Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies
2015 (English)In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 125, no 12, 4612-4624 p.Article in journal (Refereed) PublishedText
Mutations of the gene encoding four-and-a-half LIM domain 1 (FHL1) are the causative factor of several X-linked hereditary myopathies that are collectively termed FHL1-related myopathies. These disorders are characterized by severe muscle dysfunction and damage. Here, we have shown that patients with idiopathic inflammatory myopathies (IIMs) develop autoimmunity to FHL1, which is a muscle-specific protein. Anti-FHL1 autoantibodies were detected in 25% of IIM patients, while patients with other autoimmune diseases or muscular dystrophies were largely anti-FHL1 negative. Anti-FHL1 reactivity was predictive for muscle atrophy, dysphagia, pronounced muscle fiber damage, and vasculitis. FHL1 showed an altered expression pattern, with focal accumulation in the muscle fibers of autoantibody-positive patients compared with a homogeneous expression in anti-FHL1-negative patients and healthy controls. We determined that FHL1 is a target of the cytotoxic protease granzyme B, indicating that the generation of FHL1 fragments may initiate FHL1 autoimmunity. Moreover, immunization of myositis-prone mice with FHL1 aggravated muscle weakness and increased mortality, suggesting a direct link between anti-FHL1 responses and muscle damage. Together, our findings provide evidence that FHL1 may be involved in the pathogenesis not only of genetic FHL1-related myopathies but also of autoimmune IIM. Importantly, these results indicate that anti-FHL1 autoantibodies in peripheral blood have promising potential as a biomarker to identify a subset of severe IIM.
Place, publisher, year, edition, pages
2015. Vol. 125, no 12, 4612-4624 p.
Immunology in the medical area
IdentifiersURN: urn:nbn:se:uu:diva-270945DOI: 10.1172/JCI81031ISI: 000365831300026PubMedID: 26551678OAI: oai:DiVA.org:uu-270945DiVA: diva2:890900
FunderSwedish Research CouncilRagnar Söderbergs stiftelseThe Karolinska Institutet's Research FoundationSwedish Rheumatism AssociationStockholm County CouncilThe Karolinska Institutet's Research FoundationTorsten Söderbergs stiftelse