Central Role of Macrophages and Nucleic Acid Release in Myasthenia Gravis Thymus

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 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 + 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 0 3 0 -cGAMP), or dexamethasoneinduced 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.

A new gene signature associated with disulfidptosis that forecasts myasthenia gravis and suggests infiltration of immune microenvironment in thymoma patients

“…In this inflammatory state, thymic epithelial cells have the potential to excessively produce IFN-β, which specifically triggers α-AChR expression, causing self-sensitization and thymic changes that ultimately lead to AChR-MG. The results emphasize the intricacy of the immune system [ 39 ]. In our study, we observed variations in B cells between the high- and low-risk groups of TAMG.…”

Single-cell mass cytometry on peripheral cells in Myasthenia Gravis identifies dysregulation of innate immune cells

“…Non-classical monocytes could be recruited to inflammatory MG thymuses. However, our team recently observed a decrease in the number of thymic macrophages in AChR-MG patients ( 57 ). Non-classical monocytes derived from the linear differentiation of classical monocytes into intermediate monocytes associated with the loss and gain expression of CD14 and CD16, respectively.…”

Myasthenia gravis: the future is here

“…These observations have led to the hypothesis that ongoing complement attack of myoid and epithelial cells promotes germinal center formation ( 73 ). Some have hypothesized that a deficiency of macrophages leads to impaired removal of necrotic thymomcytes, promoting the proinflammatory environment ( 74 ). This would lead to activation of other self-reactive CD4 + cells by antigen-presenting cells with epitopes derived from the injured tissue, causing further tissue destruction and sensitization of CD4 + cells to an increasingly larger repertoire of tissue epitopes and antigens (“epitope spreading”) ( 75 ).…”

“…No evidence suggests other infectious agents to be associated with MG ( 86 ). Release of double-stranded DNA from necrotic macrophages may trigger the inflammatory and subsequent autoimmune reaction in the hyperplastic thymus ( 74 ). Expression profiling of the thymus supports dysregulated apoptotic pathways ( 65 ).…”