The role of autoantibodies in inflammatory myopathies
Year: 2007
Type: dissertation
Abstract: Polymyositis (PM), dermatomyositis (DM) and inclusion body myositis\n(IBM), collectively called myositis, are chronic inflammatory myopathies.\nThese disease subsets are heterogeneous but share some features, such as\nskeletal muscle weakness and inflammatory cell infiltrates in muscle\ntissue. In many patients involvement of other organs, in particular skin\nand lung, also occurs. Another characteristic feature is the presence of\nautoantibodies which are (1) myositis specific, e.g.\nanti-histidyl-transfer ribonucleic acid (RNA) synthetase (Jo-1) and\nanti-Mi-2, and (2) myositis associated e.g. anti-Ro52/SSA, anti-Ro60/SSA,\nanti-PM/Scl and anti-U1sn ribonucleoprotein (RNP) autoantibodies.\nPresence of anti-Jo-1 autoantibodies is specifically associated with\ninterstitial lung disease (ILD). Despite the clinical associations it is\nnot known whether these autoantibodies have a pathogenic role or are\nmerely an epiphenomenon in the disease mechanism.\n\nAim: The overall goal of this thesis was to evaluate the role of specific\nand associated autoantibodies in myositis pathogenesis by combining in\nvivo and in vitro approaches.\n\nResults: We demonstrated in vitro that immune complexes containing\nanti-Jo-1 or anti-Ro52/Ro60 autoantibodies and RNA may act as endogenous\ntype I interferon (IFNalpha/beta) inducers via plasmacytoid dendritic\ncells (PDCs). Patients also had increased expression of\nIFNalpha/beta-inducible human myxovirus resistance 1 (MX-1) protein in\nmuscle tissue which correlated with number of blood dendritic cell\nantigen (BDCA)-2 positive PDCs. DM patients characterized by skin rash\nalso had increased MX-1 expression in muscle tissue but this was located\nto capillaries, suggesting another induction mechanism and cellular\nIFNalpha source such as the skin. The same groups of patients displayed\nelevated levels of B cell activating factor (BAFF), suggesting an\ninduction by a local (muscle and skin) type I IFN system. Sera from PM\npatients with anti-Jo-1 autoantibodies and ILD exhibited induced\nintracellular adhesion molecule (ICAM)-1 expression in lung endothelial\ncells in vitro, which has clinical relevance as ICAM-1 is upregulated in\nvivo in endothelial cells of capillaries in muscle tissue.\n\nThe effects of high dose intravenous immunoglobulin (IVIG) treatment on\nendothelial cell activation and other immunological molecules\ninvestigated in muscle tissue varied between patients and were not\ncorrelated with improved muscle function. This could be due to the\nheterogeneity of the disease mechanisms in myositis. The effects of IVIG\ntreatment were thus considered as being limited.\n\nConclusion: There seems to be a role for anti-Jo-1 autoantibodies in the\npathogenesis of myositis patients with lung and skin involvement. The\nfindings in this thesis suggest that this role is related to the\nendogenous production of type I IFN, which perpetuates disease. Sera with\nanti-Jo-1 autoantibodies are capable of inducing endothelial cell\nactivation, enabling the influx of inflammatory cells into the muscle\ntissue. An inflammatory condition sustained by inflammatory cells and\ntheir mediators may induce changes in muscle fiber metabolism which can\nlead to muscle damage.
Source: Figshare
Author: Sevim Barbasso Helmers
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1741748082