Objectives: Extracellular vesicles (EVs) are lipid bilayer membrane vesicles that are present in various bodily fluids and have been implicated in autoimmune disease pathogenesis. Type I interferons (IFN), specifically IFN-β, are uniquely elevated in dermatomyositis (DM). The stimulator of interferon genes (STING) works as a critical nucleic acid sensor and adaptor in type I IFN signaling with possible implications in autoimmune diseases such as DM. In the current study, we investigated whether circulating EVs contribute to proinflammatory effects in DM, whether these proinflammatory responses are mediated by the STING signaling pathway, and if so, by what mechanism STING is activated. Methods: We collected and characterized EVs from plasma of healthy controls (HC) and DM patients; analyzed their abilities to trigger proinflammatory cytokines release by ELISA, and explored STING signaling pathway activation using immunoblot and immunofluorescent staining. STING signaling pathway inhibitors and RNAi were used to further investigate whether STING was involved in EVs-triggered proinflammatory response. DNase/lipid destabilizing agent was utilized to digest EVs and their captured DNA contents to evaluate how EVs triggered STING-mediated proinflammatory response in DM. Results: EVs isolated from DM plasma triggered proinflammatory cytokines including type I IFN release with STING signaling pathway activation. The activated STING pathway was preferentially mediated by dsDNA captured by EVs. Suppression of STING or its downstream signaling proteins attenuated the EVs-mediated proinflammatory response. Conclusions: Plasma-derived, DNA containing-EVs induced STING-mediated proinflammatory effects in DM. Targeting the STING pathway may be a potential therapeutic approach for DM.

Background Spinocerebellar ataxia type 1 (SCA1) causes progressive degeneration of the cerebellum and brainstem. Volumetric magnetic resonance imaging (MRI) was shown to be more sensitive to disease progression than the most sensitive clinical measure, the Scale for the Assessment and Rating of Ataxia (SARA), in longitudinal studies, and magnetic resonance spectroscopy (MRS) was shown to detect neurochemical abnormalities with high sensitivity cross‐sectionally in SCA1. Objectives The objectives of this study were to compare the sensitivities to change of volumetric MRI, MRS, and SARA in a 3‐year longitudinal study in SCA1. Methods A total of 16 early‐to‐moderate stage patients with SCA1 (SARA 0‐14) and 21 matched healthy participants were scanned up to 3 times with 1.5‐year intervals. Ataxia severity was assessed with SARA. T1‐weighted images and magnetic resonance spectra from the cerebellar vermis, cerebellar white matter, and pons were acquired at 3T. Results The pontine total N‐acetylaspartate‐to‐myo‐inositol ratio was the most sensitive MRS measure to change (−3.9 ± 4.6%/yr in SCA1 vs. −0.3 ± 3.5%/yr in controls; P < 0.02), and the pontine volume was the most sensitive MRI measure to change (−2.6 ± 1.2%/yr in SCA1 vs. −0.1 ± 1.2 in controls; P < 0.02). Effect size (mean percent change/standard deviation of percent change) of pontine volume was highest (−2.13) followed by pontine N‐acetylaspartate‐to‐myo‐inositol ratio (−0.84) and SARA (+0.60). The pontine N‐acetylaspartate‐to‐myo‐inositol ratio was abnormal for 1 premanifest patient at all visits and predicted study withdrawal as a result of disease progression in 3 patients. Conclusion Both MRI and MRS were more sensitive to disease progression than SARA in SCA1. Pontine volume was most sensitive to change, whereas MRS may have more sensitivity at the premanifest stage and predictive value for disease progression.

Dermatomyositis (DM) is an autoimmune disease that affects the skin, lungs, and muscle. Although the pathogenesis of DM is not completely understood, several environmental triggers have been linked to DM onset or flare. This article specifically examines the effects of herbal supplements, drugs, infections, ultraviolet (UV) radiation, and environmental pollutants on the onset or exacerbation of DM. Herbal supplements such as Spirulina platensis, Aphanizomenon flos-aquae, Chlorella, Echinacea, and Alfalfa have been implicated and are frequently used in health foods. Medications such as hydroxyurea, TNF-α inhibitors, immune checkpoint inhibitors (ICI), and penicillamine, as well as certain viral infections, such as parvovirus B19, coxsackie virus, polyomavirus, Epstein-Barr virus (EBV), hepatitis, influenza, and human immunodeficiency viruses (HIV) have been associated with DM onset. Bacterial infections and vaccinations have also been linked to the development of DM. Additional environmental factors, including UV radiation and air pollutants, such as silica, biological/mineral dust, and particulate air matter from vehicle and industrial emissions, may also play a role in DM pathogenesis. Overall, there is general agreement that an autoimmune attack of the skin, muscle, and lungs in DM can be triggered by various environmental factors and warrants further investigation.

Background Lenabasum is a cannabinoid type 2 receptor (CB2R) reverse agonist that demonstrates anti-inflammatory effects in vivo and in vitro in dermatomyositis (DM) and is currently being investigated for therapeutic potential. The purpose of our study is to investigate CB2R distribution as well as the effects of lenabasum in DM. Methods Immunohistochemistry staining (IHC) was utilized to examine immune cell and cytokine production changes in lesional DM skin biopsies from lenabasum and placebo-treated patients. CB2R expression in various immune cell populations within DM skin was investigated with image mass cytometry (IMC), whereas flow cytometry elucidated CB2R expression in DM peripheral blood mononuclear cells (PBMCs) as well as cytokine production by CB2R-expressing cell populations. Results After 12 weeks of lenabasum treatment, IHC staining showed that CD4+ T cells, CB2R, IL-31, IFN-γ, and IFN-β cytokines were downregulated. IFN-γ and IFN-β mRNA decreased in lesional DM skin but not in PBMCs. IMC findings revealed that CB2R was upregulated in DM lesional skin compared to HC skin and DM PBMCs (p<0.05). In DM skin, CB2R was upregulated on dendritic cells, B cells, T cells, and macrophages while dendritic cells had the greatest expression in both DM skin and PBMCs (p<0.05). These CB2R+ cells in the skin produce IL-31, IL-4, IFN-γ, and IFN-β. Conclusion Our findings of differential CB2R expression based on location and cell type suggest modes by which lenabasum may exert anti-inflammatory effects in DM and highlights dendritic cells as potential therapeutic targets.