Yves Allenbach1, Louiza Arouche-Delaperche2, Corinna Preusse2, Helena Radbruch2, Gillian Butler-Browne2, Nicolas Champtiaux2, Kuberaka Mariampillai2, Aude Rigolet2, Peter Hufnagl2, Norman Zerbe2, Damien Amelin2, Thierry Maisonobe2, Sarah Louis-Leonard2, Charles Duyckaerts2, Bruno Eymard2, Hans-Hilmar Goebel2, Cecile Bergua2, Laurent Drouot2, Olivier Boyer2, Olivier Benveniste2, Werner Stenzel2. 1. From the Departments of Neuropathology (Y.A., C.P., H.R., H.-H.G., W.S.) and Pathology (P.H., N.Z.), Charité-Universitätsmedizin, Berlin, Germany; Internal Medicine Department (Y.A., N.C., K.M., A.R., O. Benveniste), Reference for Neuro-muscular Diseases, Paris Est, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris; Myology Research Center (Y.A., L.A.-D., G.B.-B., D.A., O. Benveniste), Sorbonne Universités UPMC Univ Paris 06, INSERM UMRS974, Pitié-Salpêtrière University Hospital; Department of Neuropathology (T.M., S.L.-L., C.D.) and Institut de Myologie (B.E.), Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Paris; and Department of Immunology (C.B., L.D., O. Boyer), UNIROUEN, INSERM, U1234, Normandie University, Rouen University Hospital, France. yves.allenbach@aphp.fr. 2. From the Departments of Neuropathology (Y.A., C.P., H.R., H.-H.G., W.S.) and Pathology (P.H., N.Z.), Charité-Universitätsmedizin, Berlin, Germany; Internal Medicine Department (Y.A., N.C., K.M., A.R., O. Benveniste), Reference for Neuro-muscular Diseases, Paris Est, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris; Myology Research Center (Y.A., L.A.-D., G.B.-B., D.A., O. Benveniste), Sorbonne Universités UPMC Univ Paris 06, INSERM UMRS974, Pitié-Salpêtrière University Hospital; Department of Neuropathology (T.M., S.L.-L., C.D.) and Institut de Myologie (B.E.), Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Paris; and Department of Immunology (C.B., L.D., O. Boyer), UNIROUEN, INSERM, U1234, Normandie University, Rouen University Hospital, France.
Abstract
OBJECTIVE: To characterize muscle fiber necrosis in immune-mediated necrotizing myopathies (IMNM) with anti-signal recognition particle (SRP) or anti-3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGCR) antibodies and to explore its underlying molecular immune mechanisms. METHODS: Muscle biopsies from patients with IMNM were analyzed and compared to biopsies from control patients with myositis. In addition to immunostaining and reverse transcription PCR on muscle samples, in vitro immunostaining on primary muscle cells was performed. RESULTS: Creatine kinase levels and muscle regeneration correlated with the proportion of necrotic fibers (r = 0.6, p < 0.001). CD68+iNOS+ macrophages and a Th-1 immune environment were chiefly involved in ongoing myophagocytosis of necrotic fibers. T-cell densities correlated with necrosis but no signs of cytotoxicity were detected. Activation of the classical pathway of the complement cascade, accompanied by deposition of sarcolemmal immunoglobulins, featured involvement of humoral immunity. Presence of SRP and HMGCR proteins on altered myofibers was reproduced on myotubes exposed to purified patient-derived autoantibodies. Finally, a correlation between sarcolemmal complement deposits and fiber necrosis was observed (r = 0.4 and p = 0.004). Based on these observations, we propose to update the pathologic criteria of IMNM. CONCLUSION: These data further corroborate the pathogenic role of anti-SRP and anti-HMGCR autoantibodies in IMNM, highlighting humoral mechanisms as key players in immunity and myofiber necrosis.
OBJECTIVE: To characterize muscle fiber necrosis in immune-mediated necrotizing myopathies (IMNM) with anti-signal recognition particle (SRP) or anti-3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGCR) antibodies and to explore its underlying molecular immune mechanisms. METHODS: Muscle biopsies from patients with IMNM were analyzed and compared to biopsies from control patients with myositis. In addition to immunostaining and reverse transcription PCR on muscle samples, in vitro immunostaining on primary muscle cells was performed. RESULTS: Creatine kinase levels and muscle regeneration correlated with the proportion of necrotic fibers (r = 0.6, p < 0.001). CD68+iNOS+ macrophages and a Th-1 immune environment were chiefly involved in ongoing myophagocytosis of necrotic fibers. T-cell densities correlated with necrosis but no signs of cytotoxicity were detected. Activation of the classical pathway of the complement cascade, accompanied by deposition of sarcolemmal immunoglobulins, featured involvement of humoral immunity. Presence of SRP and HMGCR proteins on altered myofibers was reproduced on myotubes exposed to purified patient-derived autoantibodies. Finally, a correlation between sarcolemmal complement deposits and fiber necrosis was observed (r = 0.4 and p = 0.004). Based on these observations, we propose to update the pathologic criteria of IMNM. CONCLUSION: These data further corroborate the pathogenic role of anti-SRP and anti-HMGCR autoantibodies in IMNM, highlighting humoral mechanisms as key players in immunity and myofiber necrosis.
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