Role of HLA class II and gut microbiota crosstalk in determining experimental autoimmune encephalomyelitis severity 4453

Abstract Description Multiple Sclerosis (MS) is influenced by both genetic and environmental factors. The HLA class-II region, the strongest genetic risk factor for MS, and gut microbiota, a potential environmental factor linked with MS, can predispose or protect from autoimmune diseases through modulation of pro- or anti-inflammatory cytokine responses. However, whether HLA class II-driven modulation of gut microbiota composition affects MS severity is unknown. Previously, we found that HLA-DR3, HLA-DQ8, and HLA-DR3DQ8 mice have distinct fecal and mucosal microbiota and exhibit different disease phenotypes in an animal model of MS. To determine whether gut microbiota regulates immune responses in an HLA class-II restricted manner, we stimulated BMDMs from C57BL/6 mice with heat killed bacteria from HLA-DR3, -DQ8 and -DR3DQ8 mice. We observed that bacteria from HLA-DQ8 mice induced significantly higher levels of IL-6 and TNF-α. Additionally, HLA-DQ8 dendritic cells (DCs) exhibited a greater propensity to produce pro-inflammatory cytokines compared to HLA-DR3 DCs, and HLA-DQ8 mice had increased ROR??t+FOXP3- cells in the gut lamina propria. Moreover, single-cell RNA sequencing of mesenteric lymph nodes from C57BL/6 MOG35-55 immunized mice colonized with HLA-DR3 or HLA-DQ8 fecal microbiota revealed that HLA-DQ8-microbiota induces a more pronounced pro-inflammatory phenotype. This study provides evidence that HLA class II impacts immune responses through changes in gut microbiota composition. Topic Categories Mucosal and Regional Immunology (MUC)