Development of autoantibodies against musclespecific FHL1 in severe inflammatory myopathies

Inka Albrecht, Cecilia Wick, Asa Hallgren, Anna Tjärnlund, Kanneboyina Nagaraju, Felipe Andrade, Kathryn Thompson, William Coley, Aditi Phadke, Lina Marcela Diaz-Gallo, Matteo Bottai, Inger Nennesmo, Karine Chemin, Jessica Herrath, Karin Johansson, Anders Wikberg, A. Jimmy Ytterberg, Roman A. Zubarev, Olof Danielsson, Olga KrystufkovaJiri Vencovsky, Nils Landegren, Marie Wahren-Herlenius, Leonid Padyukov, Olle Kämpe, Ingrid E. Lundberg

Research output: Contribution to journalArticle


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.

Original languageEnglish (US)
Pages (from-to)4612-4624
Number of pages13
JournalJournal of Clinical Investigation
Issue number12
StatePublished - Dec 2015


ASJC Scopus subject areas

  • Medicine(all)

Cite this

Albrecht, I., Wick, C., Hallgren, A., Tjärnlund, A., Nagaraju, K., Andrade, F., Thompson, K., Coley, W., Phadke, A., Diaz-Gallo, L. M., Bottai, M., Nennesmo, I., Chemin, K., Herrath, J., Johansson, K., Wikberg, A., Jimmy Ytterberg, A., Zubarev, R. A., Danielsson, O., ... Lundberg, I. E. (2015). Development of autoantibodies against musclespecific FHL1 in severe inflammatory myopathies. Journal of Clinical Investigation, 125(12), 4612-4624.