21 research outputs found

    Inclusion body myositis and associated diseases: an argument for shared immune pathologies

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    Inclusion body myositis (IBM) is the most prevalent idiopathic inflammatory myopathy (IIM) affecting older adults. The pathogenic hallmark of IBM is chronic inflammation of skeletal muscle. At present, we do not classify IBM into different sub-entities, with the exception perhaps being the presence or absence of the anti-cN-1A-antibody. In contrast to other IIM, IBM is characterized by a chronic and progressive disease course. Here, we discuss the pathophysiological framework of IBM and highlight the seemingly prototypical situations where IBM occurs in the context of other diseases. In this context, understanding common immune pathways might provide insight into the pathogenesis of IBM. Indeed, IBM is associated with a distinct set of conditions, such as human immunodeficiency virus (HIV) or hepatitis C-two conditions associated with premature immune cell exhaustion. Further, the pathomorphology of IBM is reminiscent of other muscle diseases, notably HIV-associated myositis or granulomatous myositis. Distinct immune pathways are likely to drive these commonalities and senescence of the CD8(+) T cell compartment is discussed as a possible mechanism of pathogenesis. Future effort directed at understanding the co-occurrence of IBM and associated diseases could prove valuable to better understand the enigmatic IBM pathophysiology

    Proteomic Profiling Unravels a Key Role of Specific Macrophage Subtypes in Sporadic Inclusion Body Myositis

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    Unbiased proteomic profiling was performed toward the identification of biological parameters relevant in sIBM, thus giving hints about the pathophysiological processes and the existence of new reliable markers. For that purpose, skeletal muscle biopsies from 13 sIBM and 7 non-diseased control patients were analyzed with various methods, including liquid chromatography coupled to tandem mass spectrometry (four patients). Subsequent data analysis identified key molecules further studied in a larger cohort by qPCR, immunostaining, and immunofluorescence in situ. Proteomic signature of muscle biopsies derived from sIBM patients revealed the chaperone and cell surface marker CD74, the macrophage scavenger molecule CD163 and the transcription activator STAT1 to be among the highly and relevantly expressed proteins suggesting a significant contribution of immune cells among the myofibers expressing these markers. Moreover, in silico studies showed that 39% of upregulated proteins were involved in type I or mixed type I and type II interferon immunity. Indeed, further studies via immunohistochemistry clearly confirmed the prominent involvement of the key type I interferon signature-related molecules, ISG15 as well as IRF8 with MHC class II+ myofibers. Siglec1 colocalized with CD163+ macrophages and MHC class II molecules also co-localized with CD74 on macrophages. STAT1 co-localized with Siglec1+ macrophages in activemyofibremyophagocytosis while STAT6 colocalized with endomysial macrophages. These combined results show involvement of CD74, CD163, and STAT1 as key molecules of macrophage activation being crucially involved in mixed and specific type I interferon, and interferon gamma associated-pathways in sIBM. On a more general note, these results also highlight the type of immune-interaction between macrophages and myofibers in the etiopathology of sIBM

    Proteomic Profiling Unravels a Key Role of Specific Macrophage Subtypes in Sporadic Inclusion Body Myositis

    Get PDF
    Unbiased proteomic profiling was performed toward the identification of biological parameters relevant in sIBM, thus giving hints about the pathophysiological processes and the existence of new reliable markers. For that purpose, skeletal muscle biopsies from 13 sIBM and 7 non-diseased control patients were analyzed with various methods, including liquid chromatography coupled to tandem mass spectrometry (four patients). Subsequent data analysis identified key molecules further studied in a larger cohort by qPCR, immunostaining, and immunofluorescence in situ. Proteomic signature of muscle biopsies derived from sIBM patients revealed the chaperone and cell surface marker CD74, the macrophage scavenger molecule CD163 and the transcription activator STAT1 to be among the highly and relevantly expressed proteins suggesting a significant contribution of immune cells among the myofibers expressing these markers. Moreover, in silico studies showed that 39% of upregulated proteins were involved in type I or mixed type I and type II interferon immunity. Indeed, further studies via immunohistochemistry clearly confirmed the prominent involvement of the key type I interferon signature-related molecules, ISG15 as well as IRF8 with MHC class II+ myofibers. Siglec1 colocalized with CD163+ macrophages and MHC class II molecules also co-localized with CD74 on macrophages. STAT1 co-localized with Siglec1+ macrophages in active myofibre myophagocytosis while STAT6 colocalized with endomysial macrophages. These combined results show involvement of CD74, CD163, and STAT1 as key molecules of macrophage activation being crucially involved in mixed and specific type I interferon, and interferon gamma associated-pathways in sIBM. On a more general note, these results also highlight the type of immune-interaction between macrophages and myofibers in the etiopathology of sIBM

