Animal models in idiopathic inflammatory myopathies: How to overcome a translational roadblock?

Afzali, Ali Maisam; Ruck, Tobias; Wiendl, Heinz; Meuth, Sven G.

doi:10.1016/j.autrev.2017.03.001

Cited by 25 publications

(18 citation statements)

References 160 publications

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“…Immunisation with SRP was achieved following several boosts, which might be due to the relative difficulty to break tolerance against a completely homologous protein. It should be mentioned that, to mimic other types of myositis in which important inflammatory infiltrates are observed in patients, breakage of tolerance against muscle proteins such as protein C or myosin requires dramatically heavier protocols with complete Freund adjuvant and several boosts before inducing experimental autoimmune myositis 40 41…”

Section: Discussionmentioning

confidence: 99%

In vivo pathogenicity of IgG from patients with anti-SRP or anti-HMGCR autoantibodies in immune-mediated necrotising myopathy

Bergua

Chiavelli

Allenbach

et al. 2019

Annals of the Rheumatic Diseases

123

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ObjectivesIn autoimmunity, autoantibodies (aAb) may be simple biomarkers of disease or true pathogenic effectors. A form of idiopathic inflammatory myopathy associated with anti-signal recognition particle (SRP) or anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) aAb has been individualised and is referred to as immune-mediated necrotising myopathy (IMNM). The level of aAb correlates with IMNM activity and disease may respond to immunosuppression, suggesting that they are pathogenic. We aimed to evaluate the pathogenicity of IgG from patients with anti-SRP or anti-HMGCR aAb in vivo by developing the first mouse model of IMNM.MethodsIgG from patients suffering from anti-SRP or anti-HMGCR associated IMNM were passively transferred to wild-type, Rag2-/- or complement C3-/- mice. Muscle deficiency was evaluated by muscle strength on electrostimulation and grip test. Histological analyses were performed after haematoxylin/eosin staining or by immunofluorescence or immunohistochemistry analysis. Antibody levels were quantified by addressable laser bead assay (ALBIA).ResultsPassive transfer of IgG from patients suffering from IMNM to C57BL/6 or Rag2-/- mice provoked muscle deficiency. Pathogenicity of aAb was reduced in C3-/- mice while increased by supplementation with human complement. Breakage of tolerance by active immunisation with SRP or HMGCR provoked disease.ConclusionThis study demonstrates that patient-derived anti-SRP+ and anti-HMGCR+ IgG are pathogenic towards muscle in vivo through a complement-mediated mechanism, definitively establishing the autoimmune character of IMNM. These data support the use of plasma exchanges and argue for evaluating complement-targeting therapies in IMNM.

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Section: Discussionmentioning

confidence: 99%

In vivo pathogenicity of IgG from patients with anti-SRP or anti-HMGCR autoantibodies in immune-mediated necrotising myopathy

Bergua

Chiavelli

Allenbach

et al. 2019

Annals of the Rheumatic Diseases

123

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“…Available treatments are only partially satisfactory because of our limited insight into the pathogenesis of IIM . Preclinical studies might provide valuable information .…”

Section: Discussionmentioning

confidence: 99%

“…To investigate whether the TLR/type I IFN pathway is causally involved in IIM development, we explored the long‐term effects of TLR‐7/8 activation in a well‐characterized experimental model of myositis induced by intramuscular injection of a fragment of the mouse HisRS antigen , which elicits focal and transient autoimmunity and muscle inflammation . In this study we demonstrated that mouse myositis was exacerbated and sustained when the autoantigen was injected in the presence of R‐848, a cell‐permeable and specific TLR‐7/8 agonist .…”

mentioning

confidence: 99%

Exacerbation of Murine Experimental Autoimmune Myositis by Toll‐Like Receptor 7/8

Sciorati

Monno

Doglio

et al. 2018

Arthritis & Rheumatology

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“…In patients with dermatomyositis (DM), polymyositis (PM), immune mediated necrotizing myopathy (IMNM) and antisynthetase syndrome (AS) macrophages and dendritic cells are prominent in muscle biopsies [10], highlighting the relevance of monocytes in the immunopathology of IIM. Also, the relevance of TLRs in the pathogenesis of inflammatory myopathies has been demonstrated in animal models [11] and muscle biopsies of these patients [12]. In subjects with DM and PM, an enhanced expression of TLR2, TLR4 and TLR9 in the endomysial and perimysial inflammatory infiltrate [13] as well as an overexpression of IFN-γ, IL12p40 and myeloid differentiation factor-88 (MyD88) has been shown in muscle biopsies [14].…”

Section: Page 2 Of 12mentioning

confidence: 98%

TLR expression in peripheral monocyte subsets of patients with idiopathic inflammatory myopathies: association with clinical and immunological features

et al. 2020

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Background: Monocytes and toll-like receptors (TLR) have been found in the inflammatory infiltrate of muscle biopsies in patients with idiopathic inflammatory myopathies (IIM), suggesting an important role of these cells in the pathogenesis of myositis. The monocyte subsets, their TLR expression in peripheral blood and their relationship with the clinical characteristics of patients with IIM has not been addressed. Methods:We recruited 45 patients with IIM diagnosis and 15 age and sex-adjusted healthy controls. We assessed the disease activity and damage, performed a nailfold capillaroscopy and registered the cardio-pulmonary parameters from the medical charts. Monocyte subsets, their expression of TLR2 and TLR4 and the serum Th1/Th2/Th17 cytokines levels were evaluated by flow cytometry. We expressed quantitative variables as medians and interquartile ranges (IQR) or minimum and maximum (min-max). Differences between groups were assessed with Mann-Whitney U and the Kruskal-Wallis tests. Correlation between quantitative variables was assessed with Spearman Rho.Results: Twenty-nine patients were women (64.4%) and 32 (71.1%) had dermatomyositis. In comparison to healthy controls, patients with active IIM had a higher percentage of intermediate monocytes and lower amounts of classical monocytes. Patients with IIM had a higher expression of TLR4 in all their monocyte subsets, regardless of disease activity and prednisone treatment. Serum IL-6 correlated with the TLR2 expression in every monocyte subset and the expression of TLR2 in intermediate monocytes was higher among patients with dysphagia. Subjects with nailfold capillaroscopy abnormalities had a higher amount of TLR2+ classical and non-classical monocytes and those with interstitial lung disease (ILD) had a higher percentage of TLR4+ non-classical monocytes. The classical and intermediate monocytes from patients with anti Mi2 antibodies had a higher expression of TLR4. The percentage of intermediate monocytes and the expression of TLR4 in all monocyte subsets showed a good diagnostic capacity in patients with IIM. Conclusion:Patients with IIM have a differential pool of monocyte subsets with an enhanced expression of TLR2 and TLR4, which correlates with disease activity and distinctive clinical features including dysphagia, ILD, vasculopathy, and pro-inflammatory cytokines. These immunological features might be useful as a potential diagnostic tool as well as novel disease activity biomarkers in IIM.

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Animal models in idiopathic inflammatory myopathies: How to overcome a translational roadblock?

Cited by 25 publications

References 160 publications

In vivo pathogenicity of IgG from patients with anti-SRP or anti-HMGCR autoantibodies in immune-mediated necrotising myopathy

In vivo pathogenicity of IgG from patients with anti-SRP or anti-HMGCR autoantibodies in immune-mediated necrotising myopathy

Exacerbation of Murine Experimental Autoimmune Myositis by Toll‐Like Receptor 7/8

TLR expression in peripheral monocyte subsets of patients with idiopathic inflammatory myopathies: association with clinical and immunological features

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