Autoantibodies and the type I interferon system in idiopathic inflammatory myopathies

Idiopathic inflammatory myopathies (IIM), also known as myositis, are rare autoimmune diseases, characterized by proximal muscle weakness and inflammatory cells in skeletal muscle tissue. The most common subgroups are polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM). New subgroups have been recognized, such as immunemediated necrotizing myopathy (IMNM) and the antisynthetase syndrome (ASS). Autoantibodies are common and some of them specific for myositis. The most frequent is the anti-Jo-1 autoantibody, which is associated not only with myositis but also with interstitial lung disease (ILD) and arthritis. The etiology of IIM is still unknown but environmental and genetic factors are believed to contribute to disease susceptibility. Accumulating data indicate a role of the type I interferons (IFNs) in myositis. The treatment of IIM (glucocorticoids and immunomodulatory drugs) has limited effect. New treatments are needed, thus increased understanding of molecular disease mechanisms in IIM is required. The overall aim of my thesis was to get an increased understanding of molecular mechanisms that are involved in IIM with a focus on the type I IFN system, autoantibodies and mechanisms that may induce immune reactivity, to be able to subclassify patients.

Several new observations were made. Firstly, we found that line blot is a suitable serological test in myositis and is a reliable alternative to more time-consuming assays such as immunoprecipitation (paper I). Secondly, we concluded that smoking is associated with IIM patients who are either anti-Jo-1 autoantibody and/or HLA-DRB1*03 positive (paper II). These associations point towards a gene-environment interaction in the pathogenesis for IIM. Thirdly, we found that a high IFN score was not only associated with the subset DM, as previously reported, and IBM, but also with autoantibody monospecificity against RNA-binding proteins or with autoantibody multispecificity (paper III). Furthermore, we identified IFN-α in sera as a trigger for activation of the type I IFN pathway in peripheral blood, which supports IFN-α as a possible target for therapy in these patients. Finally, we found that PM and DM are associated with dysregulation of endothelial progenitor cell (EPC) phenotype and function that may be attributed, at least in part, to aberrant IL-18 and type I IFN pathways (paper IV).

In conclusion, this thesis confirms a role of the type I IFN system in myositis, especially in subgroups of patients, based on their autoantibody status, and implicates a relationship between the type I IFN system and endothelial disruption. Furthermore, smoking may be a trigger in the pathogenesis of IIM in genetic susceptible persons. However, the implication of our findings to disease prognosis and treatment remain to be determined.

List of scientific papers

I. A. Ghirardello, M. Rampudda, L. Ekholm, N. Bassi, E. Tarricone, S. Zampieri, M. Zen, G.A. Vattemi, I.E. Lundberg, A. Doria. Diagnostic performance and validation of autoantibody testing in myositis by a commercial line blot assay. Rheumatology (Oxford). 2010;49(12):2370-4.
https://doi.org/10.1093/rheumatology/keq281

II. H. Chinoy, S. Adimulam, F. Marriage, P. New, M. Vincze, E. Zilahi, A. Kapitány, A. Gyetvai, L. Ekholm, P. Novota, M. Remakova, P. Charles, N.J. McHugh, L. Padyukov, L. Alfredsson, J. Vencovsky, I.E. Lundberg, K. Danko, W.E. Ollier, R.G. Cooper. Interaction of HLA-DRB1*03 and smoking for the development of anti-Jo1 antibodies in adult idiopathic inflammatory myopathies: a European-wide case study. Ann Rheum Dis. 2012;71(6):961-5.
https://doi.org/10.1136/annrheumdis-2011-200182

III. L. Ekholm, S. Vosslamber, A. Tjärnlund, T .D. de Jong, Z. Betteridge, N. McHugh, L. Plestilova, M. Klein, L. Padyukov , A.E. Voskuyl, I.E.M. Bultink, D.M. Pegtel, C.P. Mavragani, M.K. Crow, J. Vencovsky, I.E. Lundberg, C.L. Verweij. Autoantibody specificities and type I Interferon pathway activation in Idiopathic Inflammatory Myopathies. Scand J Immunol. 2016;84(2):100-9.
https://doi.org/10.1111/sji.12449

IV. L. Ekholm, J.M. Kahlenberg, S. Barbasso Helmers, A. Tjärnlund, S. Yalavarthi, W. Zhao, N. Seto, Z. Betteridge, I.E. Lundberg, M.J. Kaplan. Dysfunction of endothelial progenitor cells is associated with the type I Interferon pathway in patients with polymyositis and dermatomyositis. Rheumatology (Oxford). 2016.
https://doi.org/10.1093/rheumatology/kew288