GPR109A expressed on medullary thymic epithelial cells affects thymic Treg development.

Regulatory T cells (Treg) maintain immune homeostasis due to their anti-inflammatory functions. They can be generated either centrally in the thymus or in peripheral organs. Metabolites such as short-chain fatty acids produced by intestinal microbiota can induce peripheral Treg differentiation, by activating G-protein-coupled-receptors like GPR109A. In this study, we identified a novel role for GPR109A in thymic Treg development. We found that Gpr109a-/- mice had increased Treg under basal conditions in multiple organs compared with WT mice. GPR109A was not expressed on T cells but on medullary thymic epithelial cells (mTECs), as revealed by single-cell RNA sequencing in both mice and humans and confirmed by flow cytometry in mice. mTECs isolated from Gpr109a-/- mice had higher expression of autoimmune regulator (AIRE), the key regulator of Treg development, while the subset of mTECs that did not express Gpr109a in the WT displayed increased Aire expression and also enhanced signaling related to mTEC functionality. Increased thymic Treg in Gpr109a-/- mice was associated with protection from experimental autoimmune encephalomyelitis, with ameliorated clinical signs and reduced inflammation. This work identifies a novel role for GPR109A and possibly the gut microbiota, on thymic Treg development via its regulation of mTECs.

Early microglial response, myelin deterioration and lethality in mice deficient for very long chain ceramide synthesis in oligodendrocytes.

The sphingolipids galactosylceramide (GalCer), sulfatide (ST) and sphingomyelin (SM) are essential for myelin stability and function. GalCer and ST are synthesized mostly from C22-C24 ceramides, generated by Ceramide Synthase 2 (CerS2). To clarify the requirement for C22-C24 sphingolipid synthesis in myelin biosynthesis and stability, we generated mice lacking CerS2 specifically in myelinating cells (CerS2ΔO/ΔO ). At 6 weeks of age, normal-appearing myelin had formed in CerS2ΔO/ΔO mice, however there was a reduction in myelin thickness and the percentage of myelinated axons. Pronounced loss of C22-C24 sphingolipids in myelin of CerS2ΔO/ΔO mice was compensated by greatly increased levels of C18 sphingolipids. A distinct microglial population expressing high levels of activation and phagocytic markers such as CD64, CD11c, MHC class II, and CD68 was apparent at 6 weeks of age in CerS2ΔO/ΔO mice, and had increased by 10 weeks. Increased staining for denatured myelin basic protein was also apparent in 6-week-old CerS2ΔO/ΔO mice. By 16 weeks, CerS2ΔO/ΔO mice showed pronounced myelin atrophy, motor deficits, and axon beading, a hallmark of axon stress. 90% of CerS2ΔO/ΔO mice died between 16 and 26 weeks of age. This study highlights the importance of sphingolipid acyl chain length for the structural integrity of myelin, demonstrating how a modest reduction in lipid chain length causes exposure of a denatured myelin protein epitope and expansion of phagocytic microglia, followed by axon pathology, myelin degeneration, and motor deficits. Understanding the molecular trigger for microglial activation should aid the development of therapeutics for demyelinating and neurodegenerative diseases.

Seizure triggers identified postictally using a smart watch reporting system.

Persons with epilepsy (PWE) often report that seizure triggers can influence the occurrence and timing of seizures. Some previous studies of seizure triggers have relied on retrospective daily seizure diaries or surveys pertaining to all past seizures, recent and/or remote, in respondents. To assess the characteristics of seizure triggers at the granularity of individual seizures, we used a seizure-tracking app, called EpiWatch, on a smart watch system (Apple Watch and iPhone) in a national study of PWE. Participants tracked seizures during a 16-month study period using the EpiWatch app. Seizure tracking was initiated during a pre-ictal state or as the seizure was occurring and included collection of biosensor data, responsiveness testing, and completion of an immediate post-seizure survey. The survey evaluated seizure types, auras or warning symptoms, loss of awareness, use of rescue medication, and seizure triggers for each tracked seizure. Two hundred and thirty four participants tracked 2493 seizures. Ninety six participants reported triggers in 650 seizures: stress (65.8%), lack of sleep (30.5%), menstrual cycle (19.7%), and overexertion (18%) were the most common. Participants often reported having multiple combined triggers, frequent stress with lack of sleep, overexertion, or menses. Participants who reported triggers were more likely to be taking 3 or more anti-seizure medications compared to participants who did not report triggers. Participants were able to interact with the app and use mobile technology in this national study to record seizures and report common seizure triggers. These findings demonstrate the promise of longitudinal, self-reported data to improve our understanding of epilepsy and its related comorbidities.