New research suggests that tripartite motif (TRIM) family proteins act as autoantigens in idiopathic inflammatory myopathy (IIM) and contribute to disease progression via a positive feedback loop. The findings of the study suggest that antibodies against these proteins compromise muscle membrane repair, and decreased sarcolemmal integrity leads to aberrant autoantigen presentation that promotes autoimmunity.
The research focused on the protein TRIM72 (also known as MG53), which had been previously identified as an important component of the sarcolemmal repair process in striated muscle. “We identified autoantibodies targeting TRIM72 […] in a subset of myositis patient sera and established a direct causal effect of these antibodies on defective membrane repair,” says corresponding author Noah Weisleder. “To our knowledge, we are the first to identify this autoantibody and directly demonstrate an effect on myositis disease progression.”
The researchers demonstrated that adoptive transfer of lymph node cells from Foxp3–/YSyt7–/– mice into recipient Rag1–/– mice resulted in severe inflammation in proximal muscle whereas distal muscle was spared, recapitulating the pattern seen in patients with IIM. Notably, distal skeletal muscle had impaired membrane integrity and reduced capacity for membrane repair following injury in the absence of inflammation.
Autoantibodies against TRIM72 were detected in sera from Foxp3–/YSyt7–/– mice and in adoptive transfer recipient mice, as well as in sera from patients with dermatomyositis or polymyositis.
In healthy skeletal muscle subjected to laser injury, the presence of patient sera with high levels of anti-TRIM72 autoantibodies suppressed sarcolemmal resealing, whereas this repair capacity was rescued in the presence of these same serum samples depleted of anti-TRIM72 antibodies.
“Future studies will determine if other proteins involved in the cell membrane repair response are also autoantigen[s] and to what extent these autoantigens [contribute to] disease progression,” says Weisleder. “If cell membrane integrity can be increased therapeutically,” he adds, “it may be possible to limit the extent of muscle injury and wasting caused by autoimmune diseases targeting skeletal muscle.”
McElhanon, K. E. et al. Autoantibodies targeting TRIM72 compromise membrane repair and contribute to inflammatory myopathy. J. Clin. Invest. 6, eaba4353 (2020)
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Onuora, S. Autoantibodies disrupt muscle repair and promote IIM progression. Nat Rev Rheumatol (2020). https://doi.org/10.1038/s41584-020-0488-z