uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies
Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
Karolinska Inst, Dept Med Solna, Expt Endocrinol, SE-17176 Stockholm, Sweden..
Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
Show others and affiliations
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) Published
Resource type
Text
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.

Place, publisher, year, edition, pages
2015. Vol. 125, no 12, 4612-4624 p.
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-270945DOI: 10.1172/JCI81031ISI: 000365831300026PubMedID: 26551678OAI: oai:DiVA.org:uu-270945DiVA: diva2:890900
Funder
Swedish Research CouncilRagnar Söderbergs stiftelseThe Karolinska Institutet's Research FoundationSwedish Rheumatism AssociationStockholm County CouncilThe Karolinska Institutet's Research FoundationTorsten Söderbergs stiftelse
Available from: 2016-01-05 Created: 2016-01-05 Last updated: 2017-12-01Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Landegren, NilsKämpe, Olle

Search in DiVA

By author/editor
Landegren, NilsKämpe, Olle
By organisation
Autoimmunity
In the same journal
Journal of Clinical Investigation
Immunology in the medical area

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 260 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf