Cytokines in immune-mediated inflammatory myopathies: cellular sources, multiple actions and therapeutic implications

Abstract

The idiopathic inflammatory myopathies are a heterogeneous group of disorders characterised by diffuse muscle weakness and inflammation. A common immunopathogenic mechanism is the cytokine-driven infiltration of immune cells into the muscle tissue. Recent studies have further dissected the inflammatory cell types and associated cytokines involved in the immune-mediated myopathies and other chronic inflammatory and autoimmune disorders. In this review we outline the current knowledge of cytokine expression profiles and cellular sources in the major forms of inflammatory myopathy and detail the known mechanistic functions of these cytokines in the context of inflammatory myositis. Furthermore, we discuss how the application of this knowledge may lead to new therapeutic strategies for the treatment of the inflammatory myopathies, in particular for cases resistant to conventional forms of therapy.

Keywords: autoimmunity; autoinflammatory disease; cytokines; inflammation; neuroimmunology.

Fig. 1

Immune effector cells and associated cytokines in myositis. CD4⁺ and CD8⁺ T cells are activated by autoantigen-expressing antigen-presenting cells (APCs). Activated CD4⁺ T cells differentiate into the various T helper effector cells. T helper type 1 (Th1) and Th17 cells secrete cytokines that mediate muscle damage and inflammation and the activation of additional immune cells. Th2 and Tfh cells modulate B cell function and differentiation into antibody producing plasma cells leading to complement mediated capillary damage. The presence of regulatory T cells (T_reg) reduces inflammation and tissue damage by inhibiting CD4⁺ and CD8⁺ effector T cells. A degree of plasticity can also occur in these cell types Th17 → Th1 and Th17 ↔ T_reg. MHC = major histocompatibility complex; CTL = cytotoxic T lymphocyte; CD28^−/− = CD28 null T lymphocyte; M1 = type 1 macrophage (proinflammatory); M2 = type 2 macrophage (anti-inflammatory). Adapted and modified from Rayavarapu et al.

Fig. 2

Putative cytokine targets in myositis and available blocking monoclonal antibodies. Interleukin (IL)-17RA and IL-17RC represent the A and C chains of the IL-17 receptor. IL-1R: interleukin 1 receptor; TFG-βR = transforming growth factor-β receptor; IL-23R = IL-23 receptor; IL-6R = IL-6 receptor.