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Journal Articles Annals of Neurology Year : 2022

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

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Abstract

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.
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Dates and versions

pasteur-03927224 , version 1 (06-01-2023)

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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, In press, ⟨10.1002/ana.26590⟩. ⟨pasteur-03927224⟩
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