Increased CD40 Expression on Muscle Cells of Polymyositis and Dermatomyositis: Role of CD40-CD40 Ligand Interaction in IL-6, IL-8, IL-15, and Monocyte Chemoattractant Protein-1 Production

Abstract

In polymyositis (PM)/dermatomyositis (DM), T cells infiltrate the muscle tissues and interact with muscle cells via cell surface molecules. Recently, myoblasts have been reported to express CD40, but little is known about the role of CD40 in myoblasts. In the present study we examined the expression and involvement of CD40 and CD40 ligand (CD40L) in the interaction between muscle cells and T cells in PM/DM. Immunohistochemical staining revealed that CD40 was expressed on muscle cells in five of five PM and four of five DM patients, and that infiltrating mononuclear cells (MNCs) expressed CD40L in all cases of PM/DM. These CD40L-expressing MNCs were primarily CD4+ T cells. IFN-γ, which is known to induce CD40 expression on various types of cells, was also expressed on the MNCs in four of the PM and four of the DM patients. Although cultured human myoblasts (SkMC 2859) did not express CD40 constitutively, IFN-γ induced CD40 expression in a dose-dependent manner. To clarify the functional roles of CD40-mediated signals, the effects of a trimeric form of recombinant human CD40L on cytokine production were studied in SkMC 2859 that were prestimulated with IFN-γ to express CD40. Recombinant human CD40L markedly increased the production of IL-6, IL-8, IL-15, and monocyte chemoattractant protein-1 of SkMC 2859. The expression of these humoral factors in muscle cells of PM and DM was demonstrated by immunohistochemistry. These results suggest that interaction between T cells and muscle cells via the CD40-CD40L system contributes to the immunopathogenesis of PM/DM by augmenting inflammation via cytokine production by the muscle cells.

Increased CD40 expression in skin fibroblasts from patients with systemic sclerosis (SSc): role of CD40‐CD154 in the phenotype of SSc fibroblasts

“…In an earlier study, it was reported that the CD40-CD154 system plays a part in the synovial inflammation seen in rheumatoid arthritis and in the muscle damage that occurs in polymyositis and dermatomyositis [29,30]. Zhang-Hoover et al demonstrated that the CD40-CD154 system is critical for elicitation of autoimmune-mediated pulmonary fibrosis [31].…”

Amplification of the synovial inflammatory response through activation of mitogen‐activated protein kinases and nuclear factor κB using ligation of CD40 on CD14+ synovial cells from patients with rheumatoid arthritis

“…The ELISAs for IL-6, IL-8, and MCP-1 were developed in our laboratory and are described elsewhere (22). The sensitivities of the assay systems were 7.81, 15.6, and 7.81 pg/ml for IL-6, IL-8, and MCP-1, respectively.…”

Skeletal muscle cells: from local inflammatory response to active immunity

“…57 In polymyositis biopsies, only those myofibres that were invaded and destroyed by mononuclear cells express high levels of IL-6, MCP-1 and ICAM-1. 44,58 These findings suggest that IL-6 transsignalling participates in the transition from the acute to the chronic phase of an immune response, and that it can have a much more global role in the regulation of local immune recruitment, while IL-6 acting through the membrane-bound IL-6R regulates the hepatic acute-phase reaction and B-cell stimulation. 59 A control of this form of IL-6-mediated inflammatory response may be used to induce tolerance towards genetically engineered myoblasts, and therefore it can pave the way to successful long-term gene therapy.…”

“…Human myoblasts constitutively express CD40: its levels are synergistically increased by TNF-a and IFN-g, 77 while CD40 ligation increases IL-6, IL-8, IL-15 and MCP-1 production and ICAM-1 expression (Figure 4a). 38,58 The CD40-CD40L system found a practical application in gene therapy strategies: the use of a monoclonal antibody against the CD40L inhibited Th cell activation at the time of vector delivery, with a transient prevention of both cellular and humoral immunity. 88 Classical and non-classical MHC I expression The expression of classical MHC I (HLA-ABC) on target cells represents a prerequisite for antigen-specific T-cell-mediated cytotoxicity.…”