Auto-anticorps et complément dans les Myopathies nécrosantes auto-immunes : physiopathologie et développement préclinique de nouvelles thérapeutiques

Immune mediated necrotizing myopathies (IMNM) belong to the group of idiopathic inflammatory myopathies (IIM), also known as myositis. They are characterized by acute proximal muscle weakness, histologically accompanied by necrosis of the myofibers, an inflammatory infiltrate, and complement deposits. In patients, autoantibodies (aAbs) targeting the signal recognition particle (SRP) or the 3-hydroxy-3-methylglutaryl- coenzyme A reductase (HMGCR) are found. Studies have demonstrated the pathogenicity of these aAbs in a mouse model, involving the complement system. Furthermore, in vitro studies have shown that these aAbs directly inhibit the fusion of myoblasts into myotubes, suggesting a mechanism of inhibition of muscle regeneration. Current treatments are mainly empirical and include high-dose corticosteroids, immunosuppressants, intravenous immunoglobulins, and rituximab. However, many patients are still refractory to these treatments, creating an urgent need for new therapies. In this thesis, we evaluated two targeted therapies in a mouse model of anti-HMGCR IMNM: a complement inhibitor, zilucoplan, and an FcRn inhibitor, efgartigimod. Administration of zilucoplan prevented the onset of disease but did not restore normal muscle strength in already diseased mice, suggesting that aAbs have effector mechanisms other than those mediated by complement. Evaluation of efgartigimod has shown that its administration to mice promotes the elimination of aAbs, prevents disease development and restores normal muscle strength in diseased mice. In the light of these results and with the aim of better understanding the pathogenic mechanisms of complement-independent aAbs, we evaluated the effect of anti-HMGCR aAbs on muscle regeneration in a murine model of necrosis/regeneration. No significant effect on slowing regeneration was observed in our study. However, assessment of the direct effect of purified anti-HMGCR aAbs on their target showed inhibition of HMGCR enzyme function at high aAbs concentrations. These results suggest that efgartigimod, through the elimination of aAbs, could be a promising therapy for IMNM: it is currently being evaluated in a clinical trial. Furthermore, the pathogenic effect of aAbs may involve inhibition of its enzymatic target, explaining why anti- complement monotherapy is not effective in treating this pathology.