A Mouse Herpesvirus Induces Relapse of Experimental Autoimmune Arthritis by Infection of the Inflammatory Target Tissue

Yarilin, Dmitry; Valiando, Jennifer; Posnett, David N.

doi:10.4049/jimmunol.173.8.5238

Cited by 19 publications

(22 citation statements)

References 55 publications

(56 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Gammaherpesvirus 68 infection has been previously shown to exacerbate experimental autoimmune encephalomyelitis and autoimmune arthritis in rodents (30,31). In these studies, however, viral influence on autoimmunity was only assessed for as long as 7 wk postinfection, and it is unclear whether chronic virus infection may have inhibited these responses as seen in our studies.…”

Section: Discussioncontrasting

confidence: 46%

Murine gammaherpesvirus 68 infection protects lupus-prone mice from the development of autoimmunity

Larson

Thurman

Rubtsov

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Gammaherpesvirus infections, such as those caused by EBV, have been suggested to promote the development of autoimmunity. To test this idea, we infected healthy WT and lupus-prone B6.Sle123 mice with an EBV-related and rodent-specific gammaherpesvirus, γHV68. Although acute γHV68 infection increased autoantibody levels for 4 to 6 wk, latent infection inhibited these responses for 1 y. The inhibition of autoantibody expression was only observed in B6.Sle123 females and not in males, which already displayed lower autoantibody titers. Contrary to the initial hypothesis, infection of young B6.Sle123 mice, both male and female, resulted in suppression of lymphoid activation and expansion and of glomerular inflammation and sclerosis, preserving kidney function. Moreover, γHV68 infection led to reduced autoantibody titers, lymphoid activation, and glomerular inflammation whether lupus-prone females were infected before or during disease manifestation. Finally, γHV68 infection also inhibited autoantibody production in the genetically distinct MRL/ lpr lupus-prone mice. Our findings indicate that γHV68 infection strongly inhibits the development and progression of lupus-like disease in mice that spontaneously develop this condition mediating its beneficial effects at the humoral, cellular, and organ levels. The mechanisms by which the virus exerts this down-modulatory action are not yet clear, but appear to operate via reduced activation of dendritic cells, T cells, and B cells. Gammaherpesviruses coevolved with the vertebrate immune systems, establishing lifelong infections in humans and other mammals. Our findings that γHV68 infection prevents rather than exacerbates autoimmunity in mice suggest that infection with gammaherpesviruses may be protective rather than pathological in most individuals.

show abstract

Section: Discussioncontrasting

confidence: 46%

Murine gammaherpesvirus 68 infection protects lupus-prone mice from the development of autoimmunity

Larson

Thurman

Rubtsov

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Stimulation of the TLR-2 (LTA), TLR-3 (poly[I-C]), TLR-4 (LPS and EDA), and TLR-7/8 (R848) pathways resulted in full DC maturation, which was found to be equally efficient for DCs from RA patients (n ϭ 10) and healthy controls (n ϭ 8) ( Figure 2). No effect was seen upon stimulation with EDB and III 11 , which were used as negative controls for EDA, which lacks the capacity to elicit TLR-4-mediated triggering (data not shown) (25).…”

Section: Maturation Of Dcs From Ra Patients and Healthy Controls Uponmentioning

confidence: 99%

“…in the pathogenesis of RA was further substantiated by the findings that human parvovirus B19-transgenic mice are highly susceptible to polyarthritis (10), the murine herpesvirus induces relapsing experimental autoimmune arthritis (11), and that double-stranded (viral) RNA (dsRNA) has overt arthritogenic properties (12). Several mechanisms have been attributed to the actual link between the presence of viral material and the observed immunohistopathologic changes during inflammatory synovitis; however, the precise mode of action has not been elucidated thus far.…”

mentioning

confidence: 92%

The expression of toll‐like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll‐like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells

Roelofs¹,

Joosten²,

Abdollahi‐Roodsaz³

et al. 2005

Arthritis & Rheumatism

296

219

View full text Add to dashboard Cite

Objective. To evaluate the expression of Toll-like receptors (TLRs) 3 and 7 in synovium and to study potential differences in the maturation and cytokine production mediated by TLR-2, TLR-3, TLR-4, and TLR-7/8 by dendritic cells (DCs) from rheumatoid arthritis (RA) patients and DCs from healthy controls.Methods. Synovial expression of TLR-3 and TLR-7 in RA was studied using immunohistochemistry. Monocyte-derived DCs from RA patients and healthy controls were cultured for 6 days and subsequently stimulated for 48 hours via TLR-mediated pathways (lipoteichoic acid, Pam 3 Cys, and fibroblast-stimulating lipopeptide 1 for TLR-2, poly[I-C] for TLR-3, lipopolysaccharide and extra domain A for TLR-4, and R848 for TLR-7/8). Phenotypic DC maturation was measured using flow cytometry. The secretion of tumor necrosis factor ␣ (TNF␣), interleukin-6 (IL-6), IL-10, and IL-12 was measured using the Bio-Plex system. Cell lines expressing TLR-2 and TLR-4 were used for the detection of TLR-2 and TLR-4 ligands in serum and synovial fluid from RA patients.Results. TLR-3 and TLR-7 were highly expressed in RA synovium. All TLR ligands elicited phenotypic DC maturation equally between DCs from RA patients and those from healthy controls. TLR-2-and TLR-4-mediated stimulation of DCs from RA patients resulted in markedly higher production of inflammatory mediators (TNF␣ and IL-6) compared with DCs from healthy controls. In contrast, upon stimulation of TLR-3 and TLR-7/8, the level of cytokine production was equal between DCs from RA patients and those from healthy controls. Remarkably, both TLR-3 and TLR-7/8 stimulation resulted in a skewed balance toward IL-12. Intriguingly, the combined stimulation of TLR-4 and TLR-3-7/8 resulted in a marked synergy with respect to the production of inflammatory mediators. As a proof of concept, TLR-4 ligands were increased in the serum and synovial fluid of RA patients.Conclusion. TLRs are involved in the regulation of DC activation and cytokine production. We hypothesize that various TLR ligands in the joint trigger multiple TLRs simultaneously, favoring the breakthrough of tolerance in RA.

