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Article Dans Une Revue Annals of Neurology Année : 2023

Central role of macrophages and nucleic acid release in Myasthenia Gravis thymus

Résumé

Objective: Myasthenia gravis (MG) is a neuromuscular disease mediated by antibodies against the acetylcholine receptor (AChR). The thymus plays a primary role in AChR-MG and is characterized by a type I interferon (IFN) signature linked to IFN-β. We investigated if AChR-MG was characterized by an IFN-I signature in the blood, and further investigated the chronic thymic IFN-I signature.Methods: Serum levels of IFN-β and IFN-α subtypes, and mRNA expression for IFN-I subtypes and IFN-stimulated genes in PBMCs were analyzed. The contribution of endogenous nucleic acids in thymicexpression of IFN-I subtypes was investigated in human thymic epithelial cell cultures and the mouse thymus. By immunohistochemistry, thymic CD68+ and CD163+ macrophages were analyzed in AChR-MG.To investigate the impact of a decrease in thymic macrophages, mice were treated with an anti-CSF1R antibody. Results: No IFN-I signature was observed in the periphery emphasizing that the IFN-I signature is restricted to the MG thymus. Molecules mimicking endogenous dsDNA signalization (Poly(dA:dT) and 2’3’-cGAMP), or dexamethasone-induced necrotic thymocytes increased IFN-β and α-AChR expression by thymic epithelial cells, and in the mouse thymus. A significant decrease in thymic macrophages was demonstrated in AChR-MG. In mice, a decrease in thymic macrophages led to an increase of necrotic thymocytes associated with IFN-β and α-AChR expression. Interpretation: These results suggest that the decrease of thymic macrophages in AChR-MG impairs the elimination of apoptotic thymocytes favoring the release of endogenous nucleic acids from necrotic thymocytes. In this inflammatory context, thymic epithelial cells may overexpress IFN-β, which specifically induces α-AChR, resulting in self-sensitization and thymic changes leading to AChR-MG.

Domaines

Immunologie
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Origine : Publication financée par une institution
licence : CC BY NC - Paternité - Pas d'utilisation commerciale

Dates et versions

pasteur-03927224 , version 1 (17-11-2023)

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Paternité - Pas d'utilisation commerciale

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Cloé Payet, Axel You, Odessa-Maud Fayet, Edouard Hemery, Frederique Truffault, et al.. Central role of macrophages and nucleic acid release in Myasthenia Gravis thymus. Annals of Neurology, 2023, 93 (4), pp.643-654. ⟨10.1002/ana.26590⟩. ⟨pasteur-03927224⟩
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