Virus-Induced Autoimmune Diabetes in the LEW.1WR1 Rat Requires <i>Iddm14</i> and a Genetic Locus Proximal to the Major Histocompatibility Complex

Blankenhorn, Elizabeth P.; Cort, Laura; Greiner, Dale L.; Guberski, Dennis L.; Mordes, John P.

doi:10.2337/db09-0387

Cited by 18 publications

(29 citation statements)

References 48 publications

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“…For these studies we used LEW1.WR1 rats, which develop T1D in response to rat cytomegalovirus (RCMV) infection with the same frequency and time course as BBDR rats in response to KRV (23). In our studies we found that 22% (3 of 11) of LEW1.WR1 rats treated with a single dose of RCMV developed diabetes within 16 days (Figure 5a).…”

Section: Resultsmentioning

confidence: 99%

Haptoglobin as an early serum biomarker of virus-induced autoimmune type 1 diabetes in biobreeding diabetes resistant and LEW1.WR1 rats

Kruger

Yang

Tam

et al. 2010

Exp Biol Med (Maywood)

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Proteomic profiling of serum is a powerful technique to identify differentially expressed proteins that can serve as biomarkers predictive of disease onset. In this study, we utilized 2D gel analysis followed by MALDI-TOF mass spectrometry analysis to identify putative serum biomarkers for autoimmune type 1 diabetes (T1D) in BioBreeding Diabetes Resistant (BBDR) rats induced to express disease. Treatment with toll-like receptor 3 (TLR3) ligand, polyinosinic:polycytidilic acid (pIC), plus infection with Kilham rat virus (KRV), a rat parvovirus, results in nearly 100% of young BBDR rats becoming diabetic within 11–21 days. Sera collected from pre-diabetic rats at early time points following treatment with pIC + KRV were analyzed by 2D gel electrophoresis and compared with sera from control rats treated with PBS, pIC alone, or pIC + H1, a non-diabetogenic parvovirus. None of the latter three control treatments precipitates T1D. 2D gel analysis revealed that haptoglobin, an acute phase and hemoglobin scavenger protein, was differentially expressed in the sera of rats treated with pIC + KRV relative to control groups. These results were confirmed by Western blot and ELISA studies that further validated haptoglobin levels as being differentially increased in the sera of pIC + KRV treated rats relative to controls during the first week following infection. Early elevations in serum haptoglobin were also observed in LEW1.WR1 rats that became diabetic following infection with rat cytomegalovirus (RCMV). The identification and validation of haptoglobin as a putative serum biomarker for autoimmune T1D in rats now affords us the opportunity to test the validity of this protein as a biomarker for human T1D, particularly in those situations where viral infection is believed to precede onset of disease.

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Section: Resultsmentioning

confidence: 99%

Haptoglobin as an early serum biomarker of virus-induced autoimmune type 1 diabetes in biobreeding diabetes resistant and LEW1.WR1 rats

Kruger

Yang

Tam

et al. 2010

Exp Biol Med (Maywood)

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“…Importantly, the ability of KRV to induce T1D in LEW.1WR1 and BBDR rats declines with age (45, 49), and suggests that developmental changes in susceptible hosts are determinants of viral diabetogenicity. Relevant to the low rate of T1D progression among human carriers of high risk HLA haplotypes, such viral induction protocols do not induce T1D in MHC-matched Wistar-Furth rats, suggesting that factors beyond the MHC are necessary for viral induction of T1D (51, 52). The ability to induce diabetes within the context of high genetic risk in an age-dependent manner is a significant attribute of the BBDR and LEW1.WR1 rat models that may parallel human diabetogenesis.…”

Section: Evidence Of Viral Triggering Of T1d In Genetically Susceptibmentioning

confidence: 99%

Innate inflammation in type 1 diabetes

Cabrera

Henschel

Hessner

2016

Translational Research

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Type 1 diabetes mellitus (T1D) is an autoimmune disease often diagnosed in childhood that results in pancreatic β-cell destruction and life-long insulin dependence. T1D susceptibility involves a complex interplay of genetic and environmental factors and has historically been attributed to adaptive immunity, though there is now increasing evidence for a role of innate inflammation. Here, we review studies that define a heightened age-dependent innate inflammatory state in T1D families that is paralleled with high fidelity by the T1D-susceptible BioBreeding rat. Innate inflammation may be driven by changes in interactions between the host and environment, such as through an altered microbiome, intestinal hyper-permeability, or viral exposures. Special focus is placed on the temporal measurement of plasma induced transcriptional signatures of recent onset T1D patients and their siblings as well as in the Biobreeding rat as it defines the natural history of innate inflammation. These sensitive and comprehensive analyses have also revealed that those who successfully managed T1D risk develop an age-dependent immunoregulatory state, providing a possible mechanism for the juvenile nature of T1D. Therapeutic targeting of innate inflammation has been proven effective in preventing and delaying T1D in rat models. Clinical trials of agents that suppress innate inflammation have had more modest success, but efficacy is improved by the addition of combinatorial approaches that target other aspects of T1D pathogenesis. An understanding of innate inflammation and mechanisms by which this susceptibility is both potentiated and mitigated offers important insight into T1D progression and avenues for therapeutic intervention.

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“…Previous studies showed that administration of poly (I:C) either prevents or accelerates diabetes development in NOD mice or BB rats depending on the doses or kinetics of poly (I:C) action [47-49]. However, administration of poly(I:C) can accelerate virus-induced diabetes in BBDR rats that are normally resistant to T1D development [50]. This suggests that dsRNA sensors, such as TLR3, as well as two RLRs, retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene-5 (MDA5), can promote diabetes in an IFN-dependent manner, as activation of all of these innate receptors induces strong type 1 interferon responses.…”

Section: Tlrs and T1dmentioning

confidence: 99%

“…Although the precise role of viruses in the pathogenesis of T1D remains controversial, previous studies from both mouse models and human patients have revealed that viral infection might be associated with T1D development [50-55]. The induction of prion-inflammatory cytokines by viral infection could affect islet autoimmunity and β-cell decay.…”

Section: Tlrs and T1dmentioning

confidence: 99%

The role of the innate immune system in destruction of pancreatic beta cells in NOD mice and humans with type I diabetes

Tai

Wong

2016

Journal of Autoimmunity

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Type 1 diabetes (T1D) is an organ-specific autoimmune disease characterized by T cell-mediated destruction of the insulin-producing pancreatic β cells. A combination of genetic and environmental factors eventually leads to the loss of functional β cells mass and hyperglycemia. Both innate and adaptive immunity are involved in the development of T1D. In this review, we have highlighted the most recent findings on the role of innate immunity, especially the pattern recognition receptors (PRRs), in disease development. In murine models and human studies, different PRRs, such as toll-like receptors (TLRs) and nucleotide-binding domain, leucine-rich repeat-containing (or NOD-like) receptors (NLRs), have different roles in the pathogenesis of T1D. These PRRs play a critical role in defending against infection by sensing specific ligands derived from exogenous microorganisms to induce innate immune responses and shape adaptive immunity. Animal studies have shown that TLR7, TLR9, MyD88 and NLPR3 play a disease-predisposing role in T1D, while controversial results have been found with other PRRs, such as TLR2, TLR3, TLR4, TLR5 and others. Human studies also shown that TLR2, TLR3 and TLR4 are expressed in either islet β cells or infiltrated immune cells, indicating the innate immunity plays a role in β cell autoimmunity. Furthermore, some human genetic studies showed a possible association of TLR3, TLR7, TLR8 or NLRP3 genes, at single nucleotide polymorphism (SNP) level, with human T1D. Increasing evidence suggest that the innate immunity modulates β cell autoimmunity. Thus, targeting pathways of innate immunity may provide novel therapeutic strategies to fight this disease.

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Virus-Induced Autoimmune Diabetes in the LEW.1WR1 Rat Requires Iddm14 and a Genetic Locus Proximal to the Major Histocompatibility Complex

Cited by 18 publications

References 48 publications

Haptoglobin as an early serum biomarker of virus-induced autoimmune type 1 diabetes in biobreeding diabetes resistant and LEW1.WR1 rats

Haptoglobin as an early serum biomarker of virus-induced autoimmune type 1 diabetes in biobreeding diabetes resistant and LEW1.WR1 rats

Innate inflammation in type 1 diabetes

The role of the innate immune system in destruction of pancreatic beta cells in NOD mice and humans with type I diabetes

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