Idiopathic inflammatory myopathies: pathogenic mechanisms of muscle weakness

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.

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

“…Conversely, a Th2 cell infiltrate in DM muscle has been associated with a lower severity of disease [60]. This is due possibly to the generation of M2 macrophages by Th2 cytokines leading to tissue repair [9]. This is in contrast with the view that DM is a humorally mediated disease whereby Th2 cells would drive B cell maturation and differentiation into autoantibodyproducing plasma cells, further exacerbating microvascular damage.…”

“…The Th1 response through IFN-γ secretion leads to the induction of M1 macrophages which results in further tissue damage [9]. IMNM, previously described as an immune myopathy with a limited mononuclear cell infiltrate, has also been shown to display a strong M1/Th1 response within the muscle tissue [28].…”

“…Key cellular sources of these cytokines include regenerating myocytes within myositis muscle, cells from the adaptive immune response (CD4 + and CD8 + T cells, macrophages, dendritic cells and B cells) and cells from the innate immune system such as mast cells and gamma delta T cells [1,[9][10][11].…”

Cell death, clearance and immunity in the skeletal muscle

“…108 Outcomes of Defective Apoptotic Cell Clearance: Autoimmunity IIM leads to disability, decreased quality of life and increased mortality. 109 Persistent inflammation with recruitment of autoreactive T cells characterizes the skeletal muscle. 110,111 Available evidence strongly supports the autoimmune underpinnings of IIM and commonly targeted autoantigens include proteins involved in DNA transcription or protein synthesis, such as the histidyl-tRNA synthase (HisRS).…”

“…129 Upregulation of the expression of MHC class I molecules in skeletal muscle fibers is an early feature of IIM and ectopic expression of the molecule induced ER stress response and resulted in a disease that shares several features with human IIM. 130,131 Considering that muscle injury and the associated inflammatory response represent rather common event in vivo, 109 the relative rarity of IIM indicates that a number of events must simultaneously occur to set the stage for self-sustaining autoimmunity. We have recently observed that apoptotic myoblasts are immunogenic only if appropriate adjuvants are provided in the injured/regenerating muscle.…”