The role of autoantibodies in inflammatory myopathies

Sammanfattning: Polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM), collectively called myositis, are chronic inflammatory myopathies. These disease subsets are heterogeneous but share some features, such as skeletal muscle weakness and inflammatory cell infiltrates in muscle tissue. In many patients involvement of other organs, in particular skin and lung, also occurs. Another characteristic feature is the presence of autoantibodies which are (1) myositis specific, e.g. anti-histidyl-transfer ribonucleic acid (RNA) synthetase (Jo-1) and anti-Mi-2, and (2) myositis associated e.g. anti-Ro52/SSA, anti-Ro60/SSA, anti-PM/Scl and anti-U1sn ribonucleoprotein (RNP) autoantibodies. Presence of anti-Jo-1 autoantibodies is specifically associated with interstitial lung disease (ILD). Despite the clinical associations it is not known whether these autoantibodies have a pathogenic role or are merely an epiphenomenon in the disease mechanism. Aim: The overall goal of this thesis was to evaluate the role of specific and associated autoantibodies in myositis pathogenesis by combining in vivo and in vitro approaches. Results: We demonstrated in vitro that immune complexes containing anti-Jo-1 or anti-Ro52/Ro60 autoantibodies and RNA may act as endogenous type I interferon (IFNalpha/beta) inducers via plasmacytoid dendritic cells (PDCs). Patients also had increased expression of IFNalpha/beta-inducible human myxovirus resistance 1 (MX-1) protein in muscle tissue which correlated with number of blood dendritic cell antigen (BDCA)-2 positive PDCs. DM patients characterized by skin rash also had increased MX-1 expression in muscle tissue but this was located to capillaries, suggesting another induction mechanism and cellular IFNalpha source such as the skin. The same groups of patients displayed elevated levels of B cell activating factor (BAFF), suggesting an induction by a local (muscle and skin) type I IFN system. Sera from PM patients with anti-Jo-1 autoantibodies and ILD exhibited induced intracellular adhesion molecule (ICAM)-1 expression in lung endothelial cells in vitro, which has clinical relevance as ICAM-1 is upregulated in vivo in endothelial cells of capillaries in muscle tissue. The effects of high dose intravenous immunoglobulin (IVIG) treatment on endothelial cell activation and other immunological molecules investigated in muscle tissue varied between patients and were not correlated with improved muscle function. This could be due to the heterogeneity of the disease mechanisms in myositis. The effects of IVIG treatment were thus considered as being limited. Conclusion: There seems to be a role for anti-Jo-1 autoantibodies in the pathogenesis of myositis patients with lung and skin involvement. The findings in this thesis suggest that this role is related to the endogenous production of type I IFN, which perpetuates disease. Sera with anti-Jo-1 autoantibodies are capable of inducing endothelial cell activation, enabling the influx of inflammatory cells into the muscle tissue. An inflammatory condition sustained by inflammatory cells and their mediators may induce changes in muscle fiber metabolism which can lead to muscle damage.