Ulcerative colitis is characterized by a plasmablast-skewed humoral response associated with disease activity

Abstract

B cells, which are critical for intestinal homeostasis, remain understudied in ulcerative colitis (UC). In this study, we recruited three cohorts of patients with UC (primary cohort, n = 145; validation cohort 1, n = 664; and validation cohort 2, n = 143) to comprehensively define the landscape of B cells during UC-associated intestinal inflammation. Using single-cell RNA sequencing, single-cell IgH gene sequencing and protein-level validation, we mapped the compositional, transcriptional and clonotypic landscape of mucosal and circulating B cells. We found major perturbations within the mucosal B cell compartment, including an expansion of naive B cells and IgG + plasma cells with curtailed diversity and maturation. Furthermore, we isolated an auto-reactive plasma cell clone targeting integrin αvβ6 from inflamed UC intestines. We also identified a subset of intestinal CXCL13-expressing TFH-like T peripheral helper cells that were associated with the pathogenic B cell response. Finally, across all three cohorts, we confirmed that changes in intestinal humoral immunity are reflected in circulation by the expansion of gut-homing plasmablasts that correlates with disease activity and predicts disease complications. Our data demonstrate a highly dysregulated B cell response in UC and highlight a potential role of B cells in disease pathogenesis.UC is a chronic inflammatory bowel disease (IBD) characterized by relapsing episodes of inflammation of the colonic mucosa 1 . In healthy individuals, intestinal B cell responses are dominated by the homeostatic generation of IgA-producing plasma cells (PCs) that promote under exclusive licence to Springer Nature America, Inc. 2022Reprints and permissions information is available at www.nature.com/reprints.

Peripheral Helper T Cell Responses in Human Diseases

“…This could be interpreted as Tph cells providing more help to B cells than Tfh cells in RA. Similar observations are reported in the inflamed colon of UC; switched memory B cells oligoclonally expand in the inflamed colon with low SHM ( 34 ). Colocalization of B cells and CXCL13-producing CD3 + T cells shown by multiple immunofluorescent stainings suggest that Tph cells provide help to switched memory B cells in UC-inflamed colitis ( 34 ).…”

“…DN2 cells in SLE have less SMH than other types of B cells ( 29 ). Similarly, SHM of IgG sequences from B cells of colon tissues is lower in patients with ulcerative colitis (UC) than in healthy individuals ( 34 ). These collectively indicate that human B cells differentiated at extrafollicle or peripheral tissues have less SHM than GC-B cells.…”

“…The factors regulating Tph targeting might depend on disease conditions. In UC, CD27 + switched memory B cells expand with lower SHM in the inflamed colon rather than DN2 cells ( 34 ).…”

“…Tph cells have been reported to be associated with various autoimmune diseases as well as RA. Although functions of Tph cells in peripheral tissues were investigated in a limited number of autoimmune diseases such as UC and juvenile idiopathic arthritis ( 34 , 38 ), circulating Tph (cTPh) cells with the definition of PD-1 hi CXCR5 - or PD-1 + CXCR5 - in peripheral blood may reflect the systemic status of Tph cells. This concept would be analogous to the analysis of circulating Tfh (cTfh) cells that had been established in a variety of human diseases ( 39 ).…”

Artificial Intelligence Enables Quantitative Assessment of Ulcerative Colitis Histology

“…For example, our quantitative analysis showed that both area proportion and plasma cell composition of basal plasmacytosis are correlated with increasing disease severity reflected by increased NHI score. Features quantifying plasma cells in the mucosa also correlated with increasing disease severity, highlighting the role of plasma cells in UC disease biology and progression [26]. We were also able to quantify goblet cell mucin depletion, a known feature of epithelial injury in UC that has not previously been quantified [27].…”