Overview

Cellular and non-cellular mechanisms of both the immune and non-immune systems have been identified as key regulators of inflammation in polymyositis/dermatomyositis, particularly at different stages of disease, leading to the fibrotic state that characterizes the end stage. Among these, a special role is played by an interferon signature and complement cascade with different mechanisms in polymyositis and dermatomyositis; these differences can be identified also histologically in muscle biopsies.

Chemical interactions

An autoimmune origin of PM conditions is supported by immune cell-mediated myocytotoxicity, the presence of autoantibodies and over-expression of major histocompatibility complex (MHC) class I and II molecules in myositis tissue [3–6]. However, there is still debate as to whether IBM is primarily autoimmune in origin or a degenerative myopathy with associated inflammatory features and an immune component A shared pathogenic mechanism in these diseases is the infiltration of muscle tissue by a variety of activated immune cells, a process that is heavily dependent upon the presence of multiple cytokines more recent studies detailing the presence of Th17-related cytokines such as IL-17, IL-22 and IL-6 have highlighted an alternative pathogenic mechanism and provided additional targets for therapy

In addition to their proinflammatory actions, these cytokines can also display anti-inflammatory properties and show duality of function depending on their concentrations, the local inflammatory milieu and the expression of co-stimulatory and adhesion molecules.

In addition, a number of cytokines (such as IL-1α and IL-17) may also exert direct effects on the muscle tissue . These include the activation of signaling pathways such as nuclear factor (NF)-κ B, further amplifying the inflammatory response through up-regulation of MHC-I expression and cytokine/chemokine production.(2)

While the different inflammatory myopathies share a number of common characteristics, including muscle weakness and inflammation, each type has distinct clinical and pathological features. In PM and IBM there is a mixed endomysial mononuclear inflammatory infiltrate comprising CD8+ T cells, macrophages and myeloid dendritic cells (Table 1). CD8+ cells surround and invade non-necrotic muscle fibres and are thought to cause perforin-mediated cytotoxic injury as a result of the interaction between autoantigen-presenting MHC class I molecules on muscle fibres and co-stimulatory molecules on CD8+cells.(2)
 

The release of cytokines from immune cells can be induced directly by immunoglobulin- or complement receptor-mediated signalling or by the activation of a wide variety of cellular receptors by pathogen components. One family of such receptors, the Toll-like receptors (TLRs), play a crucial role in mediating inflammation by inducing cytokine release upon engagement of the receptor by an appropriate ligand, a process that is normally tightly regulated by a number of regulatory factors including microRNAs (miRNAs). (2)
 

Increasing evidence demonstrates that a number of proinflammatory cytokines can have both stimulatory and inhibitory effects on immune cells, a phenomenon dependent upon the concentration of cytokine present, the local immune milieu and the influence of other interacting cells and molecules .(2)

Relevance

This holds great promise for the application of these therapies to the inflammatory myopathies, in particular for patients who respond poorly to current treatments. However, to date there have been few clinical trials and the application of biologicals in myositis has lagged behind its use in other autoimmune diseases. Controlled trials of sufficient size and duration are warranted to provide sufficient information and enable the introduction of additional therapies to the current repertoire .(2)
 

Diagrams

 

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 (Treg) 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↔Treg. 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. [3]

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

Footnotes:

1. Angela C. Clinical Reviews in Allergy & Immunology.pp 1-1.First online: 16 January 2016.The Immune Response and the Pathogenesis of Idiopathic Inflammatory Myositis: a Critical Review.

2 . Moran M. Clinical & Experimental ImmunologyVolume 178, Issue 3, Article first published online: 7 NOV 2014.vhttp://onlinelibrary.wiley.com/doi/10.1111/cei.12445/pdf

 

3. Rayavarapu S. Idiopathic inflammatory myopathies: pathogenic mechanisms of muscle

weakness. Skelet Muscle 2013; 3:13. https://skeletalmusclejournal.biomedcentral.com/articles/10.1186/2044-5040-3-13