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 6

Exogenous delivery of polyclonal TRIM72 antibody significantly impairs sarcolemma resealing.

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Exogenous delivery of polyclonal TRIM72 antibody significantly impairs s...
FDB muscles isolated from C57BL mice were subjected to laser-induced injury with either normal rabbit (Rb) serum (control, 1:100 dilution) or polyclonal antibody against TRIM72 (2 mg/mL diluted 1:300 and 1:100, respectively). Yellow arrowheads indicate sites of injury. (A) Representative images of FM4-64 dye influx before (0 seconds) and after (60 seconds) injury with anti-TRIM72 antibody at 1:300. (B) Representative images of FM4-64 dye influx before and after injury with anti-TRIM72 antibody at 1:100. Scale bars: 20 μm. (C) Curves depicting mean sarcolemmal resealing kinetics measured every 3 seconds for 60 seconds. Data are represented as mean ± SEM. (D) AUC calculations representing total dye influx over time (n = 7, 31, and 7 for Rb serum, anti-TRIM72 at 1:300, and anti-TRIM72 at 1:100, respectively; ANOVA, F(2,41) = 10.05, P = 0.0003; Tukey’s HSD: Rb serum vs. 1:300, P = 0.0079; Rb serum vs. 1:100, P = 0.0002; 1:100 vs. 1:300, P = 0.036). (E) Rotation damage assay performed on HEK293 cells expressing eGFP (control) or TRIM72 with and without polyclonal antibody against TRIM72 (1:100 dilution). LDH release into the supernatant was quantified as a measure of membrane resealing capacity. (eGFP –Injury –Ab, n = 6; eGFP +Injury –Ab, n = 5; eGFP +Injury +Ab, n = 3; TRIM72 –Injury –Ab, n = 6; TRIM72 +Injury –Ab, n = 6; TRIM72 +Injury +Ab, n = 4. ANOVA, F(5,24) = 80.74, P < 0.0001; Tukey’s HSD: **P < 0.005, ****P < 0.0001.) Data in D and E are represented as mean ± SD.