Microbiota-specific serum IgG links gut and joints through immune-endothelial crosstalk in arthritis

Rheumatoid arthritis (RA) pathogenesis involves early gut immune alterations that precede clinical onset and systemic bone involvement. Using mouse and human imaging mass cytometry (IMC) and tissue sequencing, this study shows that intestinal endothelial and immune changes emerge before or coincide with arthritis symptom development. In the collagen-induced arthritis (CIA) model, intestinal vascular permeability and endothelial gene activation promoting leukocyte trafficking appeared prior to synovial inflammation. Spatial mapping of murine and human ileal tissues predicted enhanced epithelial-immune interactions and lymphoid activation, suggesting mucosal immune priming before joint pathology. Both gut-selective 4{beta}7 integrin blockade with vedolizumab and endothelial barrier enhancement by imatinib significantly reduced arthritis severity in CIA mice. After clinical onset, microbiota-specific IgG responses expanded to recognize rare gut bacteria, reflecting increased microbial exposure. Bone marrow endothelium exhibited interferon-I-driven inflammation and vascular activation, indicating tissue-specific endothelial dysfunction. Microbiota-reactive IgG increased during CIA - likely a response to translocating gut bacteria and immune cell activation. Integrating mouse and human data, these findings define a mechanistic framework where endothelial barrier impairment, microbial translocation, and systemic endothelial activation initiate RA autoimmunity, revealing endothelial and mucosal pathways as targets for early intervention. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/702529v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1ef2f41org.highwire.dtl.DTLVardef@77d66org.highwire.dtl.DTLVardef@1b9e4cborg.highwire.dtl.DTLVardef@15bd170_HPS_FORMAT_FIGEXP M_FIG C_FIG