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Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies
Inka Albrecht, … , Olle Kämpe, Ingrid E. Lundberg
Inka Albrecht, … , Olle Kämpe, Ingrid E. Lundberg
Published December 1, 2015; First published November 9, 2015
Citation Information: J Clin Invest. 2015;125(12):4612-4624. https://doi.org/10.1172/JCI81031.
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Categories: Research Article Immunology

Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies

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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

Inka Albrecht, Cecilia Wick, Åsa 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 Krystufkova, Jiri Vencovsky, Nils Landegren, Marie Wahren-Herlenius, Leonid Padyukov, Olle Kämpe, Ingrid E. Lundberg

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Figure 1

IIM patients have anti-FHL1 autoantibodies that are specific to this disease.

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IIM patients have anti-FHL1 autoantibodies that are specific to this dis...
(A) Sera from patients with IIM (PM, DM, or IBM; n = 141) were analyzed by ELISA for reactivity to recombinant FHL1-MaBP fusion protein and compared with sera from sex- and age-matched HCs (n = 126). (B) A cutoff value was calculated, allowing subdivision of the patients into anti-FHL1– (aFHL1–) and anti-FHL1+ patients (cutoff = mean [norm. absorbance HC] + 2 × SD = 0.26228). (C) Anti-FHL1 positivity was confirmed by another ELISA using recombinant His-tagged FHL1 and by comparing anti-FHL1+ (n = 35) with sex- and age-matched anti-FHL1– patients (n = 30) as well as by Western blotting (D) using recombinant FHL1-MaBP fusion protein. All 35 of the anti-FHL1+ patients were analyzed (lanes 1–35). Lanes show reactivity of sera from anti-FHL1+ patients 10 and 29 to MaBP loaded next to FHL1-MaBP, of sera from 4 HCs (sera 3* with positive reactivity detected by ELISA in B), of sera from a positive control (PC) using a commercial anti-FHL1 antibody, and of sera from 3 anti-FHL1– patients. (E) Reactivity to FHL1 in sera from HCs and IIM patients was compared by ELISA with anti-FHL1 reactivity in sera from patients with MCTD (n = 19), RA (n = 67), pSS (n = 35), SLE (n = 33), and SSc (n = 32), as well as in sera from patients with neuromuscular disease (NMD; n = 9). Statistical analysis for A–C was performed using a 2-tailed Mann Whitney U test; each data point represents 1 individual, and horizontal bars indicate the mean values. For A, B, and E, normalized A405 values (norm. A405 = FHL1-MaBP-A405 minus MaBP-A405) are shown.
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