Autoimmune Disease: When a virus lies in wait
A mouse model supports the hypothesis that latent Epstein–Barr virus exacerbates the symptoms of rheumatoid arthritis.
- The Shmunis School of Biomedicine and Cancer Research, the George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel
The body’s ability to fight a wide range of external (e.g. viruses, bacteria) and internal (e.g. cancer cells) threats relies on having a fully functional immune system. The immune system can be roughly divided into two parts: the innate system, which is activated quickly and considered the first line of defense; and the adaptive system, which usually ‘kicks in’ a few days following the initial infection and evolves over time to generate a long-lasting and specific response (Murphy et al., 2017).
The power of the adaptive immune system stems from the ability of its white blood cells – T cells and B cells – to express a diverse set of immune receptors that can bind to specific pathogens (Rubelt et al., 2017). As well as having receptors bound to their surface, B cells also secrete some of their receptors in the form of antibodies.
Some B cells, however, produce ‘autoantibodies’ that recognize and bind to molecules on the body’s own cells, causing the immune system to mistakenly attack normal, healthy tissue (Sogkas et al., 2021). There are many mechanisms in place to eliminate these B cells, but if they fail autoimmune disorders can arise (Theofilopoulos et al., 2017). Autoimmune diseases, such as systemic lupus erythematosus multiple sclerosis and rheumatoid arthritis, are thought to be triggered by past viral infections (McClain et al., 2005; Mameli et al., 2012; Costenbader and Karlson, 2006). For example, rheumatoid arthritis (RA) – an inflammatory autoimmune disease that affects the joints – has been associated with Epstein-Barr virus (EBV) infection (Guo et al., 2018; Costenbader and Karlson, 2006).
Most exposures to EBV occur during childhood or adolescence without leading to RA, but the disease tends to appear after patients turn 60. Thus, it is hypothesized that EBV latency – a situation in which the virus becomes dormant within the host cell without producing more viruses – may contribute to RA symptoms appearing later in life. This is in agreement with a previous study in which mice with an autoimmune condition called experimental autoimmune encephalopathy were latently infected with a homolog of EBV called gammaherpesvirus 68 (γHV68). The infection exacerbated the autoimmune condition without changing autoantibody levels, and led to a disease that resembles multiple sclerosis (Casiraghi et al., 2012). But it is unclear whether EBV has the same effect on RA.
Now, in eLife, Marc Horwitz and colleagues from the University of British Columbia – including Isobel Mouat as first author – report that latent viral infection also worsens the symptoms of a mouse model for RA (Mouat et al., 2021). They used a mouse model for RA that suffers from an autoimmune condition called type II collagen-induced arthritis (CIA). When these mice are exposed to type II collagen, they develop arthritis with a sustained T cell response and as a result produce anti-collagen autoantibodies that can infiltrate the joints (Inglis et al., 2007).
Mouat et al. infected CIA mice with latent γHV68 to develop a mouse model that can shed light on how EBV may affect the symptoms of RA in humans. The experiments showed that infection increased the clinical parameters used to measure the severity of CIA (Figure 1), demonstrating the negative impact of the latent virus. Specifically, a subset of B cells called age-associated B cells were shown to be expressed in significantly higher proportions than in uninfected mice. Finally, Mouat et al. used a strain of γHV68 that cannot become latent to show that latency is necessary for the virus to exacerbate CIA.
Figure 1
Parameters measured to determine CIA severity.
Top: Mice were infected with latent γHV68 and treated with type II collagen to model the effects of Epstein-Barr virus on rheumatoid arthritis. This manipulation causes the symptoms of type II collagen arthritis (CIA) to become more severe and increase inflammation in the mice’s joints. Bottom: the parameters measured to assess the severity of the autoimmune disease include (circle, clockwise from top left): the levels of the cytokine IFNγ in the spleen (which increased in the CIA mice infected with γHV68); the proportions of different T cell populations (which became similar to what is observed during infections); the phenotypes of B cells in the spleen (more age-associated B cells were observed); and the time until onset of the disease (which decreased). Created with BioRender.com.
Mouat et al. show that latent γHV68 infection in mice clearly alters autoimmune disease onset and severity, potentially reflecting how latent EBV infection affects RA in humans. Future research will be needed to reveal exactly how B cells are impacted by EBV. Notably, the development and validation of the RA model in mice will facilitate future studies aiming to better understand the nature of the relationship between EBV infection and RA.
References
-
Epstein-Barr virus and rheumatoid arthritis: is there a link?Arthritis Research & Therapy 8:204.https://doi.org/10.1186/ar1893
-
Cellular and molecular mechanisms breaking immune tolerance in inborn errors of immunityCellular & Molecular Immunology 18:1122–1140.https://doi.org/10.1038/s41423-020-00626-z
Article and author information
Author details
Publication history
- Version of Record published: August 4, 2021 (version 1)
Copyright
© 2021, Taussig and Wine
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 9,245
- views
-
- 181
- downloads
-
- 1
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Autoimmune Disease: When a virus lies in wait
eLife 10:e71121.
https://doi.org/10.7554/eLife.71121
Further reading
-
- Chromosomes and Gene Expression
- Immunology and Inflammation
Ikaros is a transcriptional factor required for conventional T cell development, differentiation, and anergy. While the related factors Helios and Eos have defined roles in regulatory T cells (Treg), a role for Ikaros has not been established. To determine the function of Ikaros in the Treg lineage, we generated mice with Treg-specific deletion of the Ikaros gene (Ikzf1). We find that Ikaros cooperates with Foxp3 to establish a major portion of the Treg epigenome and transcriptome. Ikaros-deficient Treg exhibit Th1-like gene expression with abnormal production of IL-2, IFNg, TNFa, and factors involved in Wnt and Notch signaling. While Ikzf1-Treg-cko mice do not develop spontaneous autoimmunity, Ikaros-deficient Treg are unable to control conventional T cell-mediated immune pathology in response to TCR and inflammatory stimuli in models of IBD and organ transplantation. These studies establish Ikaros as a core factor required in Treg for tolerance and the control of inflammatory immune responses.
-
- Evolutionary Biology
- Immunology and Inflammation
CD4+ T cell activation is driven by five-module receptor complexes. The T cell receptor (TCR) is the receptor module that binds composite surfaces of peptide antigens embedded within MHCII molecules (pMHCII). It associates with three signaling modules (CD3γε, CD3δε, and CD3ζζ) to form TCR-CD3 complexes. CD4 is the coreceptor module. It reciprocally associates with TCR-CD3-pMHCII assemblies on the outside of a CD4+ T cells and with the Src kinase, LCK, on the inside. Previously, we reported that the CD4 transmembrane GGXXG and cytoplasmic juxtamembrane (C/F)CV+C motifs found in eutherian (placental mammal) CD4 have constituent residues that evolved under purifying selection (Lee et al., 2022). Expressing mutants of these motifs together in T cell hybridomas increased CD4-LCK association but reduced CD3ζ, ZAP70, and PLCγ1 phosphorylation levels, as well as IL-2 production, in response to agonist pMHCII. Because these mutants preferentially localized CD4-LCK pairs to non-raft membrane fractions, one explanation for our results was that they impaired proximal signaling by sequestering LCK away from TCR-CD3. An alternative hypothesis is that the mutations directly impacted signaling because the motifs normally play an LCK-independent role in signaling. The goal of this study was to discriminate between these possibilities. Using T cell hybridomas, our results indicate that: intracellular CD4-LCK interactions are not necessary for pMHCII-specific signal initiation; the GGXXG and (C/F)CV+C motifs are key determinants of CD4-mediated pMHCII-specific signal amplification; the GGXXG and (C/F)CV+C motifs exert their functions independently of direct CD4-LCK association. These data provide a mechanistic explanation for why residues within these motifs are under purifying selection in jawed vertebrates. The results are also important to consider for biomimetic engineering of synthetic receptors.
