Fresh Ideas, Foundational Experiments (FIFE): Immunology and Diabetes 2016 FIFE Symposium

The first Fresh Ideas, Foundational Experiments (FIFE): Immunology and Diabetes symposia workshop took place in 2016 and exemplified the active interest of a number of several investigators interested the global rise in the incidence of type 1 diabetes (T1D). This increase does not correlate with genetic drift and indicates that environmental exposures are playing an increasingly significant role. Despite major biomedical and technological advances in diagnosis and treatment, treatments are frequently insufficient as they do not inhibit the progression of the underlying autoimmune response and often fail to prevent life-threatening complications. T1D is the result of autoimmune destruction of the insulin-producing beta cells of the pancreas, and the precise, mechanistic contribution of the immune system to disease pathogenesis and progression remains to be fully characterized. Ultimately, the combinatorial effect of concurrent factors, including beta cell fragility, exogenous stressors, and genetic priming of the innate and adaptive immune system, work together to induce T1D autoimmunity. Thus, T1D is the result of immunological defects and environmental pathogens, requiring the sustained attention of collaborative research teams such as FIFE: I & D with varied perspectives, unified by the universally held goal of finding a sustainable, life-long cure. Herein, the authors provide perspective on various fields in T1D research highlighted by speakers participating in the inaugural FIFE symposium

Age-associated B cells in gammaherpesvirus infection and autoimmunity

Multiple sclerosis (MS) and rheumatoid arthritis (RA) are two of the most common autoimmune diseases, but the etiologies are not well understood. Both genetic and environmental factors contribute to disease susceptibility. In particular, a history of Epstein-Barr virus (EBV) infection, a common gammaherpesvirus, is epidemiologically and clinically associated with the development of MS and RA, though the immunological mechanisms(s) that mediate this relationship are not well understood. We hypothesize that latent EBV infection contributes to MS and RA via a common immunologic mechanism. Here, I present evidence towards a novel model by which gammaherpesvirus infection contributes to arthritis. Mice with latent gammaherpesvirus infection prior to the induction of collagen-induced arthritis display exacerbated joint swelling and a more inflammatory immune response compared to non-infected mice. This builds off of our prior work that demonstrated that latent gammaherpesvirus infection exacerbates disease in a murine model of MS. These two in vivo models were studied, along with samples from adults with MS, to investigate immunological mechanisms of the viral contribution to autoimmunity and age-associated B cells (ABCs). ABCs are a recently identified B cell population that increases in number during both viral infection and autoimmunity. Here, I performed a side-by-side comparison of the ABC population during viral infection and autoimmunity. I show that the circulating ABC population is expanded in people with MS and that EBV infection and MS status differentially impact the ABC phenotype. Mouse models of infection and disease are studied to characterize ABC abundance and phenotype and I found that ABCs are required for viral exacerbation of disease in models of both RA and MS. In the final chapter, ABCs were characterized throughout acute and latent gammaherpesvirus infection. I demonstrated that during infection, there was a female sex bias resulting towards increased frequency of ABCs and that a portion of ABCs were infected with gammaherpesvirus. Finally, while ABCs are dispensable for the development and maintenance of latency in steady-state conditions, I showed that ABCs are critical for controlling gammaherpesvirus latency during challenge. Here, the ABC population is identified as a critical mediator of latent gammaherpesvirus infection and autoimmunity.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat