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Review
. 2018 Dec 18:9:2951.
doi: 10.3389/fimmu.2018.02951. eCollection 2018.

Systemic and Tissue Inflammation in Juvenile Dermatomyositis: From Pathogenesis to the Quest for Monitoring Tools

Affiliations
Review

Systemic and Tissue Inflammation in Juvenile Dermatomyositis: From Pathogenesis to the Quest for Monitoring Tools

Judith Wienke et al. Front Immunol. .

Abstract

Juvenile Dermatomyositis (JDM) is a systemic immune-mediated disease of childhood, characterized by muscle weakness, and a typical skin rash. Other organ systems and tissues such as the lungs, heart, and intestines can be involved, but may be under-evaluated. The inflammatory process in JDM is characterized by an interferon signature and infiltration of immune cells such as T cells and plasmacytoid dendritic cells into the affected tissues. Vasculopathy due to loss and dysfunction of endothelial cells as a result of the inflammation is thought to underlie the symptoms in most organs and tissues. JDM is a heterogeneous disease, and several disease phenotypes, each with a varying combination of affected tissues and organs, are linked to the presence of myositis autoantibodies. These autoantibodies have therefore been extensively studied as biomarkers for the disease phenotype and its associated prognosis. Next to identifying the JDM phenotype, monitoring of disease activity and disease-inflicted damage not only in muscle and skin, but also in other organs and tissues, is an important part of clinical follow-up, as these are key determinants for the long-term outcomes of patients. Various monitoring tools are currently available, among which clinical assessment, histopathological investigation of muscle and skin biopsies, and laboratory testing of blood for specific biomarkers. These investigations also give novel insights into the underlying immunological processes that drive inflammation in JDM and suggest a strong link between the interferon signature and vasculopathy. New tools are being developed in the quest for minimally invasive, but sensitive and specific diagnostic methods that correlate well with clinical symptoms or reflect local, low-grade inflammation. In this review we will discuss the types of (extra)muscular tissue inflammation in JDM and their relation to vasculopathic changes, critically assess the available diagnostic methods including myositis autoantibodies and newly identified biomarkers, and reflect on the immunopathogenic implications of identified markers.

Keywords: autoantibodies; biomarkers; disease monitoring; interferon signature; juvenile dermatomyositis; personalized medicine; tissue inflammation; vasculopathy.

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Figures

Figure 1
Figure 1
Histopathological features and biomarkers in JDM. JDM is characterized by vasculopathic changes in the tissues, with loss and dysfunction of endothelial cells, leading to capillary dropout and subsequent atrophy of muscle fibers. The exact chain of events leading to loss of blood vessels and muscle fibers is not known, but it is thought that both overexpression of MHC-I (and MHC-II) on myocytes and endothelial damage are early events in the cascade (159, 170). They result in the first attraction of immune cells to the tissue, probably by a stress response of the myocytes and endothelial cells, leading to a first production of chemoattractants. The immune cell infiltrates, which can be organized in lymphoid structures, consist mostly of CD4+ and CD8+ memory T cells, B cells, mature plasmacytoid dendritic cells (pDC) and monocytes. CD4+ and CD8+ T cells are considered responsible for direct killing of muscle cells. pDC are considered the main producers of type I interferons (IFNs), which explains the IFN-I signature that is found in the muscles of JDM patients. Some typical IFN-inducible chemokines, CXCL9 (MIG), CXCL10 (IP-10), and CXCL11 (ITAC), are known for their angiostatic properties. The receptor for these cytokines, CXCR3, is upregulated on endothelial cells in JDM muscle, which may be one of the factors contributing to endothelial dysfunction (137). Other factors include anti-endothelial circulating antibodies (AECA), complement and membrane attack complex (MAC) deposition on endothelial cells. Endothelial cells in muscle also express high levels of ICAM-1 and VCAM-1, which further enables extravasation of immune cells into the tissues and promotes a positive feedback loop resulting in further tissue damage. Not only immune cells in the tissues, but also circulating immune cells show a type I IFN signature and increased IFNα activity. Various circulating markers reflecting immune activation and endothelial activation or distress are increased during active disease in JDM and can potentially be used as biomarkers for disease activity.

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