MICE-AE – MICE-AE

Organ-specific autoimmunity is typically associated with adaptive immune responses targeting self-antigens, yet the triggers and cause of these conditions remain poorly understood. This proposal posits that autoimmune encephalitis (AIE) serves as an ideal model for exploring immune-environment interactions due to clearly defined autoantigen targets, HLA associations, and ability to track autoantigen-specific immune cells. AIE constitutes a group of rare diseases marked by autoantibodies targeting neuronal or glial antigens, causing significant morbidity. Prior studies focussing on two common AIE-subtypes (LGI1 and CASPR2) have linked plasma cell expansion in cerebrospinal fluid (CSF) to T cell help, with microbial mimicry potentially directing anti-neuronal autoimmunity in genetically predisposed individuals.
In fact, we previously observed a notable reduction of innate-like mucosal associated invariant chain T (MAIT) cells in both cerebrospinal fluid (CSF) and blood of these patients. Using a murine model, we tentatively showed that MAIT cells suppressed the formation of AIE-associated auto-antibodies, emphasising their potential regulatory role in autoimmunity. This proposal aims to dissect the role of MAIT cells in AIE, particularly their interaction with plasma cells in the brain and their influence on autoantibody glycosylation. Taking advantage of existing biomaterial banks and collaborations, in work package (WP) 1 we will deeply characterise brain- and meningeal-infiltrating MAIT cells in human biomaterial. In WP2 we will define innate functions and compare autoantibody profiles between blood and CSF in these AIE subtypes. In WP3, we will understand the effect of microbiota on autoantigen-specific conventional T- and on MAIT cells. Finally, in WP4, we will functionally link intestinal MAIT cells with brain autoimmunity in newly developed animal models.
The present research consortium, comprising experts in neuroimmunology, MAIT cell biology, and autoantibody mechanisms, will employ single-cell transcriptomics and spatial analysis on autopsy samples to map MAIT cell dynamics and their interaction with conventional T cells and B cells. Additionally, stool metagenomics and MAIT cell bioassays will elucidate the gut-brain axis's role in AIE. This multi-disciplinary approach capitalises on existing infrastructure and will uncover the mechanistic pathways linking environmental factors, microbial antigens, and immune regulation in AIE, potentially revealing novel biomarkers and therapeutic targets.