Auto‐antibodies Targeting Components of Sarcolemma Repair Represent a Pathogenic Mechanism in Idiopathic Immune Myopathies

Abstract

Idiopathic immune myopathies (IIM) represent a group of disorders causing chronic inflammation and significant damage to skeletal muscle due to an unchecked autoimmune response. The main challenge slowing study of IIM is an understanding of the pathogenic mechanism responsible for initiation and progression of skeletal muscle inflammation. Two mouse models of IIM have recently provided new insights into the pathogenesis of the disease. The synaptotagmin VII null (Syt VII−/−) mouse is characterized by defects in membrane resealing and presents with a mild form myositis at 2 months of age. A more robust model of IIM combines knock‐out of Syt VII with a FoxP3 mutation resulting in a mouse with impaired membrane resealing and regulatory T‐cell deficiency. Adoptive transfer of lymphocyte preparations isolated from this double mutant mouse model to recombination‐activating gene 1 (RAG‐1) null mice results in severe skeletal muscle inflammation. Plasma membrane resealing is a highly conserved mechanism allowing an injured cell to survive following a disruption to the lipid bilayer that compromises barrier function. Given the importance of plasma membrane barrier function in preventing exposure of intracellular antigens to the immune system, specifically in an immune‐compromised environment, it is possible that compromised sarcolemma resealing could drive pathogenesis of IIM. We show, for the first time, that a deficiency in T‐regulatory cells is not sufficient to induce sarcolemma fragility, however, purified antibodies against critical proteins facilitating the sarcolemma repair process are sufficient to reduce membrane integrity. We also demonstrate that sarcolemma integrity is reduced in distal skeletal muscle in the absence of inflammation in our novel murine model of IIM. We have established by direct ELISA that auto‐antibodies against multiple proteins involved in sarcolemma repair are elevated in IIM patient sera and find that exogenous delivery of IIM positive patient serum can compromise sarcolemma resealing in healthy skeletal muscle. These findings represent a novel mechanism that drives the progression of IIM when decreased sarcolemma integrity induces a vicious cycle of antigen presentation that directly contributes to the pathophysiology of idiopathic immune myopathies.Support or Funding InformationNIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases Award Number F31AR071745This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.