br Conflict of Interest Statement br

Conflict of Interest Statement
Search Strategy and Selection Criteria Data for this review were identified by searches of PubMed, using the following search terms in various combinations: “NFIB”, “cancer”, “development”, “cellular differentiation”, “NFI transcription factors”. Articles resulting from these searches and references cited in those articles were selected based on their relevance to the topic covered in the review. Only articles published in English between 1982 and 2017 were included. The majority of the articles reported were published in the last 5years.
Acknowledgments We are grateful to Dr. William W. Lockwood for critical reading of the manuscript and stimulating discussions, and to Sonia H.Y. Kung for assistance with illustrations. This work was supported by grants from the Canadian Institutes of Health Research (CIHR FDN-143345 to WLL) and NYSTEM (C030133 to RMG). DDBS was supported by a Vanier Canada Graduate Scholarship.
Introduction Type 1 Diabetes (T1D) is a disease characterized by the discriminatory destruction of pancreatic beta cells (Gillespie, 2006). T1D is a process that requires both autoimmunity and autoinflammation where the pancreas is infiltrated by immune cells such as macrophages, dendritic cells and natural killer cells secreting pro-inflammatory cytokines, and autoreactive B and T cells specific for islet antigens such as insulin, glutamic SB 239063 decarboxylase (GAD)-65, and islet antigen(IA)-2 (Li et al., 2014; Arvan et al., 2012). Although no single etiology is known for T1D, epidemiological and genome-wide association studies have linked T1D with both genetic factors i.e. polymorphisms in human leukocyte antigen (HLA) haplotypes, and environmental factors such as viral infections (Christoffersson et al., 2016; Richardson and Horwitz, 2014). While T1D is canonically considered a T-cell mediated disease (Berry and Waldner, 2013; Kelly et al., 2003), research has demonstrated that the mere presence of autoreactive T cells is not the initiating factor but rather a determinant of disease progression (Laitinen et al., 2014; Serreze et al., 2000). Additionally, the presence of autoantibodies can be detected years before clinical disease, and not all islet autoantibody-positive individuals develop T1D (Reynier et al., 2010; Kulmala et al., 1998). Thus, we propose the inflammatory pathway as a focus for understanding early triggering events in T1D, and viral infections in acceleration of an established autoimmune/inflammatory process. Here, we review T1D inflammation as it relates to the interferon (IFN) signature, and establish a link with Type 1 interferonopathies (type 1 IFN-opathies) and viruses, specifically Coxsackieviruses. Type 1 IFN-opathies constitute a group of human diseases associated with overproduction of the pro-inflammatory type I IFNs, and are widely thought to be controlled by genetics (Crow and Manel, 2015; Lee-Kirsch et al., 2015). These diseases, often systemic and clinically symptomatic, are associated with destructive inflammation as well as development of autoimmune phenomena. We propose that persistent or chronic Coxsackievirus infections in pancreatic islet cells simulate a local type 1 IFN-opathy in the islet microenvironment that is clinically silent before diabetes onset. As several of the candidate susceptibility genes are involved in IFN responses and because virus infections would amplify genetic tendencies for a heightened IFN response, we propose that the underlying molecular mechanisms associated with type 1 IFN-opathies can serve as a foundation or reference point for the evaluation of inflammatory processes of T1D. With the increasing incidence of T1D worldwide (Tuomilehto, 2013; Patterson et al., 2009), deciphering the inflammatory pathways represents a direct and relevant approach for the development of new targeted therapeutics to prevent, interrupt, or overturn progression of disease.