Overview

Although the pathogenesis of PM has not been elucidated, cytotoxic CD8⁺ T cells are thought to have a prominent role in the development of myositis . Recently, the C protein-induced myositis (CIM) model was established as an animal model for PM . The skeletal muscle C protein is a myosin-binding protein that regulates muscle filament components . This murine myositis is readily induced by a single immunization with recombinant skeletal muscle C protein fragments in C57BL/6 mice. CIM elicits abundant perforin-positive CD8⁺ T cells that infiltrate endomysial sites. In addition, CD8⁺ T cell depletion inhibits the progression of myositis. In the CIM model, inflammatory cytokines, including interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α, mediate the induction and development of myositis This CIM model is primarily utilized to examine the inflammatory phase of PM. (1,2)

Leukocyte recruitment into inflammatory sites is accomplished by constitutive or inducible expression of multiple adhesion molecules . L-selectin (CD62L), which primarily mediates leukocyte capture and rolling on the endothelium, is constitutively expressed by most leukocytes . In addition, L-selectin plays significant roles in the activation of multiple intracellular signaling pathways . ICAM-1 (CD54) is a member of the Ig superfamily that is constitutively expressed on endothelial cells, subsets of leukocytes, fibroblasts, and epithelial cells . It can be transcriptionally up-regulated by several proinflammatory cytokines, such as TNF-α, interferon (IFN)-γ, and IL-1 . L-selectin and ICAM-1 act in concert with each other during leukocyte migration from blood to extravascular tissues where inflammatory responses occur in vivo .(2,3)

Deficiency of both L-selectin and ICAM-1 did not exhibit a synergistic effect . Introducing defective ICAM-1 into L-selectin-deficient (L-selectin^-/-) mice resulted in a profoundly decreased pulmonary fibrosis compared to that observed in mice with a deficiency of a single adhesion molecule in a bleomycin-induced pulmonary fibrosis model . However, wound healing was not inhibited by L-selectin deficiency, while delayed wound healing was observed in ICAM-1-deficient (ICAM-1^-/-) mice . Nevertheless, the relative contributions and interaction of L-selectin and ICAM-1 in the CIM model remain unknown. (1,4)

Trials

In one study CIM was induced in wild type mice, L-selectin-deficient (L-selectin^-/-) mice, ICAM-1-deficient (ICAM-1^-/-) mice, and both L-selectin- and ICAM-1-deficient (L-selectin^-/-ICAM-1^-/-) mice. The severity of myositis, inflammatory cell infiltration, and mRNA expression in the inflamed muscles were examined. The effect of dendritic polyglycerol sulfate (dPGS), a synthetic inhibitor that suppresses the function of L-selectin and endothelial P-selectin, was also examined. L-selectin^-/- mice and L-selectin^-/-ICAM-1^-/- mice developed significantly less severe myositis compared to wild type mice, while ICAM-1 deficiency did not inhibit the development of myositis. L-selectin^-/- mice transferred with wild type T cells developed myositis. Wild type mice treated with dPGS significantly diminished the severity of myositis compared to control-treated wild type mice. (1)

Summary 

L-selectin expression on leukocytes may be important not only for leukocyte infiltration, but also for subsequent cytokine production. In the CIM model, IL-6 deficiency inhibited the progression of myositis, and IL-6 blockade reduced the severity of myositis . Consistent with this previous report, one study showed that IL-6 mRNA expression in the inflamed muscles of L-selectin^-/- mice was significantly decreased compared to wild type mice . Moreover, other inflammatory cytokines, including IL-12 and IFN-γ, were decreased in L-selectin^-/- mice as well. The incidence of myositis in IL-1- and TNF-α-deficient mice was significantly lower than wild type mice . Although the differences did not reach significance, IL-1β and TNF-α tended to decrease in L-selectin^-/- mice compared to wild type mice in this study Collectively, L-selectin expression appears to influence cytokine production in inflamed muscles. However, the mechanism how L-selectin is involved in cytokine regulation, needs to be evaluated. (5,6)

Therapy

Establishing effective polymyositis therapies has been long awaited. Corticosteroids have been proven to be beneficial, but serious adverse effects can frequently occur. To date, several studies targeting adhesion molecules have been performed. Bimosiamose is a small-molecule and pan-selectin antagonist that targets E-, P- and L-selectin . Inhaled administration of Bimosiamose in asthmatic patients attenuated late asthmatic reactions . Subcutaneous administration of Bimosiamose improved the clinical scores in patients with psoriasis . A humanized anti-L-selectin monoclonal antibody (aselizumab) significantly increased survival time and decreased mortality in a baboon model of hemorrhagic-traumatic shock . However, intravenous administration of aselizumab for multiple traumatized patients resulted in no significant improvement of efficacy in a phase II clinical trial . Also caution should be paid in developing biological therapies targeting adhesion molecules. A humanized anti-CD11a monoclonal antibody, efalizumab, was effective for the treatment of psoriasis, but a long-term follow-up study revealed several fatal cases of progressive multifocal leukoencephalopathy by JC virus , leading to voluntary withdrawal of the therapeutic from the market. In this study, the synthetic compound dPGS, which is an inhibitor that suppresses the function of leukocytic L-selectin and endothelial P-selectin, improved myositis severity . Therefore, we assume that a selectin-targeted therapy could still be an option for the treatment of polymyositis. (7)

 

Relevance 

These data indicate that L-selectin plays a major role in the development of CIM, whereas ICAM-1 plays a lesser, if any, role in the development of CIM. L-selectin-targeted therapy may be a candidate for the treatment of PM.

Footnotes

1. Kyosuke O.A crucial role of L-selectin in C protein-induced experimental polymyositis of mice.Arthritis Rheumatol. 2014 Jul; 66(7): 1864–1871. doi:  10.1002/art.38630PMCID: PMC4239294 NIHMSID: NIHMS631031. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239294/

 

 

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