Background/Purpose: Myositis is associated with an inflammatory process that results in pronounced muscle weakness and is observed in some regulatory T cell (Treg) deficient mouse models.  Autoimmune pathogenesis has been strongly implicated in myositis and is the focus of both standardized and emerging therapeutics.  It has been shown that patients with dermatomyositis have decreased numbers of Tregs in peripheral blood and at skin lesions when compared to healthy controls.  Scurfy (Forkhead box P3, FOXP3-/y) mice lack Tregs and display autoimmune inflammation of multiple organs, but exhibit very little evidence of myositis.  In contrast, Syt7 (Synaptotagmin 7) mice which have no Treg deficits develop an inflammatory response involving the muscles.  We hypothesized that Treg deficient myositis could be induced by myosin protein and that muscle-specific inflammatory effector cells could be suppressed through Treg supplementation.

Methods: We crossed scurfy mice with Syt7 mice, which results in a double knockout that is deficient in Treg cells and membrane resealing.  Lymph node preparations of these double knockout mice or scurfy mice were adoptively transferred into Rag1^null males with or without Tregs isolated using Dynabeads from wild-type mice or with purified myosin protein.  Histology of muscle tissue was examined four weeks post-injection.  Immunohistochemistry was performed on flash frozen and/or paraffin embedded tissue.

Results: Scurfy lymph node preparations injected into Rag1^null males intraperitoneally in conjunction with purified myosin protein induced robust skeletal muscle inflammation.  The infiltrates consisted predominantly of CD4⁺ and CD8⁺ T cells, limited macrophages, but no B cells.  Even more robust myositis was seen in similar experiments using lymph node preparations from Syt7/FOXP3 double knockout mice. However, myositis was not seen in adoptive transfers using single knockout mice.  This myositis was completely suppressed with the co-transfer of purified Treg cells from wild type mice. 

Conclusion: Taken together, these data demonstrate the critical role of the muscle antigen, myosin, in the pathogenesis of myositis.  Hence, myosin could be one possible target antigen of the immune response.   We also demonstrate the roles of Treg deficiency and aberrant muscle antigen release in the induction of myositis and the role of Treg as a therapeutic tool to treat myositis. 

This novel model has the potential of examining the interplay between chemical injury and inflammatory pathogenesis in myositis.  Ongoing work will use this model to examine the myopathy associated with statins and will examine the role of other endogenous muscle tissue antigens in this disease.

---

« Back to 2012 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/myosin-skews-effector-immune-cells-of-scurfy-mice-to-target-muscles-in-an-adoptive-transfer-model-of-myositis/