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Central Role of Macrophages and Nucleic Acid Release in Myasthenia Gravis Thymus.
- Source :
-
Annals of neurology [Ann Neurol] 2023 Apr; Vol. 93 (4), pp. 643-654. Date of Electronic Publication: 2023 Jan 25. - Publication Year :
- 2023
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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.<br />Methods: Serum levels of IFN-β and IFN-α subtypes, and mRNA expression for IFN-I subtypes and IFN-stimulated genes in peripheral mononuclear blood cells (PBMCs) were analyzed. The contribution of endogenous nucleic acids in thymic expression of IFN-I subtypes was investigated in human thymic epithelial cell cultures and the mouse thymus. By immunohistochemistry, thymic CD68 <superscript>+</superscript> and CD163 <superscript>+</superscript> macrophages were analyzed in AChR-MG. To investigate the impact of a decrease in thymic macrophages, mice were treated with an anti-CSF1R antibody.<br />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.<br />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. ANN NEUROL 2023;93:643-654.<br /> (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
Details
- Language :
- English
- ISSN :
- 1531-8249
- Volume :
- 93
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Annals of neurology
- Publication Type :
- Academic Journal
- Accession number :
- 36571580
- Full Text :
- https://doi.org/10.1002/ana.26590