The Toll of too much Interferon

Abstract

Primary Sjögren's Syndrome (pSS) is an autoimmune disease characterized by accumulation of white blood cells in the salivary and lachrymal glands. Characteristic symptoms are dry eyes and mouth. Other manifestations frequently present in pSS involve among others the skin, joints, muscles, kidneys, and lungs, indicating that pSS is a systemic disease. pSS patients often experience disabling fatigue and a depressed mood as their most severe symptoms, reducing overall health­ related quality of life. The consequences of pSS for social functioning of the patient are serious and frequently result in unemployment. To date it is however largely unknown what factors cause these disabling symptoms. The prevalence of pSS is estimated between 0.05-1%, with a nine fold predominance in females. The diagnosis of pSS can be difficult due to lack of specific markers and the heterogeneity of the symptoms. The criteria for establishing a diagnosis of pSS consist of six clinical elements, both subjective and objective. At present, no common evidence-based intervention therapy is available and treatment is mainly symptomatic . Thus, a further unravelling of the pathophysiology of pSS is essential for finding novel biomarkers and identifying new treatment targets. Interferon (IFN) type I has been proposed as a biomarker for systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and pSS.

IFN type I is a large family of IFNs comprising 17 different subtypes. IFN type I is produced in healthy individuals following a viral infection, finding its origin as being discovered and named for its potent ability to readily "interfere" with viruses. The research described in this thesis was aimed at unraveling the role of IFN type I activity in pSS with the following overall aims: I) Determine the prevalence of IFN type I activation and its relation to clinical symptoms in pSS II) To unravel the biological pathways underlying IFN type I activity in pSS Ill) To study downstream effects of systemic IFN type I activation in pSS The overall findings are discussed, addressing the toll that pSS patients have to pay for the presence of too much IFN. The identified different pathogenic pathways probably underlie the heterogeneity of pSS, indicating that patients with pSS will most likely benefit from optimizing therapies tailored to specific subgroups of the disease. In this thesis we provide our perspective on the importance of subdividing pSS patients according to their IFN signature(s).