Remodeling of colon plasma cell repertoire within ulcerative colitis patients

Abstract

Plasma cells (PCs) constitute a significant fraction of colonic mucosal cells and contribute to inflammatory infiltrates in ulcerative colitis (UC). While gut PCs secrete bacteria-targeting IgA antibodies, their role in UC pathogenesis is unknown. We performed single-cell V(D)J- and RNA-seq on sorted B cells from the colon of healthy individuals and patients with UC. A large fraction of B cell clones is shared between different colon regions, but inflammation in UC broadly disrupts this landscape, causing transcriptomic changes characterized by an increase in the unfolded protein response (UPR) and antigen presentation genes, clonal expansion, and isotype skewing from IgA1 and IgA2 to IgG1. We also directly expressed and assessed the specificity of 152 mAbs from expanded PC clones. These mAbs show low polyreactivity and autoreactivity and instead target both shared bacterial antigens and specific bacterial strains. Altogether, our results characterize the microbiome-specific colon PC response and how its disruption might contribute to inflammation in UC.

HIV-1 infection is associated with depletion of germinal center B cells and a decrease in IgA+plasma cells in the GI tract

“…Inflammatory stimuli, in particular TH1 cytokines such as IFN-g redirect immunoglobulin class switching towards IgG (91). While this is well described in the context of chronic inflammation such as in inflammatory bowel diseases (92)(93)(94)(95), and in response to intestinal pathogenic infections (96), here we describe an increase in intestinal IgG and IgM response during viremic HIV infection. We observe that suppression of plasma HIV VL results in 'normalization' of intestinal IgA responses, consistent with a prior report by Zaunders et al (97) but in contrast to Planchais and colleagues' findings (98).…”

Gut-associated lymphoid tissue attrition associates with response to anti-α4β7 therapy in ulcerative colitis

“…Given that gut-homing α4β7 + PCs are generated in the GALT ( 7 ) and that IgG + PCs are increased in the circulation and colon of patients with UC ( 27 , 28 ), we hypothesized that GALT attenuation in responders would result in reduced PC frequencies. The frequency of total IgG + and total IgA + PCs (cohort 1) in circulation was reduced in responders (fig.…”

Antigen receptor signaling and cell death resistance controls intestinal humoral response zonation

“…Which signals, and at which step of PC differentiation, control the upregulation of mucosal homing receptors in PCs remain to be elucidated. We described the existence of a process that equips IgA+ PCs with gut homing receptors during responses to commensals in order to direct antibody production into the intestinal lamina propria; however, whether such process remains in place or are altered during enteric infection or dysbiosis, situations that can lead to non-IgA+ PC homing to the lamina propria, 78–80 will require additional studies.…”