Multiple Sclerosis-Like Symptoms in Mice Are Driven by Latent γHerpesvirus-68 Infected B Cells

Márquez, Ana; Shanina, Iryna; Horwitz, Marc S.

doi:10.3389/fimmu.2020.584297

Cited by 10 publications

(9 citation statements)

References 46 publications

(54 reference statements)

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“…Yet another interesting development is the accommodation of the crucial pathogenic role of EBV B cells in the MS autoimmune pathogenic process in the EAE model. Horwitz et al introduced the mouse γ -herpesvirus 68 strain in his EAE models and documented a similar effect on the disease as we observed in the marmoset EAE model [79] . Moreover, humanized mouse models have been developed in which pathogenic aspects of EBV infection can be investigated [80] .…”

Section: Future Perspectives On Translation In Drug Developmentsupporting

confidence: 78%

Multiple sclerosis and drug discovery: A work of translation

Hart

Luchicchi²,

Schenk³

et al. 2021

EBioMedicine

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Multiple sclerosis (MS) is after trauma the most important neurological disease in young adults, affecting 1 per 10 0 0 individuals. With currently available medications, most of these targeting the immune system, satisfactory results have been obtained in patients with relapsing MS, but these can have serious adverse effects. Moreover, despite some promising developments, such as with B cell targeting therapies or sphingosine-1-phosphate modulating drugs, there still is a high unmet need of safe drugs with broad efficacy in patients with progressive MS. Despite substantial investments and intensive preclinical research, the proportion of promising lead compounds that reaches the approved drug status remains disappointingly low. One cause lies in the poor predictive validity of MS animal models used in the translation of pathogenic mechanisms into safe and effective treatments for the patient. This disturbing situation has raised criticism against the relevance of animal models used in preclinical research and calls for improvement of these models. This publication presents a potentially useful strategy to enhance the predictive validity of MS animal models, namely, to analyze the causes of failure in forward translation (lab to clinic) via reverse translation (clinic to lab). Through this strategy new insights can be gained that can help generate more valid MS models.

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Section: Future Perspectives On Translation In Drug Developmentsupporting

confidence: 78%

Multiple sclerosis and drug discovery: A work of translation

Hart

Luchicchi²,

Schenk³

et al. 2021

EBioMedicine

View full text Add to dashboard Cite

show abstract

“…Quantification of γHV68 load was done as previously described ( Márquez et al, 2020 ). Genomic DNA (gDNA) was extracted from 4 × 10 6 splenocytes with PureLink Genomic DNA mini kit (Thermo Fisher), according to the manufacturer’s instructions, and stored at −20°C.…”

Section: Methodsmentioning

confidence: 99%

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

Mouat

Morse

Shanina

et al. 2021

eLife

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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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“…Full-minusone controls used for gating. Quantification of gHV68 load was done as previously described(49). gDNA was extracted from 4x 10 6 splenocytes with PureLink Genomic DNA mini kit (Thermo Fisher Scientific), according to the manufacturer's instructions, and stored at -20°C.…”

mentioning

confidence: 99%

Gammaherpesvirus infection licenses age-associated B cells for pathogenicity in MS and EAE

Mouat

Allanach

Fan

et al. 2021

Preprint

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While age-associated B cells (ABCs) are known to expand and persist following viral infection and during autoimmunity, their interactions are yet to be studied together in these contexts. Epstein-Barr virus (EBV) infection has long been implicated in multiple sclerosis (MS), and it is not known whether ABCs could play a role in mediating viral contribution to autoimmunity. Here, we show that the circulating ABC population is expanded in people with MS and that EBV infection and MS status differentially impact the circulating ABC phenotype. We then directly compared ABCs during viral infection and autoimmunity using mouse models of EBV, gammaherpesvirus 68 (γHV68), and MS, experimental autoimmune encephalomyelitis (EAE). We observed that splenic ABCs are expanded in a sex-biased manner during both latent virus infection and EAE, and each event drives the ABC population to opposing phenotypes. We have previously shown that latent γHV68 infection exacerbates EAE and here we show that mice lacking ABCs fail to display γHV68-enhanced disease. Collectively, these findings indicate that latent viral infection and central nervous system autoimmunity differentially impact the ABC population and suggests that viral infections such as EBV prime ABCs to contribute pathogenically in MS.

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Multiple Sclerosis-Like Symptoms in Mice Are Driven by Latent γHerpesvirus-68 Infected B Cells

Cited by 10 publications

References 46 publications

Multiple sclerosis and drug discovery: A work of translation

Multiple sclerosis and drug discovery: A work of translation

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

Gammaherpesvirus infection licenses age-associated B cells for pathogenicity in MS and EAE

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