Abstract
Idiopathic inflammatory myopathies (IIMs) are a heterogenous group of complex muscle diseases of unknown etiology. These diseases are characterized by progressive muscle weakness and damage, together with involvement of other organ systems. It is generally believed that the autoimmune response (autoreactive lymphocytes and autoantibodies) to skeletal muscle-derived antigens is responsible for the muscle fiber damage and muscle weakness in this group of disorders. Therefore, most of the current therapeutic strategies are directed at either suppressing or modifying immune cell activity. Recent studies have indicated that the underlying mechanisms that mediate muscle damage and dysfunction are multiple and complex. Emerging evidence indicates that not only autoimmune responses but also innate immune and non-immune metabolic pathways contribute to disease pathogenesis. However, the relative contributions of each of these mechanisms to disease pathogenesis are currently unknown. Here we discuss some of these complex pathways, their inter-relationships and their relation to muscle damage in myositis. Understanding the relative contributions of each of these pathways to disease pathogenesis would help us to identify suitable drug targets to alleviate muscle damage and also improve muscle weakness and quality of life for patients suffering from these debilitating muscle diseases.
Highlights
Idiopathic inflammatory myopathies (IIMs) are a heterogenous group of complex muscle diseases of unknown etiology
Toll-like receptors (TLR) recognize patterns in microorganisms termed as pathogen-associated molecular patterns (PAMPs) and endogenous ligands termed as damage associated molecular patterns (DAMPs), and initiate immune signaling [15,16]
PAMPs are associated with infectious agents whereas DAMPs are host-encoded molecules released during tissue injury, necrosis and cell death
Summary
The exact mechanisms by which HRS cleavage and release from muscle cells occurs is unclear, but there is evidence that HRS-expressing immature muscle cells express high levels of MHC class I and likely become targets of cytotoxic T-cells and granzyme B-mediated cleavage of the HRS antigen [26] Another well-characterized DAMP that is involved in myositis pathogenesis is high mobility group box protein 1 (HMGB1). TLR-2/4 signaling results in the synthesis of pro-IL-1β, and inflammasomes process pro-IL-1β into mature IL-1β; signaling by released extracellular ATP via P2X7 receptors (DAMP signaling) facilitates the secretion of mature IL-1β from the skeletal muscle cells [32] Another recent study has characterized the mechanism of IL-1β secretion following respiratory syncytial virus (RSV) infection of airways [33].
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