Objectives In 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.
Methods IgG 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).
Results Passive 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.
Conclusion This 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.
- autoimmune diseases
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LD and OB contributed equally.
Handling editor Josef S Smolen
Contributors CB, LD and OBo designed, performed and interpreted experiments presented in this manuscript. They also wrote and edited most of the manuscript content. HC, CA, GB, LJ and RZ performed experiments presented in this manuscript. YA, LA-D, NG, MM and OBe interpreted the experiments. OBo and DL are also the principal investigators of the study.
Funding The work presented in this study was supported in part by Association Française contre les Myopathies (#16624), CSL Behring Foundation (France), the European Union and the Normandie Regional Council with the European Regional Development Fund (ERDF). Europe gets involved in Normandie with the ERDF.
Competing interests OBo is member of the Scientific Committee of CSL Behring Foundation (France) and received consulting fees from Inova Diagnostics.
Patient consent Not required.
Ethics approval The study was conducted on approval of the Ile-de-France III ethics committee. All patient consents were obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement No additional data are available.
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