Rotavirus acceleration of murine type 1 diabetes is associated with increased MHC class I-restricted antigen presentation by B cells and elevated proinflammatory cytokine expression by T cells

Pane, Jessica A.; Webster, Nicole L; Zufferey, Christel; Coulson, Barbara S.

doi:10.1016/j.virusres.2013.11.009

Cited by 14 publications

(26 citation statements)

References 51 publications

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“…Given the elevated BAFF levels in NOD high sera, such mechanisms may raise T1D incidence in the NOD high environment. Interestingly, B cells have recently been implicated in rotavirus acceleration of T1D in NOD mice [60], though in contrast to the present study, rotavirus is diabetogenic in adult animals.…”

Section: Discussioncontrasting

confidence: 90%

“…Many previous studies showed that microbial exposures in adulthood, well after the age of weaning, are sufficient to affect T1D development in NOD mice [23, 24, 26, 27, 49, 60–62]. Antibiotic treatment of pregnant NOD dams creates a simplified microbiome and increases T1D development in their offspring [27], but that study did not examine the effects of post-weaning exposure.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of type 1 diabetes development and B-cell activation in nonobese diabetic mice by early life exposure to a diabetogenic environment

et al. 2017

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Microbes, including viruses, influence type 1 diabetes (T1D) development, but many such influences remain undefined. Previous work on underlying immune mechanisms has focussed on cytokines and T cells. Here, we compared two nonobese diabetic (NOD) mouse colonies, NODlow and NODhigh, differing markedly in their cumulative T1D incidence (22% vs. 90% by 30 weeks in females). NODhigh mice harbored more complex intestinal microbiota, including several pathobionts; both colonies harbored segmented filamentous bacteria (SFB), thought to suppress T1D. Young NODhigh females had increased B-cell activation in their mesenteric lymph nodes. These phenotypes were transmissible. Co-housing of NODlow with NODhigh mice after weaning did not change T1D development, but T1D incidence was increased in female offspring of co-housed NODlow mice, which were exposed to the NODhigh environment both before and after weaning. These offspring also acquired microbiota and B-cell activation approaching those of NODhigh mice. In NODlow females, the low rate of T1D was unaffected by cyclophosphamide but increased by PD-L1 blockade. Thus, environmental exposures that are innocuous later in life may promote T1D progression if acquired early during immune development, possibly by altering B-cell activation and/or PD-L1 function. Moreover, T1D suppression in NOD mice by SFB may depend on the presence of other microbial influences. The complexity of microbial immune regulation revealed in this murine model may also be relevant to the environmental regulation of human T1D.

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Section: Discussioncontrasting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Regulation of type 1 diabetes development and B-cell activation in nonobese diabetic mice by early life exposure to a diabetogenic environment

et al. 2017

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“…Infectious rotavirus spreads to the PLN and MLN [14], where it infects or is phagocytosed by a minor pDC population. Within endosomes, viral dsRNA is degraded and triggers TLR7 signaling.…”

Section: Discussionmentioning

confidence: 99%

“…The pancreatic lymph nodes (PLN), where islet-autoreactive cells accumulate, also contain infectious RRV [12]. Dendritic cells (DC) and T cells in the PLN of RRV-infected NOD mice express increased pro-inflammatory cytokine levels, and B cells show increased MHC I expression [14]. Rotavirus does not associate with B or T cells in MLN or PLN of NOD mice [12].…”

Section: Introductionmentioning

confidence: 99%

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Rotavirus Activates Lymphocytes from Non-Obese Diabetic Mice by Triggering Toll-Like Receptor 7 Signaling and Interferon Production in Plasmacytoid Dendritic Cells

