Latent gammaherpesvirus exacerbates arthritis through modification of age-associated B cells

Epstein-Barr virus (EBV) infection is associated with rheumatoid arthritis (RA) in adults, though the nature of the relationship remains unknown. Herein, we examine the contribution of viral infection to the severity of arthritis in mice. We provide the first evidence that latent gammaherpesvirus infection enhances clinical arthritis, modeling EBV's role in RA. Mice latently infected with a murine analog of EBV, gammaherpesvirus 68 (gHV68), develop more severe collagen-induced arthritis and a Th1-skewed immune profile reminiscent of human disease. We demonstrate that disease enhancement requires viral latency and is not due to active virus stimulation of the immune response. Age-associated B cells (ABCs) are associated with several human autoimmune diseases, including arthritis, though their contribution to disease is not well understood. Using ABC knockout mice, we provide the first evidence that ABCs are mechanistically required for viral enhancement of disease, thereby establishing that ABCs are impacted by latent gammaherpesvirus infection and provoke arthritis.

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Latent gammaherpesvirus exacerbates arthritis and requires age-associated B cells

10.1101/2021.02.02.429395 ◽

2021 ◽

Author(s):

Isobel C. Mouat ◽

Zach J. Morse ◽

Iryna Shanina ◽

Kelly L. Brown ◽

Marc S. Horwitz

Keyword(s):

B Cells ◽

Conflict Of Interest ◽

Collagen Induced Arthritis ◽

Barr Virus ◽

Latently Infected ◽

Clinical Arthritis ◽

Interest Statement ◽

Epstein Barr ◽

Gammaherpesvirus 68 ◽

The Relationship

AbstractEpstein-Barr virus (EBV) infection is associated with rheumatoid arthritis (RA) in adults, though the nature of the relationship remains unknown. Herein, we examine the contribution of viral infection to the severity of arthritis in mice. We provide the first evidence that latent gammaherpesvirus infection enhances clinical arthritis, modeling EBV’s role in RA. Mice latently infected with a murine analog of EBV, gammaherpesvirus 68 (γHV68), develop more severe collagen-induced arthritis and a Th1-skewed immune profile reminiscent of human disease. We demonstrate that disease enhancement requires viral latency and is not due to active virus stimulation of the immune response. Age-associated B cells (ABCs) are associated with several human autoimmune diseases, including arthritis, though their contribution to disease is not well understood. Using ABC knockout mice, we provide the first evidence that ABCs are mechanistically required for viral enhancement of disease, thereby establishing that latent gammaherpesvirus infection stimulates ABCs to provoke arthritis.Conflict of interest statementThe authors have declared that no conflict of interest exists.

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Secretion of Epstein-Barr Virus-encoded BARF1 oncoprotein from latently infected B cells

Virology Journal ◽

10.1186/1743-422x-5-70 ◽

2008 ◽

Vol 5 (1) ◽

pp. 70 ◽

Cited By ~ 20

Author(s):

Sylvie Fiorini ◽

Tadamasa Ooka

Keyword(s):

B Cells ◽

Epstein Barr Virus ◽

Barr Virus ◽

Latently Infected ◽

Epstein Barr

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IMMUNOSUPPRESSION CAUSES REACTIVATION OF EPSTEIN-BARR VIRUS AND EXPANSION OF LATENTLY INFECTED RESTING MEMORY B CELLS BUT NOT TRANSFORMED B BLASTS IN THE PERIPHERAL BLOOD.

Transplantation Journal ◽

10.1097/00007890-199805131-00734 ◽

1998 ◽

Vol 65 (Supplement) ◽

pp. 263

Author(s):

L L Decker ◽

G J Babcock ◽

R B Freeman ◽

D A. Thorley-Lawson

Keyword(s):

B Cells ◽

Peripheral Blood ◽

Epstein Barr Virus ◽

Memory B Cells ◽

Barr Virus ◽

Latently Infected ◽

Epstein Barr

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Cells Expressing the Epstein-Barr Virus Growth Program Are Present in and Restricted to the Naive B-Cell Subset of Healthy Tonsils

Journal of Virology ◽

10.1128/jvi.74.21.9964-9971.2000 ◽

2000 ◽

Vol 74 (21) ◽

pp. 9964-9971 ◽

Cited By ~ 78

Author(s):

Alexandra M. Joseph ◽

Gregory J. Babcock ◽

David A. Thorley-Lawson

Keyword(s):