    Mass cytometry reveals an impairment of B cell homeostasis in anti-synthetase syndrome

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    International audienceRecent data suggest the implication of T, B and NK cells in the anti-synthetase syndrome (ASyS); nevertheless their role and activation states are poorly described. We performed deep immune-profiling using 37 markers on peripheral blood cells from 10 ASyS patients versus 17 healthy donors (HD) and 26 myositis control patients. We show decreased percentages of memory B cells in ASyS patients (mean ± SEM: ASyS = 13 ± 3%, HD = 37 ± 4% and 'myositis controls' = 32 ± 3), counterbalanced by increased percentages of naïve B cells. Interestingly, perifascicular infiltrations of memory B cells within muscle biopsies of ASyS patients suggest that they niche within the muscle

    Morphological Characteristics of Idiopathic Inflammatory Myopathies in Juvenile Patients

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    Background: In juvenile idiopathic inflammatory myopathies (IIMs), morphological characteristic features of distinct subgroups are not well defined. New treatment strategies require a precise diagnosis of the subgroups in IIM, and, therefore, knowledge about the pathomorphology of juvenile IIMs is warranted. Methods: Muscle biopsies from 15 patients (median age 8 (range 3–17) years, 73% female) with IIM and seven controls were analyzed by standard methods, immunohistochemistry, and transmission electron microscopy (TEM). Detailed clinical and laboratory data were accessed retrospectively. Results: Proximal muscle weakness and skin symptoms were the main clinical symptoms. Dermatomyositis (DM) was diagnosed in 9/15, antisynthetase syndrome (ASyS) in 4/15, and overlap myositis (OM) in 2/15. Analysis of skeletal muscle tissues showed inflammatory cells and diffuse upregulation of MHC class I in all subtypes. Morphological key findings were COX-deficient fibers as a striking pathology in DM and perimysial alkaline phosphatase positivity in anti-Jo-1-ASyS. Vascular staining of the type 1 IFN-surrogate marker, MxA, correlated with endothelial tubuloreticular inclusions in both groups. None of these specific morphological findings were present in anti-PL7-ASyS or OM patients. Conclusions: Morphological characteristics discriminate IIM subtypes in juvenile patients, emphasizing differences in aetiopathogenesis and supporting the notion of individual and targeted therapeutic strategies

    The NKG2D-IL-15 signaling pathway contributes to T-cell mediated pathology in inflammatory myopathies

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    NKG2D is an activating receptor on T cells, which has been implicated in the pathogenesis of autoimmune diseases. T cells are critically involved in idiopathic inflammatory myopathies (IIM) and have been proposed as specific therapeutic targets. However, the mechanisms underlying T cell-mediated progressive muscle destruction in IIM remain to be elucidated. We here determined the involvement of the NKG2D - IL-15 signaling pathway. Primary human myoblasts expressed NKG2D ligands, which were further upregulated upon inflammatory stimuli. In parallel, shedding of the soluble NKG2D ligand MICA (sMICA) decreased upon inflammation potentially diminishing inhibition of NKG2D signaling. Membrane-related expression of IL-15 by myoblasts induced differentiation of naive CD8+^+ T cells into highly activated, cytotoxic CD8+NKG2DhighCD8^+NKG2D^{high} T cells demonstrating NKG2D-dependent lysis of myoblasts in vitro. CD8+NKG2DhighCD8^+NKG2D^{high} T cell frequencies were increased in the peripheral blood of polymyositis (PM) patients and correlated with serum creatinine kinase concentrations, while serum sMICA levels were not significantly changed. In muscle biopsy specimens from PM patients expression of the NKG2D ligand MICA/B was upregulated, IL-15 was expressed by muscle cells, CD68+^+ macrophages as well as CD4+^+ T cells, and CD8+NKG2D+CD8^+NKG2D^+ cells were frequently detected within inflammatory infiltrates arguing for a local signaling circuit in the inflammatory muscle milieu. In conclusion, the NKG2D - IL-15 signaling pathway contributes to progressive muscle destruction in IIM potentially opening new therapeutic avenues
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