show abstract

“…The viral DNA polymerase inhibitor cidofovir {(S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine; Sigma-Aldrich} was diluted to 5 mg/ml in phosphate-buffered saline (PBS) and stored at 4°C. For suppression of latent reactivation, mice were weighed prior to treatment, administered 25 mg of cidofovir/kg of body weight subcutaneously in the scruff 23, 24, 27, and 30 days postinfection (dpi), and harvested at 32 dpi (16). Control mice were similarly weighed and administered an equivalent calculated volume of PBS.…”

Section: Methodsmentioning

confidence: 99%

Type I Interferon Signaling Enhances CD8⁺T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection

Jennings

Grayson

Barton

2014

J Virol

View full text Add to dashboard Cite

CD8؉ T cell responses are critical to the control of replication and reactivation associated with gammaherpesvirus infection. Type I interferons (IFNs) have been shown to have direct and indirect roles in supporting CD8؉ T cell development and function during viral infection; however, the role of type I interferons during latent viral infection has not been examined. Mice deficient in type I IFN signaling (IFNAR1 ؊/؊ mice) have high levels of reactivation during infection with murine gammaherpesvirus 68 (MHV68), a murine gammaherpesvirus model for Epstein-Barr virus. We hypothesized that type I IFNs function to enhance the anti-gammaherpesvirus CD8 ؉ T cell response. To test this, IFNAR1 ؊/؊ mice were infected with MHV68 and the CD8 ؉ T cell response was analyzed. In the absence of type I IFN signaling, there was a marked increase in short-lived effector CD8 ؉ T cells, and MHV68-specific CD8 ؉ T cells had upregulated expression of PD-1 and reduced tumor necrosis factor alpha (TNF-␣), gamma IFN (IFN-␥), and interleukin-2 (IL-2) production. Suppressing MHV68 replication early in infection using the antiviral cidofovir rescued CD8 ؉ T cell cytokine production and reduced PD-1 expression. However, suppressing high levels of reactivation in IFNAR1؊/؊ mice failed to improve CD8 ؉ T cell cytokine production during latency. T cell-specific abrogation of type I IFN signaling showed that the effects of type I IFNs on the CD8 ؉ T cell response during MHV68 infection are independent of direct type I IFN signaling on T cells. Our findings support a model in which type I IFNs likely suppress MHV68 replication, thus limiting viral antigen and facilitating an effective gammaherpesvirus-directed CD8 ؉ T cell response. IMPORTANCE The murine gammaherpesvirus MHV68 has both genetic and biologic homology to the human gammaherpesvirus Epstein-Barr virus (EBV), which infects over 90% of humans. Latent EBV infection and reactivation are associated with various life-threatening diseases and malignancies. Host suppression of gammaherpesvirus latency and reactivation requires both CD8 T he gammaherpesvirus-directed CD8ϩ T cell response is critical to the control of replication and reactivation associated with Epstein-Barr virus (EBV) infection, and individuals with either genetic or acquired immunodeficiencies are highly susceptible to EBV-associated diseases (1-3). Adoptive transfer of EBVspecific CD8 ϩ T cells has been successfully utilized to treat EBVassociated lymphoproliferative disease (4, 5). In addition, CD8 ϩ T cells prevent in vivo tumor outgrowth of B cell cancer lines immortalized by murine gammaherpesvirus 68 (MHV68), a wellcharacterized virus model for EBV (6). Thus, CD8ϩ T cells can suppress gammaherpesvirus-associated malignancies. The promise of immunotherapy and vaccine development relies on our understanding of factors that promote a highly effective gammaherpesvirus-directed CD8 ϩ T cell response. CD8 ϩ T cells responding to their cognate antigen require three signals for survival and differentiation: antige...

show abstract

A Mouse Herpesvirus Induces Relapse of Experimental Autoimmune Arthritis by Infection of the Inflammatory Target Tissue

Cited by 19 publications

References 55 publications

Murine gammaherpesvirus 68 infection protects lupus-prone mice from the development of autoimmunity

Murine gammaherpesvirus 68 infection protects lupus-prone mice from the development of autoimmunity

The expression of toll‐like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll‐like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells

Type I Interferon Signaling Enhances CD8⁺T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection

Contact Info

Product

Resources

About

A Mouse Herpesvirus Induces Relapse of Experimental Autoimmune Arthritis by Infection of the Inflammatory Target Tissue

Cited by 19 publications

References 55 publications

Murine gammaherpesvirus 68 infection protects lupus-prone mice from the development of autoimmunity

Murine gammaherpesvirus 68 infection protects lupus-prone mice from the development of autoimmunity

The expression of toll‐like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll‐like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells

Type I Interferon Signaling Enhances CD8+T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection

Contact Info

Product

Resources

About

Type I Interferon Signaling Enhances CD8⁺T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection