Meningeal lymphoid hubs support autoreactive immune responses 2306190

Abstract

Abstract Introduction Immune cells within the meninges are increasingly recognized as key regulators of CNS homeostasis and disease. The dura mater, which contains diverse innate and adaptive immune populations, also supports B cell development. We recently identified organized lymphoid architecture surrounding a fenestrated venous plexus at the rostral—rhinal confluence of sinuses, termed the rostral-rhinal venolymphatic hub (hub). Following intranasal viral infection, this hub mounts robust germinal center (GC) responses composed of T follicular helper (Tfh) cells and GC B cells undergoing proliferation, class-switch recombination, and somatic hypermutation. Here we evaluate the role of the hub in the development of autoimmunity. Methods Using complementary structural and functional approaches as molecular biology, imaging and flow cytometric analysis. Results We show that this same hub also supports autoimmune responses to CNS antigens, particularly myelin debris that preferentially accumulates at this site. This deposition appears to result from a loose glial limitans over the olfactory bulbs and the proximity of fenestrated vasculature that drains into the hub. B cells act as key “housekeepers,” as their depletion markedly increases myelin accumulation. Beyond debris clearance, hub-resident B cells express PDL-1 and TGFβ, suggesting a regulatory program that may reinforce tolerance to self-antigens. During autoimmune priming, myelin oligodendrocyte glycoprotein (MOG)—reactive CD4+ T cells preferentially localize to the hub, engage B cells, proliferate, and differentiate into Tfh cells. B cell depletion augments the accumulation of these autoreactive T cells in the hub and accelerates onset of EAE. Conclusion Collectively, these findings reveal how dural lymphoid architecture positioned around a specialized vascular plexus can sample foreign and self-antigens, generating responses that either protect against infection or drive autoimmune pathology in the adjacent CNS. Funding Source National Institutes of Health Topic Categories Neuroimmunology (NEUR)