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-1{beta} 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-{gamma} 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. O_FIG O_LINKSMALLFIG WIDTH=168 HEIGHT=200 SRC="FIGDIR/small/507066v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1449ae8org.highwire.dtl.DTLVardef@116045borg.highwire.dtl.DTLVardef@77f3f2org.highwire.dtl.DTLVardef@130a271_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryB cells fuel intestinal inflammation