Latent gammaherpesvirus exacerbates arthritis and requires age-associated B cells

  1. Isobel C. Mouat
  2. Zach J. Morse
  3. Iryna Shanina
  4. Kelly L. Brown
  5. Marc S. Horwitz

  • Curated by eLife

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    Evaluation Summary:

    This study could help shed light on mechanistic connections between latent infection by EBV with an age-dependent autoimmune condition, such as rheumatoid arthritis. The authors use two models: a murine model of rheumatoid arthritis (CIA), and a murine analog of human EBV: 𝜸HV68. The use of these two models allows the investigation of how latent viral infection exacerbates the autoimmune condition via the action of a special class of B cells: Age-associated B cells.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

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Abstract

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 (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 statement

The authors have declared that no conflict of interest exists.

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  1. eLife

    Author Response:

    Reviewer #1:

    In this manuscript, Mouat et al. investigated the contribution of viral infection to the severity of arthritis in mice. Epstein-Barr virus (EBV) infection is associated with rheumatoid arthritis (RA). By assessing arthritis progression in type II collagen-induced arthritis (CIA) induced mice with or without latent 𝜸HV68 (murine gammaherpesvirus 68) infection, authors showed that latent 𝜸HV68 exacerbates progression of CIA. Additionally, profile of immune cells infiltrating the synovium was altered in 𝜸HV68-CIA subjects - these subjects presented with a Th1-skewed immune profile, which is also observed in human RA patients. Assessment of immune cells in the spleen and inguinal lymph nodes also showed that latent 𝜸HV68 infection alters T cell response towards pathogenic profile during CIA. Lastly, authors showed age-associated B cells (ABCs) are required for the effects of latent 𝜸HV68 infection on arthritis progression exacerbation.

    Findings presented in the manuscript provides important insights and resource to clinical RA research.

    There are some statistical analyses that need to be updated for completeness and appropriateness of use. In addition, the authors will need to highlight that all analyses were conducted in young mice, whereas RA occurs in aged individuals.

    We appreciate the thoughtful feedback from this reviewer. In response to their suggestions, we have updated our statistical analyses throughout the manuscript. In addition, we have added information on the age of primary EBV infection and age of RA onset to clarify that our age of infection and CIA induction model the timing in humans of EBV infection during adolescence and arthritis development typically during adulthood. We thank the reviewer for their feedback which has aided in strengthening this manuscript.

    Reviewer #2:

    In this study, the authors investigate the long-appreciated but little understood link between chronic infection with Epstein-Barr virus and rheumatoid arthritis (RA). Using a collagen-induced (CI)-model of arthritis and a natural murine analog of EBV (gammaherpesvirus 68, HV68), the authors demonstrate that latent infection with HV68 exacerbates clinical progression of CI-arthritis and is associated with changes in the immune cell and cytokine profile in the spleens and joints of HV68 infected mice. The most compelling finding is that an infection can indeed exacerbate the progression of secondary diseases, and the requirement of age-associated B-cells (ABCs) to the severe disease progression. While this study addresses a timely and important question-how chronic infections affect subsequent or secondary disease progression-additional work as well as a clarification of the experimental design is encouraged to understand some of the key conclusions.

    We thank this reviewer for their helpful comments and agree that further understanding the link between chronic infections and subsequent diseases is important.

    Based on their helpful comments we have clarified experimental approaches throughout the manuscript, such as timing of disease induction following ACRTA- γHV68 infection and further explanations of why certain parameters were examined, which have improved the manuscript. We appreciate the time this reviewer took to provide us with thoughtful and helpful comments.

    Reviewer #3:

    The authors developed an in vivo model of EBV's contribution to RA that recapitulates aspects of human disease. They examined the role of age-associated B cells and find that they are critical mediators of the viral-enhancement of arthritis. The manuscript is written in a well-structured form that facilitates the reading and following the incremental experimental setups. The manuscript is appropriate for publication after revisions.

    Some of the statistical measures did not show significant values while the author based several statements as if there is a difference (they rather used phrases as increased/fold change). Whether this is strong enough to support their statements is not clear.

    Overall, this report provides important insights regarding the association between latency, age-associated B cells, and the enhancement of RA in a mouse model. If these insights are translatable to RA immunology in humans is to be further investigated.

    We thank the reviewer for their comments and appreciation of our work. We have edited the text to more accurately describe the differences that we observe in support of our conclusions.

  2. eLife

    Evaluation Summary:

    This study could help shed light on mechanistic connections between latent infection by EBV with an age-dependent autoimmune condition, such as rheumatoid arthritis. The authors use two models: a murine model of rheumatoid arthritis (CIA), and a murine analog of human EBV: 𝜸HV68. The use of these two models allows the investigation of how latent viral infection exacerbates the autoimmune condition via the action of a special class of B cells: Age-associated B cells.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

  3. eLife

    Reviewer #1 (Public Review):

    In this manuscript, Mouat et al. investigated the contribution of viral infection to the severity of arthritis in mice. Epstein-Barr virus (EBV) infection is associated with rheumatoid arthritis (RA). By assessing arthritis progression in type II collagen-induced arthritis (CIA) induced mice with or without latent 𝜸HV68 (murine gammaherpesvirus 68) infection, authors showed that latent 𝜸HV68 exacerbates progression of CIA. Additionally, profile of immune cells infiltrating the synovium was altered in 𝜸HV68-CIA subjects - these subjects presented with a Th1-skewed immune profile, which is also observed in human RA patients. Assessment of immune cells in the spleen and inguinal lymph nodes also showed that latent 𝜸HV68 infection alters T cell response towards pathogenic profile during CIA. Lastly, authors showed age-associated B cells (ABCs) are required for the effects of latent 𝜸HV68 infection on arthritis progression exacerbation.

    Findings presented in the manuscript provides important insights and resource to clinical RA research.

    There are some statistical analyses that need to be updated for completeness and appropriateness of use. In addition, the authors will need to highlight that all analyses were conducted in young mice, whereas RA occurs in aged individuals.

  4. eLife

    Reviewer #2 (Public Review):

    In this study, the authors investigate the long-appreciated but little understood link between chronic infection with Epstein-Barr virus and rheumatoid arthritis (RA). Using a collagen-induced (CI)-model of arthritis and a natural murine analog of EBV (gammaherpesvirus 68, HV68), the authors demonstrate that latent infection with HV68 exacerbates clinical progression of CI-arthritis and is associated with changes in the immune cell and cytokine profile in the spleens and joints of HV68 infected mice. The most compelling finding is that an infection can indeed exacerbate the progression of secondary diseases, and the requirement of age-associated B-cells (ABCs) to the severe disease progression. While this study addresses a timely and important question-how chronic infections affect subsequent or secondary disease progression-additional work as well as a clarification of the experimental design is encouraged to understand some of the key conclusions.

  5. eLife

    Reviewer #3 (Public Review):

    The authors developed an in vivo model of EBV's contribution to RA that recapitulates aspects of human disease. They examined the role of age-associated B cells and find that they are critical mediators of the viral-enhancement of arthritis.
    The manuscript is written in a well-structured form that facilitates the reading and following the incremental experimental setups. The manuscript is appropriate for publication after revisions.

    Some of the statistical measures did not show significant values while the author based several statements as if there is a difference (they rather used phrases as increased/fold change). Whether this is strong enough to support their statements is not clear.

    Overall, this report provides important insights regarding the association between latency, age-associated B cells, and the enhancement of RA in a mouse model. If these insights are translatable to RA immunology in humans is to be further investigated.

  6. Version published to 10.1101/2021.02.02.429395 on bioRxiv