs actively produced EBV viral particles, suggesting possible amplification of EBV infection within the lesion. Our study thus brings conclusive evidence showing that OLP is commonly infiltrated with EBV+ PCs, adding a further puzzling element to OLP pathogenesis, given that PCs are now considered to be major regulatory immune cells involved in several autoimmune diseases (ClinicalTrials.gov NCT02276573).

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Characterization of Epstein-Barr virus-encoded small RNA gene variations in virus associated lymphomas in Northern China

Archives of Virology ◽

10.1007/s00705-017-3278-4 ◽

2017 ◽

Vol 162 (6) ◽

pp. 1609-1616 ◽

Cited By ~ 1

Author(s):

Zhenzhen Zhao ◽

Lingling Sun ◽

Song Liu ◽

Jun Shu ◽

Bing Luo

Keyword(s):

Small Rna ◽

Epstein Barr Virus ◽

Northern China ◽

Barr Virus ◽

Epstein Barr

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Functional Epstein-Barr virus reservoir in plasma cells derived from infected peripheral blood memory B cells

Blood ◽

10.1182/blood-2008-02-136903 ◽

2009 ◽

Vol 113 (3) ◽

pp. 604-611 ◽

Cited By ~ 26

Author(s):

Yassine Al Tabaa ◽

Edouard Tuaillon ◽

Karine Bollore ◽

Vincent Foulongne ◽

Gael Petitjean ◽

...

Keyword(s):

B Lymphocytes ◽

Epstein Barr Virus ◽

Plasma Cells ◽

Lytic Cycle ◽

Barr Virus ◽

Ebv Dna ◽

Epstein Barr ◽

Immediate Early Antigen ◽

Culture Supernatants ◽

Healthy Carriers

AbstractThe Epstein-Barr virus (EBV) causes infectious mononucleosis, establishes latency in resting memory B lymphocytes, and is involved in oncogenesis through poorly understood mechanisms. The EBV lytic cycle is initiated during plasma cell differentiation by mRNAs transcripts encoded by BZLF1, which induce the synthesis of EBV proteins such as the immediate-early antigen ZEBRA and the late membrane antigen gp350. Therefore, we assessed the capacity of circulating EBV-infected B lymphocytes from healthy EBV-seropositive subjects to enter and complete the EBV lytic cycle. Purified B lymphocytes were polyclonally stimulated and BZLF1- or gp350-secreting cells (BZLF1-SCs or gp350-SCs) were enumerated by ELISpot assays. The number of BZLF1-SCs ranged from 50 to 480/107 lymphocytes (median, 80; 25th-75th percentiles, 70-150) and gp350-SCs from 10 to 40/107 lymphocytes (median, 17; 25th-75th percentiles, 10-20). gp350-SCs represented only 7.7% to 28.6% of BZLF1-SCs (median, 15%; 25th-75th percentiles, 10.5%-20%). This EBV functional reservoir was preferentially restricted to plasma cells derived from CD27+ IgD− memory B lymphocytes. In 9 of 13 subjects, EBV DNA quantification in B-cell culture supernatants gave evidence of completion of EBV lytic cycle. These results demonstrate that EBV proteins can be secreted by EBV-infected B lymphocytes from healthy carriers, a majority generating an abortive EBV lytic cycle and a minority completing the cycle.

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Expression of Epstein–Barr Virus–Encoded Small RNA (by the EBER-1 Gene) in Liver Specimens from Transplant Recipients with Post-Transplantation Lymphoproliferative Disease

New England Journal of Medicine ◽

10.1056/nejm199212103272403 ◽

1992 ◽

Vol 327 (24) ◽

pp. 1710-1714 ◽

Cited By ~ 141

Author(s):

Parmjeet S. Randhawa ◽

Ronald Jaffe ◽

Anthony J. Demetris ◽

Michael Nalesnik ◽

Thomas E. Starzl ◽

...

Keyword(s):

Small Rna ◽

Epstein Barr Virus ◽

Lymphoproliferative Disease ◽

Transplant Recipients ◽

Post Transplantation ◽

Barr Virus ◽

Epstein Barr

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Plasmacytic differentiation of circulating Epstein-Barr virus-infected B lymphocytes during acute infectious mononucleosis.

Journal of Experimental Medicine ◽

10.1084/jem.153.2.235 ◽

1981 ◽

Vol 153 (2) ◽

pp. 235-244 ◽

Cited By ~ 55

Author(s):

J E Robinson ◽

D Smith ◽

J Niederman

Keyword(s):

Infectious Mononucleosis ◽

Epstein Barr Virus ◽

Plasma Cells ◽

Phase 1 ◽

Acute Disease ◽

Nuclear Antigen ◽

Barr Virus ◽

Infected Cells ◽

Epstein Barr ◽

Acute Infectious Mononucleosis

During the acute phase (1 wk of symptoms or less) of infectious mononucleosis (IM), 70--80% of circulating Epstein-Barr virus nuclear antigen (EBNA)-positive cells have differentiated toward plasma cells. Thus the characteristics of the infected cells in the majority of IM patients during early disease are indistinguishable from EBNA-positive tumor cells of a previously reported child who developed lymphoma during IM. IgA and IgG were the most frequent and IgM the least frequent immunoglobulin isotypes detected in EBNA-positive cells. In acute disease EBNA was present in 5.5--20% of T cell-depleted blood lymphocytes but in the 2nd or 3rd wk of illness the number of EBNA-positive cells sharply decreased to 0.4--1.4%. At the same time the fraction of antigen-positive cells containing cytoplasmic immunoglobulins also diminished, suggesting either that differentiation of infected cells was altered during the disease or that nondifferentiated antigen-positive cells had a survival advantage. Both the high proportion of plasmacytic EBNA-positive cells seen during acute disease and the apparent loss of differentiation by these cells later in disease may be regulated by host immunologic factors. Immunoglobulin-producing EBNA-positive cells may be the source of heterophile antibodies and other seemingly inappropriate antibodies usually found in serum during IM; however, increased numbers of noninfected plasma cells were present in some patients and may also be a potential source of these unusual antibodies.

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