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

Gadjalova, I.; Heinze, J. M.; Goess, M. C.; Hofmann, J.; Albers, J. J.; Spallek, R.; Blissenbach, B.; Buck, A.; Weber, M.-C.; Scherer, E.; Kampick, M.; Oellinger, R.; Krut, O.; Rad, R.; Steiger, K.; Winter, C.; Janssen, K.-P.; Neumann, P.-A.; Geha, R. S.; Ruland, J.; Keppler, S. J.

doi:10.1101/2022.09.12.507066

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bioRxiv · 10.1101/2022.09.12.507066

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

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Abstract

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

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Gadjalova, I., Heinze, J. M., Goess, M. C., Hofmann, J., Albers, J. J., Spallek, R., Blissenbach, B., Buck, A., Weber, M.-C., Scherer, E., Kampick, M., Oellinger, R., Krut, O., Rad, R., Steiger, K., Winter, C., Janssen, K.-P., Neumann, P.-A., Geha, R. S., Ruland, J., Keppler, S. J.. 2022-09-15. B/T cell crosstalk and aberrant inflammatory IgG exacerbate autoimmune intestinal inflammation. https://doi.org/10.1101/2022.09.12.507066

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