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Unravelling disease mechanisms in juvenile dermatomyositis

By E.F. Elst

Abstract

The pathogenesis of autoimmune diseases remains largely obscure despite extensive research. The role of triggering factors in the onset is unquestionable. However, at present, the focus of research lies in the mechanisms that locally control immune responses. Especially, enforcing the induction of regulatory T cells by self-antigens that are involved in the ongoing inflammation opens the way for new forms of specific immunotherapy. In this thesis, we aimed at exploring the mechanisms related to the ongoing inflammation in juvenile dermatomyositis (JDM) as a model for autoimmune disease. JDM is a multisystem inflammatory disease that involves primarily the muscle and skin, but may affect many other systems We describe the spectrum of the disease, with emphasis on indicators for disease prognosis and new instruments to evaluate disease activity. These parameters are warranted for optimal choice of treatment regimens. Because disease prognosis and disease activity are correlated with the extent of the inflammatory process, underlying immunological mechanisms contributing to disease were analyzed. We focussed on regulatory T cells (Treg) as main players in peripheral tolerance. We were able to describe the characteristics of Treg in JDM and found possible clues pointing at impaired Treg function. The selection of heat shock proteins (HSP) as the self-antigens possibly involved in the inflammatory process was made because of their specific characteristics and because of the results of previous research in other autoimmune diseases. We showed that HSP60 and HSP60 epitopes can induce T cell regulation in vitro in JDM. In this disease, to our knowledge, no previous studies on these subjects were presented. Interestingly, HSP70 did not seem to induce adaptive immune responses. On the other hand, overexpression of HSP70 at the inflammatory site can be regarded as a sign of protection against further damage. Because immune reactivity to the HSP60 epitopes is also demonstrated in other autoimmune diseases, these epitopes could be related to inflammation in general and thus be applied in a broader patient population. T cell responses to HSP60 epitopes could also be used as biomarkers for disease activity and prognosis or for follow-up of future immunotherapy studies with epitopes. Altogether, this thesis offers intriguing new insights in the pathogenesis of an autoimmune disease that lacks an adequate animal model for thorough research. It is of importance to confirm our findings in a larger group of JDM patients which, because of the rarity of these diseases, necessitates a multicenter approach

Topics: Geneeskunde, autoimmune, juvenile dermatomyositis, functional ability, regulatory T cells, heat shock protein, mucosal tolerance
Publisher: Utrecht University
Year: 2007
OAI identifier: oai:dspace.library.uu.nl:1874/20946
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