Session Type: ACR Concurrent Abstract Session
Session Time: 2:30PM-4:00PM
The mechanisms that contribute to the pathogenesis of the idiopathic inflammatory myopathies remains largely unknown. This heterogeneous group of diseases involve autoimmunity toward muscles that results in tissue destruction. Previous studies on the synaptotagmin VII-knockout (Syt VII-/-) mouse model revealed these mice develop myositis that could be exacerbated by combining the Syt VII-/- model with regulatory T-cell deficiency (FoxP3-/Y) by adoptively transferring into immunodeficient (RAG1-/-) recipients. Other studies indicate that Syt VII-/- mice have impaired sarcolemmal membrane resealing capacity, a defect that results in increased membrane permeability and resulting exposure of intracellular antigens to the extracellular space. Additional genes have been linked to membrane resealing, including members of the large tripartite motif (TRIM) gene family, where deletion of these genes result in myopathy. Our previous studies show that TRIM72/MG53 is essential for sarcolemmal membrane repair in striated muscles. Alteration of the expression levels of, or autoantibody responses to, TRIM72/MG53 and related TRIM proteins levels could alter membrane repair in the context of myositis and contribute to progression of the disease. Here, we examined protein expression levels of several related novel TRIM proteins in muscle tissue from this myositis mouse model and human myositis patients. Additional studies screened for autoantibody responses to these TRIM proteins in serum samples from other human myositis patients.
Methods: Muscle biopsies from myositis patients were collected and analyzed by standard Western immunoblotting and by immunohistochemistry. Overexpression constructs for target TRIM proteins tagged with a green fluorescent protein (GFP) tag were transfected into HEK293 cells and resulting protein extracts were enriched for the TRIM proteins using co-immunoprecipitation approaches. Enriched extracts were used for Western immunoblotting using myositis patient serum samples as the primary antibody.
Results: We identified multiple TRIM family proteins that display altered expression in myositis muscle from both mice and humans. TRIM72/MG53 and other related TRIM proteins displayed altered expression in muscle extracts from both a myositis mouse model and human myositis patients. In particular, TRIM27 showed increased expression in myositis muscle from both humans and mice. We next examined if we could detect antibodies against these TRIM family proteins in the serum of human myositis patients. Autoantibodies were detected in the serum against TRIM72/MG53, TRIM27 and TRIM2 in multiple myositis patients but not in healthy controls
Conclusion: We have identified altered expression of TRIM proteins in skeletal muscle in a myositis mouse model and in muscle biopsies from human myositis patients. Autoantibodies targeting some of these TRIM proteins could be detected in the blood serum of myositis patients. These results highlight an association of decreased sarcolemmal membrane integrity in the development of myositis and suggest a mechanism that could be targeted for diagnostics and therapeutics in these diseases.
To cite this abstract in AMA style:McElhanon K, Alloush J, Young NA, Sahenk Z, Aggarwal R, Oddis CV, Jarjour WN, Weisleder N. Novel Tripartite Motif Proteins Linked to Membrane Integrity As Biomarkers of Dermatomyositis and Polymyositis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/novel-tripartite-motif-proteins-linked-to-membrane-integrity-as-biomarkers-of-dermatomyositis-and-polymyositis/. Accessed .
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