Murine Gammaherpesvirus-68 Infection Alters Self-Antigen Presentation and Type 1 Diabetes Onset in NOD Mice

Smith, Kendra Schank; Efstathiou, Stacey; Cooke, Anne

doi:10.4049/jimmunol.179.11.7325

Cited by 42 publications

(31 citation statements)

References 45 publications

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“…Acute infection of DCs with γHV68 decreases their ability to present antigen and to express proinflammatory cytokines (20,21,29,61,71). Reduced endocytic function of DCs during γHV68 acute infection was also observed in the context of the autoimmune NOD genetic background (29). We found that, during acute and latent γHV68 infection, B6.Sle123 mice harbor a reduced frequency of activated DCs.…”

Section: Discussionmentioning

confidence: 54%

“…The virus may otherwise alter the development of autoimmunity by modulating DCs, which are known to contribute to the development of lupus in B6.Sle123 mice by producing large amounts of proinflammatory cytokines and driving high levels of B-cell and T-cell proliferation (68)(69)(70). Acute infection of DCs with γHV68 decreases their ability to present antigen and to express proinflammatory cytokines (20,21,29,61,71). Reduced endocytic function of DCs during γHV68 acute infection was also observed in the context of the autoimmune NOD genetic background (29).…”

Section: Discussionmentioning

confidence: 99%

“…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. In the context of a different autoimmune pathology, γHV68 leads to a delay in the development of diabetes in NOD mice when evaluated through 30 wk after infection (29). The effect of the virus on the onset of diabetes was subtle, resulting in a 5-to 10-wk delay and only if the mice were infected between 8 and 9 wk of age (29).…”

Section: Discussionmentioning

confidence: 99%

“…In the context of a different autoimmune pathology, γHV68 leads to a delay in the development of diabetes in NOD mice when evaluated through 30 wk after infection (29). The effect of the virus on the onset of diabetes was subtle, resulting in a 5-to 10-wk delay and only if the mice were infected between 8 and 9 wk of age (29). Moreover, these studies suggested that the inhibitory effect was only mediated by the acute phase of infection and not through latency.…”

Section: Discussionmentioning

confidence: 99%

“…Because of this persistence and the fact that the autoantibodies were of the IgG class, it was suggested that γHV68 infection might trigger autoimmune disease in mice (12), potentially mimicking EBV in humans. When γHV68 infection was more directly tested in the context of murine autoimmunity, it was shown to delay the onset of diabetes in NOD female mice infected at 8 to 9 wk of age (29), but also to exacerbate experimental arthritis in K/BxN mice (30) and experimental autoimmune encephalomyelitis in SJL mice and in Lewis rats (31). These studies, therefore, suggest that γHV68 infection can increase or decrease symptoms of autoimmunity in mice, perhaps depending on the type of autoimmune disease and the genetics of the host.…”

Section: Antibody | Mouse Gammaherpesvirusmentioning

confidence: 99%

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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.

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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.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Antibody | Mouse Gammaherpesvirusmentioning

confidence: 99%

See 3 more Smart Citations

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.

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PD‐L1 blockade overrides Salmonella typhimurium‐mediated diabetes prevention in NOD mice: No role for Tregs

et al. 2011

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Increasingly, evidence suggests that there is a strong environmental component to the development of the autoimmune disease type 1 diabetes. Our previous data showed that NOD mice are protected from developing diabetes after infection with Salmonella typhimurium and there is some evidence that changes within the DC compartment play a crucial role in this protective effect. This paper further characterises this Salmonella‐modulated protective phenotype. We find that, contrary to other infection‐mediated models of type 1 diabetes protection, there was no expansion of Foxp3+ Tregs. Furthermore, transcriptome analysis of DCs identified a distinct Salmonella‐induced signature in which the inhibitory receptor PD‐L1 was up‐regulated. This was confirmed by flow cytometry. In vivo blockade of the PD1/PD‐L1 interaction was found to ablate the protective function of Salmonella infection. These data provide evidence for a novel regulatory DC phenotype proficient at controlling autoreactive T cells for an extended duration in the NOD mouse model of diabetes.

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Toll-Like Receptors and Type 1 Diabetes

Zipris¹

2010

Advances in Experimental Medicine and Biology

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Type 1 diabetes (T1D) is an autoimmune disease that results in the progressive loss of insulin producing cells. Studies performed in humans with T1D and animal models of the disease over the past two decades have suggested a key role for the adaptive immune system in disease mechanisms. The role of the innate immune system in triggering T1D was shown only recently. Research in this area was greatly facilitated by the discovery of toll-like receptors (TLRs) that were found to be a key component of the innate immune system that detect microbial infections and initiate antimicrobial host defense responses. New data indicate that in some situations, the innate immune system is associated with mechanisms triggering autoimmune diabetes. In fact, studies preformed in the BioBreeding Diabetes Resistant (BBDR) and LEW1.WR1 rat models of T1D demonstrate that virus infection leads to islet destruction via mechanisms that may involve TLR9-induced innate immune system activation. Data from these studies also show that TLR upregulation can synergize with virus infection to dramatically increase disease penetrance. Reports from murine models of T1D implicate both MyD88-dependent and MyD88-independent pathways in the course of disease. The new knowledge about the role of innate immune pathways in triggering islet destruction could lead to the discovery of new molecules that may be targeted for disease prevention.

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Murine Gammaherpesvirus-68 Infection Alters Self-Antigen Presentation and Type 1 Diabetes Onset in NOD Mice

Cited by 42 publications

References 45 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

PD‐L1 blockade overrides Salmonella typhimurium‐mediated diabetes prevention in NOD mice: No role for Tregs

Toll-Like Receptors and Type 1 Diabetes

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