2014

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It has been proposed that rotavirus infection promotes the progression of genetically-predisposed children to type 1 diabetes, a chronic autoimmune disease marked by infiltration of activated lymphocytes into pancreatic islets. Non-obese diabetic (NOD) mice provide a model for the human disease. Infection of adult NOD mice with rhesus monkey rotavirus (RRV) accelerates diabetes onset, without evidence of pancreatic infection. Rather, RRV spreads to the pancreatic and mesenteric lymph nodes where its association with antigen-presenting cells, including dendritic cells, induces cellular maturation. RRV infection increases levels of the class I major histocompatibility complex on B cells and proinflammatory cytokine expression by T cells at these sites. In autoimmunity-resistant mice and human mononuclear cells from blood, rotavirus-exposed plasmacytoid dendritic cells contribute to bystander polyclonal B cell activation through type I interferon expression. Here we tested the hypothesis that rotavirus induces bystander activation of lymphocytes from NOD mice by provoking dendritic cell activation and proinflammatory cytokine secretion. NOD mouse splenocytes were stimulated with rotavirus and assessed for activation by flow cytometry. This stimulation activated antigen-presenting cells and B cells independently of virus strain and replicative ability. Instead, activation depended on virus dose and was prevented by blockade of virus decapsidation, inhibition of endosomal acidification and interference with signaling through Toll-like receptor 7 and the type I interferon receptor. Plasmacytoid dendritic cells were more efficiently activated than conventional dendritic cells by RRV, and contributed to the activation of B and T cells, including islet-autoreactive CD8+ T cells. Thus, a double-stranded RNA virus can induce Toll-like receptor 7 signaling, resulting in lymphocyte activation. Our findings suggest that bystander activation mediated by type I interferon contributes to the lymphocyte activation observed following RRV infection of NOD mice, and may play a role in diabetes acceleration by rotavirus.

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Association Between Rotavirus Vaccination and Type 1 Diabetes in Children

et al. 2020

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IMPORTANCE Because rotavirus infection is a hypothesized risk factor for type 1 diabetes, live attenuated rotavirus vaccination could increase or decrease the risk of type 1 diabetes in children.OBJECTIVE To examine whether there is an association between rotavirus vaccination and incidence of type 1 diabetes in children aged 8 months to 11 years. DESIGN, SETTING, AND PARTICIPANTSA retrospective cohort study of 386 937 children born between January 1, 2006, and December 31, 2014, was conducted in 7 US health care organizations of the Vaccine Safety Datalink. Eligible children were followed up until a diagnosis of type 1 diabetes, disenrollment, or December 31, 2017.EXPOSURES Rotavirus vaccination for children aged 2 to 8 months. Three exposure groups were created. The first group included children who received all recommended doses of rotavirus vaccine by 8 months of age (fully exposed to rotavirus vaccination). The second group had received some, but not all, recommended rotavirus vaccines (partially exposed to rotavirus vaccination). The third group did not receive any doses of rotavirus vaccines (unexposed to rotavirus vaccination). MAIN OUTCOMES AND MEASURESIncidence of type 1 diabetes among children aged 8 months to 11 years. Type 1 diabetes was identified by International Classification of Diseases codes: 250.x1, 250.x3, or E10.xx in the outpatient setting. Cox proportional hazards regression models were used to analyze time to type 1 diabetes incidence from 8 months to 11 years. Hazard ratios and 95% CIs were calculated. Models were adjusted for sex, race/ethnicity, birth year, mother's age, birth weight, gestational age, number of well-child visits, and Vaccine Safety Datalink site. RESULTSIn a cohort of 386 937 children (51.1% boys and 41.9% non-Hispanic white), 360 169 (93.1%) were fully exposed to rotavirus vaccination, 15 765 (4.1%) were partially exposed to rotavirus vaccination, and 11 003 (2.8%) were unexposed to rotavirus vaccination. Children were followed up a median of 5.4 years (interquartile range, 3.8-7.8 years). The total person-time follow-up in the cohort was 2 253 879 years. There were 464 cases of type 1 diabetes in the cohort, with an incidence rate of 20.6 cases per 100 000 person-years. Compared with children unexposed to rotavirus vaccination, the adjusted hazard ratio was 1.03 (95% CI, 0.62-1.72) for children fully exposed to rotavirus vaccination and 1.50 (95% CI, 0.81-2.77) for children partially exposed to rotavirus vaccination. CONCLUSIONS AND RELEVANCEThe findings of this study suggest that rotavirus vaccination does not appear to be associated with type 1 diabetes in children.

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Rotavirus acceleration of murine type 1 diabetes is associated with increased MHC class I-restricted antigen presentation by B cells and elevated proinflammatory cytokine expression by T cells

Cited by 14 publications

References 51 publications

Regulation of type 1 diabetes development and B-cell activation in nonobese diabetic mice by early life exposure to a diabetogenic environment

Regulation of type 1 diabetes development and B-cell activation in nonobese diabetic mice by early life exposure to a diabetogenic environment

Rotavirus Activates Lymphocytes from Non-Obese Diabetic Mice by Triggering Toll-Like Receptor 7 Signaling and Interferon Production in Plasmacytoid Dendritic Cells

Association Between Rotavirus Vaccination and Type 1 Diabetes in Children

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