title: Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies.
abstract: 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.
authors.forename: Inka
authors.initials: I
authors.lastname: Albrecht
authors.forename: Cecilia
authors.initials: C
authors.lastname: Wick
authors.forename: Åsa
authors.initials: Å
authors.lastname: Hallgren
authors.forename: Anna
authors.initials: A
authors.lastname: Tjärnlund
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
authors.forename: Felipe
authors.initials: F
authors.lastname: Andrade
authors.forename: Kathryn
authors.initials: K
authors.lastname: Thompson
authors.forename: William
authors.initials: W
authors.lastname: Coley
authors.forename: Aditi
authors.initials: A
authors.lastname: Phadke
authors.forename: Lina-Marcela
authors.initials: LM
authors.lastname: Diaz-Gallo
authors.forename: Matteo
authors.initials: M
authors.lastname: Bottai
authors.forename: Inger
authors.initials: I
authors.lastname: Nennesmo
authors.forename: Karine
authors.initials: K
authors.lastname: Chemin
authors.forename: Jessica
authors.initials: J
authors.lastname: Herrath
authors.forename: Karin
authors.initials: K
authors.lastname: Johansson
authors.forename: Anders
authors.initials: A
authors.lastname: Wikberg
authors.forename: A Jimmy
authors.initials: AJ
authors.lastname: Ytterberg
authors.forename: Roman A
authors.initials: RA
authors.lastname: Zubarev
authors.forename: Olof
authors.initials: O
authors.lastname: Danielsson
authors.forename: Olga
authors.initials: O
authors.lastname: Krystufkova
authors.forename: Jiri
authors.initials: J
authors.lastname: Vencovsky
authors.forename: Nils
authors.initials: N
authors.lastname: Landegren
authors.forename: Marie
authors.initials: M
authors.lastname: Wahren-Herlenius
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.forename: Olle
authors.initials: O
authors.lastname: Kämpe
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Lundberg
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D001327:Autoimmune Diseases / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D053804:Granzymes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000097:blood / Q000235:genetics / Q000276:immunology*; D060588:LIM Domain Proteins / Q000097:blood / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000097:blood / Q000235:genetics / Q000276:immunology*; D009135:Muscular Diseases / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000473:pathology
chemical_list: D001323:Autoantibodies; C101149:FHL1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009124:Muscle Proteins; C509213:GZMB protein, human; D053804:Granzymes