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Abstract
Type I diabetes (T1D) is an autoimmune disease caused by a combination of genetic and environmental factors. Previous studies have linked infections with enteroviruses, such as coxsackievirus B4 (CVB4), with an increased risk of T1D. This dissertation examines the impact of both exogenous virus (i.e. CVB4) and endogenous retroviruses (ERVs) residing in the mammalian genome on the development of chronic inflammation and autoimmunity.
Following CVB4 infection, T1D-susceptible mice displayed exaggerated tissue damage and signs of chronic inflammation after viral clearance. Ongoing inflammation in these mouse strains was linked to an increased infiltration of T follicular helper cells (Tfh) and germinal centre-like B cells in the pancreas. Furthermore, genome-wide expression analyses of pancreatic beta cells from CVB4-infected mice revealed the activation of virus response genes associated with type I/II interferon (IFN) signalling, accompanied by tissue-specific induction of ERVs. In addition, our data highlight an important role for ERVs in the transcriptional regulation of immune response genes. Remarkably, pancreatic beta cells from uninfected T1D-susceptible mice revealed similar gene enrichment profiles to those found in CVB4-infected mice, emphasizing the role of viral sensing in autoimmune diabetes.
To further explore the role of viral recognition in autoimmunity, we made use of a novel mutant mouse strain that carries a point mutation within the MAVS (mitochondrial antiviral-signalling) protein, a crucial mediator of cytoplasmic nucleic acid sensing. MAVSlos mice immunised with RNA substrates exhibited diminished production of type I IFN and subsequent reduction of Tfh expansion and germinal centre formation. These findings demonstrate the significant role of (viral) nucleic acid sensing for appropriate activation of effector cells, but also illustrate how dysregulation of innate anti-viral signalling may translate into inappropriate (diminished or exaggerated) adaptive immunity.