IFNβ Accelerates Autoimmune Type 1 Diabetes in Nonobese Diabetic Mice and Breaks the Tolerance to β Cells in Nondiabetes-Prone Mice

Abstract

Genetic and environmental factors are decisive in the etiology of type 1 diabetes. Viruses have been proposed as a triggering environmental event and some evidences have been reported: type I IFNs exist in the pancreata of diabetic patients and transgenic mice expressing these cytokines in β cells develop diabetes. To determine the role of IFNβ in diabetes, we studied transgenic mice expressing human IFNβ in the β cells. Autoimmune features were found: MHC class I islet hyperexpression, T and B cells infiltrating the islets and transfer of the disease by lymphocytes. Moreover, the expression of β2-microglobulin, preproinsulin, and glucagon in the thymus was not altered by IFNβ, thus suggesting that the disease is caused by a local effect of IFNβ, strong enough to break the peripheral tolerance to β cells. This is the first report of the generation of NOD (a model of spontaneous autoimmune diabetes) and nonobese-resistant (its homologous resistant) transgenic mice expressing a type I IFN in the islets: transgenic NOD and nonobese-resistant mice developed accelerated autoimmune diabetes with a high incidence of the disease. These results indicate that the antiviral cytokine IFNβ breaks peripheral tolerance to β cells, influences the insulitis progression and contributes to autoimmunity in diabetes and nondiabetes- prone mice.

Prevention of Allograft Tolerance by Bacterial Infection with Listeria monocytogenes

“…In NOD mice, IFN-␤ accelerates autoimmune diabetes and breaks the tolerance to ␤ cells in nondiabetes-prone mice (37). In humans, increased serum levels of type I IFNs have been described in lupus patients where type I IFN signaling is thought to promote the maturation of DCs, resulting in enhanced T cell activation (38).…”

Toll-like Receptor 3 and STAT-1 Contribute to Double-stranded RNA+ Interferon-γ-induced Apoptosis in Primary Pancreatic β-Cells

“…The data presented here, together with other recent reports (64,65), suggest that excessive TLR and IFN signaling may also be involved in pro-apoptotic and proinflammatory effects, potentially leading to an autoimmune response in genetically predisposed individuals. Of note, expression of human IFN-␤ in ␤-cells of NOD mice and non-obese-resistant mice breaks ␤-cell peripheral tolerance and accelerates progression of insulitis and diabetes (66), and it was recently suggested that the degree of TLRinduced activation of the immune system is related to the development of virus-induced diabetes (67). Furthermore, TLR3-dependent inflammatory responses in the central nervous system modulate the ability of viruses to invade cells and to induce neuronal injury through inflammation-induced cell death (68).…”

Reg (regenerating) gene overexpression in islets from non-obese diabetic mice with accelerated diabetes: role of IFNβ

“…Transgenic NOD mice were generated by backcrossing CD-1 RIP-HuIFNβ ten times to the NOD background. The acquisition of the genetic background was controlled by the analysis of microsatellites [8]. NOD RIP-HuIFNβ mice were crossed onto the NOD-SCID strain to generate NOD-SCID RIPHuIFNβ.…”

“…A weak increase in REG expression was also observed in the exocrine tissue from NOD RIP-HuIFNβ in close contact with the islets. As positive control of the effect of HuIFNβ, we determined the MHC class I hyperexpression in the islets from NOD RIP-HuIFNβ as described elsewhere [8]. In order to correlate REG overexpression with the insulitis score, we compared the staining pattern in healthy NOD animals with advanced insulitis (14 weeks of age) with that of NOD mice with early insulitis (4 weeks of age), but no differences were found; this was in agreement with our microarray results (data not shown).…”

“…genic expression of the human gene for IFNβ (HuIFNβ) in islet beta cells [8] accelerates autoimmune diabetes in nonobese diabetic (NOD) mice [9] and breaks the tolerance in non-diabetes prone strains. In this paper we report that the beta cell regeneration factor REG, also described as a diabetes autoantigen [10,11] is overexpressed in islets from RIP-HuIFNβ transgenic mice.…”