Periodontal disease is more common in individuals with rheumatoid arthritis (RA) who have detectable anti-citrullinated protein antibodies (ACPAs), implicating oral mucosal inflammation in RA pathogenesis. Here, we performed paired analysis of human and bacterial transcriptomics in longitudinal blood samples from RA patients. We found that patients with RA and periodontal disease experienced repeated oral bacteremias associated with transcriptional signatures of ISG15 ⁺ HLADR ^hi and CD48 ^high S100A2 ^pos monocytes, recently identified in inflamed RA synovia and blood of those with RA flares. The oral bacteria observed transiently in blood were broadly citrullinated in the mouth, and their in situ citrullinated epitopes were targeted by extensively somatically hypermutated ACPAs encoded by RA blood plasmablasts. Together, these results suggest that (i) periodontal disease results in repeated breaches of the oral mucosa that release citrullinated oral bacteria into circulation, which (ii) activate inflammatory monocyte subsets that are observed in inflamed RA synovia and blood of RA patients with flares and (iii) activate ACPA B cells, thereby promoting affinity maturation and epitope spreading to citrullinated human antigens.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by antinuclear antibodies (ANAs). Epstein-Barr virus (EBV) infection has been epidemiologically associated with SLE, yet its role in pathogenesis remains incompletely defined. Here, we developed an EBV-specific single-cell RNA-sequencing platform and used it to demonstrate that EBV infection reprograms autoreactive antinuclear antigen B cells to drive autoimmunity in SLE. We demonstrated that, in SLE, EBV ⁺ B cells are predominantly CD27 ⁺ CD21 ^low memory B cells that are present at increased frequencies and express ZEB2 , TBX21 (T-bet), and antigen-presenting cell transcriptional pathways. Integrative analysis of chromatin immunoprecipitation sequencing (ChIP-seq), assay for transposase-accessible chromatin sequencing (ATAC-seq), and RNA polymerase II occupancy data revealed EBV nuclear antigen 2 (EBNA2) binding at the transcriptional start sites and regulatory regions of CD27 , ZEB2 , and TBX21 , as well as the antigen-presenting cell genes demonstrated to be up-regulated in SLE EBV ⁺ B cells. We expressed recombinant antibodies from SLE EBV ⁺ B cells and demonstrated that they bind prototypical SLE nuclear autoantigens, whereas those from healthy individuals do not. We further found that SLE EBV ⁺ B cells can serve as antigen-presenting cells to drive activation of T peripheral helper cells with concomitant activation of related EBV ⁻ antinuclear double-negative 2 B cells and plasmablasts. Our results provide a mechanistic basis for EBV being a driver of SLE through infecting and reprogramming nuclear antigen-reactive B cells to become activated antigen-presenting cells with the potential to promote systemic disease–driving autoimmune responses.

The interaction between the mammalian host and its resident gut microbiota is known to license adaptive immune responses. Nutritional constituents strongly influence composition and functional properties of the intestinal microbial communities. Here, we report that omission of a single essential amino acid - tryptophan – from the diet abrogates CNS autoimmunity in a mouse model of multiple sclerosis. Dietary tryptophan restriction results in impaired encephalitogenic T cell responses and is accompanied by a mild intestinal inflammatory response and a profound phenotypic shift of gut microbiota. Protective effects of dietary tryptophan restriction are abrogated in germ-free mice, but are independent of canonical host sensors of intracellular tryptophan metabolites. We conclude that dietary tryptophan restriction alters metabolic properties of gut microbiota, which in turn have an impact on encephalitogenic T cell responses. This link between gut microbiota, dietary tryptophan and adaptive immunity may help to develop therapeutic strategies for protection from autoimmune neuroinflammation.

Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS), which is linked to Epstein–Barr virus (EBV) infection, preceding the disease. The molecular mechanisms underlying this connection are only partially understood. We previously described molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and three human CNS proteins: anoctamin-2 (ANO2), alpha-B crystallin (CRYAB), and glial cellular adhesion molecule (GlialCAM). Here, we investigated antibody responses against EBNA1 and GlialCAM in a large cohort of 650 MS patients and 661 matched population controls and compared them to responses against CRYAB and ANO2. We confirmed that elevated IgG responses against EBNA1 and all three CNS-mimic antigens associate with increased MS risk. Blocking experiments confirmed the presence of cross-reactive antibodies and molecular mimicry between EBNA1 and GlialCAM, and accompanying antibody responses against adjacent peptide regions of GlialCAM suggest epitope spreading. Antibody responses against EBNA1, GlialCAM, CRYAB, and ANO2 are elevated in MS patients carrying the main risk allele HLA-DRB1*15:01, and combinations of HLA-DRB1*15:01 with anti-EBNA1 and anti-GlialCAM antibodies increase MS risk significantly and in an additive fashion. In addition, antibody reactivities against more than one EBNA1 peptide and more than one CNS-mimic increase the MS risk significantly but modestly. Overall, we show that molecular mimicry between EBNA1 and GlialCAM is likely an important molecular mechanism contributing to MS pathology.