L-Selectin in C protein-induced mice.

Overview

Polymyositis (PM) is a chronic autoimmune inflammatory myopathy. It affects striated muscles and induces varying degrees of weakness, especially in the proximal muscles . Although the pathogenesis of PM has not been elucidated, cytotoxic CD8+ T cells are thought to play a prominent role in the development of myositis . Recently, the C protein–induced myositis (CIM) model was established as an animal model of 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-1 (IL-1), IL-6, and tumor necrosis factor α (TNFα), mediate the induction and development of myositis. The CIM model is primarily used to examine the inflammatory phase of PM. (1)

 

L SELECTIN

Leukocyte recruitment into sites of inflammation 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 . Intercellular adhesion molecule 1 (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 TNFα, interferon-γ (IFNγ), 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 . (1)

L Selectin and ICAM 1

One study reveals  the role  of adhesion molecules in the development of CIM, a murine model of PM. Specifically, L-selectin, but not ICAM-1, was critical for the development of myositis. The development of myositis was also prevented by treatment with dendritic polyglycerol sulfate, which binds to L-selectin and endothelial P-selectin and prevents leukocytes from binding to inflamed vascular endothelia. Thus, our findings indicate that L-selectin plays a critical role in the development of CIM, and that L-selectin could be a target for the treatment of PM. (2)

Trials

Previous studies clearly indicate that CD8+ T cells play a more significant role than CD4+ T cells in the development of CIM. Other studies reported that the percentage of L-selectin–positive cells in CD8+ T cells was greater than that in CD4+ T cells, especially in lymphoid tissues, and that L-selectin expression levels were higher on CD8+ T cells than on CD4+ T cells in wild-type mice. In contrast, L-selectin deficiency did not affect ICAM-1 expression (. Thus, the different expression levels of L-selectin between CD4+ and CD8+ T cells may partly explain the finding that L-selectin deficiency had a greater effect on the degree of myositis than ICAM-1 did in the present study. Alternatively, the greater role of L-selectin may be explained by the fact that L-selectin is important for antiviral immunity  and antitumor activity , in which CD8+ cytotoxic T cells play a substantial role. The etiologic role of CD8+ cytotoxic T cells may be another reason why L-selectin is more important than ICAM-1 in the CIM model. (3,4)

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 to multiple traumatized patients resulted in no significant improvement of efficacy in a phase II clinical trial . Also, caution should be paid in developing biologic therapies targeting adhesion molecules. A humanized anti-CD11a monoclonal antibody, efalizumab, was effective for the treatment of psoriasis, but a long-term followup study revealed several fatal cases of progressive multifocal leukoencephalopathy by JC virus , leading to voluntary withdrawal of the drug from the market.  the synthetic compound dendritic polyglycerol sulfate, 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 PM. (5)

L selectin deficiency

The relative contributions of L-selectin and ICAM-1 are largely dependent on the type of model of inflammation being used. For instance, in the immediate-type hypersensitivity model, deficiency of either L-selectin or ICAM-1 resulted in the immune response being reduced to similar degrees. 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. (5)

Footnotes: 

1. Okiyama N.Therapeutic effects of interleukin-6 blockade in a murine model of polymyositis that does not require interleukin-17A. Arthritis Rheum 2009;60:2505–12.

            Direct Link: Abstract

1. Sugihara T. Definitive engagement of cytotoxic CD8 T cells in C protein–induced myositis, a murine model of polymyositis. Arthritis Rheum 2010;62:3088–92.

           Direct Link: Abstract

1. Leonardi C. Menter. Efalizumab: results of a 3-year continuous dosing study for the long-term control of psoriasis. Br J Dermatol 2008;158:1107–16.Direct Link:Abstract
2. Seekamp A, The effect of anti-L-selectin (aselizumab) in multiple traumatized patients–results of a phase II clinical trial. Crit Care Med 2004;32:2021–8. CrossRef,
3. Kyosuke.Crucial Role of L-Selectin in C Protein–Induced Experimental Polymyositis in Mice.Article first published online: 27 JUN 2014.DOI: 10.1002/art.38630. http://onlinelibrary.wiley.com/doi/10.1002/art.38630/full