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Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies
Karolinska Institute, Sweden.
Karolinska Institute, Sweden.
Karolinska Institute, Sweden.
Karolinska Institute, Sweden.
Vise andre og tillknytning
2015 (engelsk)Inngår i: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 125, nr 12, s. 4612-4624Artikkel i tidsskrift (Fagfellevurdert) Published
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Abstract [en]

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.

sted, utgiver, år, opplag, sider
AMER SOC CLINICAL INVESTIGATION INC , 2015. Vol. 125, nr 12, s. 4612-4624
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URN: urn:nbn:se:liu:diva-123783DOI: 10.1172/JCI81031ISI: 000365831300026PubMedID: 26551678OAI: oai:DiVA.org:liu-123783DiVA, id: diva2:892947
Merknad

Funding Agencies|Swedish Research Council; Ragnar Soderberg Foundation; Karolinska Institutet; Borje Dahlin Foundation; Swedish Rheumatism Association; King Gustaf V 80-year Foundation; Stockholm County Council; Karolinska Institutet on medical training and clinical research (ALF); Swedish Strategic Foundation (PRIMI); Torsten Soderberg Foundation

Tilgjengelig fra: 2016-01-11 Laget: 2016-01-11 Sist oppdatert: 2017-11-30

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