FUNCTIONAL IMPACT OF NOVEL SJÖGRENS SYNDROME-ASSOCIATED GENETIC POLYMORPHISMS

Autoimmunity is defined as the failure of our immune system to distinguish self from non-self. This is a state wherein the host?s immune system initiates an immune response against its own cells, tissues and components. These autoimmune reactions involve the presence of self-reactive immune cells (autoantibodies) that can lead to the development of autoimmune diseases, affecting approximately 5% of the world?s population. An example of such diseases is the chronic rheumatic disease Sjögrens syndrome (SS), where 90% of those affected are female. A characteristic feature of SS is the progressive destruction of the salivary and tear glands, resulting in the common symptoms of dry mouth and dry eyes. Patients with SS are also characterised by the production of the autoantibodies anti-SSA and anti-SSB, which are used as diagnostic markers for this disease. Many factors have been associated with the development of SS. These include viral infections, environmental factors, and genetics. Nonetheless, much like other autoimmune diseases, the cause of SS remains unknown. As a consequence, the treatment of SS has been more focused on relieving the common symptoms of the disease. Hence, a deeper understanding of disease development is needed. Our project deals with understanding genetic mutations (polymorphisms) in SS. We focus on identifying how these genes and their related pathways differ in relation to healthy individuals, and how this contributes to disease development. These genetic analyses are being combined with functional immunological assays, utilising patient material, such as lower lip biopsies and peripheral blood, from both Norwegian and Swedish registries. Our studies are conducted in Sweden at the Karolinska Institute, Stockholm and Uppsala University, Uppsala, as part of a collaborative mobility grant with the University of Oslo, Norway, where collaborators at the University of Bergen, Norway are also involved. Our findings reveal a genetic predisposition amongst SS patients for disease development, where these polymorphisms also affect disease progression on a cellular level in the patients, further resulting in altered immune reactions. These findings may in turn contribute towards identifying strategies suitable for novel preventive measures, diagnostics and targeted treatment of human autoimmune diseases.

Our project aimed to understand the functional impact of novel disease-associated polymorphisms identified in Sjögren's syndrome, focusing on CXCR5 and FAM167A. We have successfully identified how these genes and their related cellular pathways have perturbed functions in relation to healthy individuals, and how this contributes to disease development. These findings are important for understanding disease progression and how tissue damage is mediated, contributing to identifying targets and strategies suitable for novel preventive measures, diagnostics and treatment. Moreover, this collaboration has strengthened the Scandinavian Sjögren's Syndrome network, as we benefited from each other's expertise and established laboratory techniques, accessing unique patient material from well-characterised cohorts. The acquired molecular and genetic cutting edge technology can now be established and implemented at the University of Oslo, and the University of Bergen in Norway.

Autoimmune disorders are a major cause of disease and disability, affecting more than 5% of the population. Sjögrens syndrome (SS) is a systemic rheumatic autoimmune disease affecting the exocrine glandular function, where the salivary and lacrimal glands are the primary sites of inflammation. This results in the common symptoms of dry mouth and dry eyes (xerostomia and keratoconjuctivitis sicca). Our studies from Swedish and Norwegian cohorts have identified several single nucleotide polymorphisms (SNPs) in the lymphotoxin-alpha, lymphotoxin-beta, tumour necrosis factor (LTA/LTB/TNF) locus that lead to amino acid changes associated with primary SS (pSS) (Bolstad AI, et al. Annals of the rheumatic diseases, 2012). Moreover, it has recently been shown that variants at multiple loci that are implicated in both innate and adaptive immune responses are associated with SS, including IRF5, STAT4, CXCR5 and DDX6 (Lessard, CJ et al. Nature genetics, 2013). This project aims at understanding the functional impact of these disease-associated polymorphisms, focusing on the DDX6/CXCR5 locus. We aim to identify how these genes and their related pathways have perturbed functions in relation to healthy individuals, and how this contributes to disease development. Through a strong and additive collaboration between University of Bergen, Uppsala University and the Karolinska Institute our strategic setup enables us to move from a clinical problem to a molecular understanding of the disease and back to the patient. Studies will be performed in humans, animal models and in vitro systems. The results obtained will be important for the understanding of how a rheumatic autoimmune disease develops and how tissue damage is mediated. Our findings will also have broader implications for other B cell related conditions, including lymphoma, and contribute towards identifying targets and strategies suitable for novel preventive measures, diagnostics and treatment of human autoimmune diseases.