Study Objective: We aim to determine the antigen presentation capacity of enteric glial cells in response to challenge with Epstein-Barr virus (EBV). Hypothesis: Enteric glial cells are innate immune competent and express antigens via HLA/MHC class I and II moieties in addition to their roles in supporting neuronal function. We recently showed that enteric glial cells are reactive in the progressive multiple sclerosis (MS) colon and found stool levels of the enteric glial proteins glial fibrillary acidic protein (GFAP) and S100b to be starkly elevated in progressive MS vs. relapsing-remitting MS (RRMS) and healthy controls (Neurol Neuroimm Neurinflamm, 12(6):e200466, 2025. Downstream impacts of enteric glial antigen presentation in the human gut wall remain unknown. Enteric glial cells express myelin proteins including proteolipid protein 1 (PLP-1) yet are non-myelinating glia. The infective capacity of enteric glial cells, particularly with viruses relevant to MS etiology like EBV is not known. We hypothesize that infection of enteric glial cells by EBV induces antigen presentation of peptides with myelin protein sequence homology, triggering the induction of autoreactive T cells. Methods: Duodenum and colon tissue from healthy controls and MS subjects was analyzed via immunohistochemistry for PLP-1, GFAP, S100b, and HLA class I and class II alleles. An immortalized human enteric glial cell line was used to investigate responses to EBV challenge via immunohistochemistry. We investigated peptide expression by HLAs in EBV, heat-killed EBV, and vehicle treated glial cell cultures before processing for global immunopeptidomics for HLA-(A/B/C) and HLA-DR/DQ. Results: Intestinal tissue from MS subjects showed elevated levels of enteric glial cells as marked by immunoreactivity to PLP-1, S100b, and GFAP. We found that enteric glia from MS subjects expressed substantially more immunoreactive EBV receptor (anti-CD21) and EBV nuclear antigen (EBNA1) when compared to healthy control tissue. When we investigated the response of human enteric glial cell cultures to EBV challenge, we found an elevation in immunoreactive HLAs from class I and II. Immunopeptidomics showed an elevation in peptides presented by both HLA class I and class II alleles after challenge with EBV vs. heat killed EBV or vehicle controls. Conclusions: The results indicate an intestinal neural phenotype in MS, with enteric glial cell reactivity and antigen presentation in the MS gut and in response to EBV challenge in vitro. Peptide presentation profiles will guide future investigations that allow for targeted immunotherapies at the enteric glial – T cell interface. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Schwerdtfeger et al. (Fri,) studied this question.