Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10.

Area of Science:

• Neuroimmunology
• Microbiome-Immune Interactions
• Autoimmune Diseases

Background:

• Plasma cells (PCs) in the central nervous system (CNS) of multiple sclerosis (MS) patients are observed, but their origin and function remain elusive.
• The gut microbiome's influence on CNS autoimmunity is increasingly recognized, yet specific cellular mechanisms are not fully understood.

Purpose of the Study:

• To investigate the origin and role of immunoglobulin A (IgA) producing plasma cells (PCs) in the CNS during experimental autoimmune encephalomyelitis (EAE), a model for MS.
• To determine if gut-derived IgA+ PCs influence the course of neuroinflammation.

Main Methods:

• Tracking the origin of CNS plasma cells in a mouse model of EAE.
• Quantifying IgA+ plasma cells and IgA-bound bacteria in the gut and CNS.
• Manipulating plasmablast (PB) and PC populations and assessing EAE severity.
• Evaluating the role of interleukin-10 (IL-10) in IgA+ PB/PC mediated resistance.

Main Results:

• A subset of CNS PCs in EAE mice originate from the gut and produce IgA.
• Both gut IgA+ PCs and IgA-bound fecal bacteria are reduced during EAE and MS relapse.
• Depletion of PBs/PCs exacerbated EAE, which was reversed by introducing gut-derived IgA+ PCs.
• Overabundance of IgA+ PBs/PCs conferred resistance to EAE, dependent on IL-10 expression.

Conclusions:

• Gut-derived IgA+ plasmablasts and plasma cells play a crucial, unexpected role in suppressing neuroinflammation.
• Mobilization of IgA+ PCs from the gut represents a potential therapeutic avenue for MS.
• Interleukin-10 produced by IgA+ PBs/PCs is essential for conferring resistance to neuroinflammation in EAE.