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.
| Original language | English |
|---|---|
| Pages (from-to) | 4440-4455 |
| Number of pages | 16 |
| Journal | Journal of Clinical Investigation |
| Volume | 140 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 3 2020 |
Bibliographical note
Publisher Copyright:Copyright: © 2020, American Society for Clinical Investigation.
Funding
The research reported in this publication was partially supported by a National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, National Research Service Award individual predoctoral fellowship under award number 1F31AR071745-01 to KEM. Images were generated at The Ohio State University Campus Microscopy and Imaging Facility, which is supported in part by grant P30 CA016058, National Cancer Institute, Bethesda, Maryland, USA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors thank the participants and staff involved in these studies. The authors also acknowledge the contributions of Zarife Sahenk (Nationwide Children’s Research Institute, Columbus, Ohio, USA), Lisa G. Rider, and Frederick W. Miller (NIH/National Institute of Environmental Health Sciences, Bethesda, Maryland, USA). The research reported in this publication was partially supported by a National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, National Research Service Award individual predoctoral fellowship under award number 1F31AR071745-01 to KEM. Images were generated at The Ohio State University Campus Microscopy and Imaging Facility, which is supported in part by grant P30 CA016058, National Cancer Institute, Bethesda, Maryland, USA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors thank the participants and staff involved in these studies. The authors also acknowledge the contributions of Zarife Sahenk (Nationwide Children?s Research Institute, Columbus, Ohio, USA), Lisa G. Rider, and Frederick W. Miller (NIH/National Institute of Environmental Health Sciences, Bethesda, Maryland, USA).
| Funders | Funder number |
|---|---|
| NIH/National Institute of Environmental Health Sciences | |
| National Institutes of Health (NIH) | P30 CA016058 |
| National Institutes of Health (NIH) | |
| National Childhood Cancer Registry – National Cancer Institute | |
| National Institute of Arthritis and Musculoskeletal and Skin Diseases | F31AR071745 |
| National Institute of Arthritis and Musculoskeletal and Skin Diseases |
ASJC Scopus subject areas
- General Medicine