B/T cell crosstalk and aberrant inflammatory IgG exacerbate autoimmune intestinal inflammation

Dysregulated B cell responses have been described in inflammatory-bowel disease (IBD) patients; however, the role of B cells in IBD pathology remained incompletely understood. We here described Wiskott-Aldrich Syndrome interacting protein deficient ( Wipf1 -/- ) mice as novel mouse model of spontaneous, chronic colitis modelling human IBD. Concomitant with aberrant IgG production in colonic tissue of Wipf1 -/- mice, we identified systemic, hypo-sialylated IgG as drivers of IL-1β production in monocytes. Pathological antibody production was promoted by the hyper-reactivity of Wipf1 -/- B cells in response to LPS stimulation, resulting in efficient activation of the MAPK/Erk and mTOR/Akt/4E-BP1 pathways and heightened metabolic activity. In addition to abundant inflammatory IgG, we found that B cells directly promoted the production of pro-inflammatory cytokines by intestinal CD4+ T cells. B/T co-culture assays defined the co-stimulatory molecule CD86 as driver of IFN-γ and GM-CSF production by CD4+ T cells. CD86 expression was further enhanced by the presence of sCD40L, which was elevated in sera of Wipf1 -/- mice. Similarly, colonic B cells of IBD patients expressed increased mRNA levels of CD86 correlating with enhanced levels of systemic sCD40L. Together, B cell-mediated pro-inflammatory cytokine secretion and B cell-derived inflammatory antibody production contributed to exacerbated pathogenesis during intestinal inflammation. ![Figure][1] One Sentence Summary B cells fuel intestinal inflammation ### Competing Interest Statement The authors have declared no competing interest. [1]: pending:yes