Autoantibodies targeting TRIM72 compromise membrane repair and contribute to inflammatory myopathy
Kevin E. McElhanon, … , Wael N. Jarjour, Noah Weisleder
Kevin E. McElhanon, … , Wael N. Jarjour, Noah Weisleder
Published July 20, 2020
Citation Information: J Clin Invest. 2020;130(8):4440-4455. https://doi.org/10.1172/JCI131721.
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Research Article Autoimmunity Muscle biology

Autoantibodies targeting TRIM72 compromise membrane repair and contribute to inflammatory myopathy

Abstract

Idiopathic inflammatory myopathies (IIM) involve chronic inflammation of skeletal muscle and subsequent muscle degeneration due to an uncontrolled autoimmune response; however, the mechanisms leading to pathogenesis are not well understood. A compromised sarcolemmal repair process could promote an aberrant exposure of intramuscular antigens with the subsequent initiation of an inflammatory response that contributes to IIM. Using an adoptive transfer mouse model of IIM, we show that sarcolemmal repair is significantly compromised in distal skeletal muscle in the absence of inflammation. We identified autoantibodies against TRIM72 (also known as MG53), a muscle-enriched membrane repair protein, in IIM patient sera and in our mouse model of IIM by ELISA. We found that patient sera with elevated levels of TRIM72 autoantibodies suppress sarcolemmal resealing in healthy skeletal muscle, and depletion of TRIM72 antibodies from these same serum samples rescues sarcolemmal repair capacity. Autoantibodies targeting TRIM72 lead to skeletal muscle fibers with compromised membrane barrier function, providing a continuous source of autoantigens to promote autoimmunity and further amplifying humoral responses. These findings reveal a potential pathogenic mechanism that acts as a feedback loop contributing to the progression of IIM.

Authors

Kevin E. McElhanon, Nicholas Young, Jeffrey Hampton, Brian J. Paleo, Thomas A. Kwiatkowski, Eric X Beck, Ana Capati, Kyle Jablonski, Travis Gurney, Miguel A. Lopez Perez, Rohit Aggarwal, Chester V. Oddis, Wael N. Jarjour, Noah Weisleder

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Figure 7

IIM sera with elevated TRIM72 autoantibody levels compromise sarcolemmal repair in healthy skeletal muscle.

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IIM sera with elevated TRIM72 autoantibody levels compromise sarcolemmal...
FDB muscles isolated from C57BL mice injured by an infrared laser with healthy subject serum or serum from subjects diagnosed with PM or DM. Serum was diluted 1:200 in Tyrode’s buffer before laser injury. Yellow arrowheads indicate sites of injury. Data in B, E, and H are represented as mean ± SEM. Data in C, F, and I are represented as mean ± SD. (A) Representative images of FM4-64 dye influx before (0 seconds) and after (60 seconds) injury at baseline (Basal) or after addition of healthy subject serum (Serum). (B) Sarcolemmal resealing kinetics measured every 3 seconds for 60 seconds as depicted in A. (C) AUC calculations of B representing total dye influx over time (n = 10 and 12 for Basal and Serum, respectively; t test, t(df=0.8109) = 20; P = 0.4296). (D) Representative images of FM4-64 dye influx before and after injury at baseline and after addition of PM subject serum. (E) Sarcolemmal resealing kinetics depicted in D. (F) AUC calculations of E representing total dye influx over time (n = 3 and 8 for Basal and Serum, respectively; t test, t(df=4.751) = 9; P = 0.001). (G) Representative images of FM4-64 dye influx before and after injury at baseline and after addition of DM subject serum. (H) Sarcolemmal resealing kinetics depicted in G. (I) AUC calculations of H (n = 6 and 5 for Basal and Serum, respectively; t test, t(df=4.717) = 4.8; P = 0.0057). Scale bars: 20 μm.