B Cells ◽

B Cell ◽

Epstein Barr Virus ◽

Cell Subset ◽

Pcr Analysis ◽

Virus Growth ◽

Barr Virus ◽

Latently Infected ◽

Infected Cells ◽

Epstein Barr

ABSTRACT In this paper we demonstrate, for the first time, that Epstein-Barr virus (EBV)-infected cells expressing the lymphoblastoid growth program are present in healthy carriers of the virus. Previously we observed that latently infected naive B cells are present in tonsils only when viral replication is detected, suggesting that these may represent newly infected B cells. We have tested this idea by performing a reverse transcription-PCR analysis for the expression of latent genes (EBNA2 and the EBNA3s) that are characteristically expressed only by newly infected cells expressing the growth latency program. EBNA2 expression is regularly detected in purified naive (IgD+) tonsillar B cells (13 of 16 tonsils tested) but was never found in the IgD− population (0 of 16). More detailed analysis revealed that the mRNAs for the latent genes EBNA1 (3 of 3 tonsils tested), EBNA3a (3 of 5), EBNA3b (3 of 5), EBNA3c (3 of 5), LMP1 (6 of 6), and LMP2 (5 of 6) were also present in the IgD+ population, but the EBNA1Q-K transcript, characteristic of nonlymphoblastoid forms of latency, was never detected (0 of 6). Finally, we demonstrate that the latently infected naive (IgD+) cells express CD80 (B7.1), a marker characteristically expressed on activated naive lymphoblasts but absent from resting naive B cells. The infected naive (IgD+) population in the tonsil therefore has the viral and cellular phenotype of a B-cell directly infected with EBV—an activated lymphoblast expressing the growth program.

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Epstein-Barr Virus–Infected Resting Memory B Cells, Not Proliferating Lymphoblasts, Accumulate in the Peripheral Blood of Immunosuppressed Patients

Journal of Experimental Medicine ◽

10.1084/jem.190.4.567 ◽

1999 ◽

Vol 190 (4) ◽

pp. 567-576 ◽

Cited By ~ 218

Author(s):

Gregory J. Babcock ◽

Lisa L. Decker ◽

Richard B. Freeman ◽

David A. Thorley-Lawson

Keyword(s):

B Cells ◽

Peripheral Blood ◽

Epstein Barr Virus ◽

Memory B Cells ◽

Barr Virus ◽

Latently Infected ◽

Immunosuppressed Patients ◽

Infected Cells ◽

Epstein Barr ◽

Healthy Carriers

When Epstein-Barr virus (EBV) infects B cells in vitro, the result is a proliferating lymphoblast that expresses at least nine latent proteins. It is generally believed that these cells are rigorously controlled in vivo by cytotoxic T cells. Consistent with this, the latently infected cells in the peripheral blood of healthy carriers are not lymphoblasts. Rather, they are resting memory B cells that are probably not subject to direct immunosurveillance by cytotoxic T lymphocytes (CTLs). When patients become immunosuppressed, the viral load increases in the peripheral blood. The expansion of proliferating lymphoblasts due to the suppressed CTL response is believed to account for this increase and is considered to be a major risk factor for posttransplant lymphoproliferative disease (PTLD) and AIDS-associated B cell lymphoma. Here we show that there is an increase in the numbers of latently infected cells in the peripheral blood of immunosuppressed patients. However, the cells are not proliferating lymphoblasts. They are all latently infected, resting, memory B cells—the same population of infected cells found in the blood of healthy carriers. These results are discussed in the context of a model for EBV persistence that explains why PTLD is usually limited to the lymph nodes.

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Expression of Epstein-Barr Virus BamHI-A Rightward Transcripts in Latently Infected B Cells From Peripheral Blood

Blood ◽

10.1182/blood.v93.9.3026.409k28_3026_3032 ◽

1999 ◽

Vol 93 (9) ◽

pp. 3026-3032 ◽

Cited By ~ 7

Author(s):

Honglin Chen ◽

Paul Smith ◽

Richard F. Ambinder ◽

S. Diane Hayward

Keyword(s):

B Cells ◽

Peripheral Blood ◽

Epstein Barr Virus ◽

Open Reading Frames ◽

Viral Gene ◽

Barr Virus ◽

Restricted Form ◽

Latently Infected ◽

Epstein Barr

In addition to the Epstein-Barr virus (EBV) EBNA and LMP latency genes, there is a family of alternatively spliced BamHI-A rightward transcripts (BARTs). These latency transcripts are highly expressed in the EBV-associated malignancies nasopharyngeal carcinoma and Burkitt’s lymphoma, and are expressed at lower levels in latently EBV-infected B-cell lines. The contribution of the BARTs to EBV biology or pathogenesis is unknown. Resting B cells have recently been recognized as a reservoir for EBV persistence in the peripheral blood. In these cells, EBV gene expression is tightly restricted and the only viral gene known to be consistently expressed is LMP2A. We used cell sorting and reverse-transcriptase polymerase chain reaction (RT-PCR) to examine whether BARTs are expressed in the restricted form of in vivo latency. Our results demonstrated that RNAs with splicing diagnostic for transcripts containing the BART RPMS1 and BARFO open-reading frames (ORFs) were expressed in CD19+ but not in CD23+ B cells isolated from peripheral blood of healthy individuals. The product of the proximal RPMS1 ORF has not previously been characterized. The RPMS1 ORF was shown to encode a 15-kD protein that localized to the nucleus of transfected cells. Expression of the BARTs in peripheral blood B cells suggests that the proteins encoded by these transcripts are likely to be important for maintenance of in vivo latency.

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