Background/Purpose: Idiopathic inflammatory myopathies (IIM) are a group of disorders in which autoimmune responses produce a chronic state of inflammation resulting in degeneration of skeletal muscle structure and function. The pathogenic mechanisms involved in IIM are not completely defined, however we have previously shown that defective sarcolemmal membrane repair mechanisms increase exposure of intracellular antigens such as histidyl-tRNA synthetase (HRS) and TRIM72 to the immune system leading to aberrant inflammatory activation and autoantibody production. These autoantibodies directed toward intracellular membrane resealing proteins leads to a positive feedback cycle in which the antibodies effectively block membrane resealing exposing the intracellular milieu, further exacerbating the immune response which likely contributes to the progression and pathogenesis of myositis.

Poloxamers are a unique class of amphipathic synthetic tri-block copolymers containing central hydrophobic chains of poly(propylene oxide) sandwiched between two hydrophilic chains of poly(ethylene oxide). Members of this class of compounds, P188 and P182, are known to increase membrane integrity when used both in vitro and in vivo. We hypothesize that these compounds may be able to stabilize the sarcolemmal membrane, decrease aberrant antigen exposure to the immune system and reduce the overall pathogenicity associated with myositis.

Methods: Levels of antibodies against repair proteins were measured in dermatomyositis and polymyositis patient serum samples with custom ELISA. Membrane repair function was determined using mechanical glass bead wounding or multi-photon infrared laser microscopy to damage the cell membrane of muscle fibers and live cell imaging to record the entry of fluorescent FM4-64 dye in the presence of myositis patient serum with P188 or P182. HRS was injected intramuscularly to induce myositis and P182 was injected subcutaneously at 3mpk 3 days per week for 3 weeks. Additionally, we injected exogenous antibodies against membrane repair proteins into myositis mice and determined changes to the myositis phenotype in vivo.

Results: We have identified novel autoantibodies against TRIM72 in IIM patient serum and show that these antibodies can compromise membrane repair in isolated healthy muscles. IIM patient serum with high titers of TRIM72 antibodies can compromise membrane repair in healthy muscle ex vivo while P188 can ameliorate these defects. We also demonstrate the potential therapeutic value of P182 in a mouse model of myositis.

Conclusion: These findings represent a novel mechanism in IIM whereby decreased sarcolemma integrity induces a vicious cycle of aberrant antigen presentation that directly contributes to the pathophysiology of idiopathic immune myopathies. Poloxamers represent a novel potential therapeutic for the treatment of IIM.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/poloxamers-188-182-are-effective-in-repairing-the-membrane-resealing-defect-in-myositis/