Investigating the role of the actin cytoskeleton in regulating TLR-mediated B cell responses during inflammatory challenges
Final Report Abstract
B cells, as part of the adaptive immune response, play a major role in maintaining immune homeostasis. Correct B cell activation leads to proliferation and differentiation into antibodysecreting plasma cells (PC). Aberrant B cell activation and antibody production has been implicated in the development of autoimmune diseases, as seen in Wiskott-Aldrich Syndrome (WAS). WAS is an immunodeficiency associated with an increased susceptibility to infections. At the same time, WAS patients develop a heightened risk of systemic autoimmune manifestations, such as inflammatory bowel disease (IBD) or IgA nephropathy. Cause of disease are genetic mutations leading to defective expression of the actin-regulators WAS protein (WASP) or the WASP interacting protein (WIP). Murine B cells deficient in WIP are hyper-proliferative to both BCR and TLR signaling and demonstrate enhanced class-switch recombination to IgG1 after TLR4 stimulation in vitro. Mechanistically, our current research indicated that hyper-reactivity of WIP KO B cells towards LPS stimulation led to a state of heightened metabolic activity mediated by efficient activation of the MAPK/Erk and mTOR/Akt/4E-BP1 pathways needed for B cell proliferation, differentiation and class-switch recombination. We hypothesized that the presence of hyperreactive B cells in the gut might enhance inflammation during IBD development. IBD, including Crohn's disease (CD) and ulcerative colitis (UC), is a group of immune-mediated disorders of the intestine and has been considered one of the most prevalent gastrointestinal diseases today with increasing incidence. The cause of IBD remains unclear and is likely to be a combination of genetic and environmental risk factors. Dysregulated B cell responses and imbalanced intestinal IgG production have been described in UC patients and correlate with disease severity; however, the role of B cells and antibody-secreting cells (ASC) in IBD pathology still remained elusive. Our current research provided evidence for autoreactive B cells as crucial drivers of immunemediated IBD pathogenesis. We presented WIP KO mice as novel mouse model of spontaneous chronic colitis that mimics human IBD. Using multi-parametric flow and mass cytometry, we found increased pro-inflammatory cytokine production of CD4 T cells (GM-CSF, IFN-g, IL-17) and increased germinal centre formation accompanied by enhanced IgA and IgG1 production in the lamina propria of the inflamed colon of WIP KO mice. B cell depletion in WIP KO mice diminished this pro-inflammatory cytokine production by CD4 T cells. Adoptive T cell transfer into immunodeficient RAG KO mice revealed that co-transferred WIP KO B cells further enhanced the pro-inflammatory cytokine production of WT T cells during intestinal inflammation. Our preliminary data indicated that B cell specific IL-6 production pushes proinflammatory T cell differentiation. Future studies will further investigate the role of B cell intrinsic pro-inflammatory cytokine production during colitis development. Together, our results demonstrated that elevated B cell-mediated pro-inflammatory cytokine secretion and B cell-derived inflammatory antibody production contributed to exacerbated intestinal inflammation. Our current research hence provides evidence for B cells as mediators of IBD pathogenesis and suggest that our mouse model can be of immense value to test treatment options targeting B cells during IBD.
Publications
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Efficient Tissue Clearing and Multi-Organ Volumetric Imaging Enable Quantitative Visualization of Sparse Immune Cell Populations During Inflammation. Frontiers in Immunology, 11.
Hofmann, Julian; Gadjalova, Iana; Mishra, Ritu; Ruland, Jürgen & Keppler, Selina J.
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The Wanderings of Gut-Derived IgA Plasma Cells: Impact on Systemic Immune Responses. Frontiers in Immunology, 12.
Keppler, Selina J.; Goess, Marie Christine & Heinze, Julia M.
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Tissue clearing and 3D imaging – putting immune cells into context. Journal of Cell Science, 134(15).
Hofmann, Julian & Keppler, Selina J.
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B/T cell crosstalk and aberrant inflammatory IgG exacerbate autoimmune intestinal inflammation. Cold Spring Harbor Laboratory.
Gadjalova, Iana; Heinze, Julia M.; Goess, Marie Christine; Hofmann, Julian; Albers, Julian J.; Spallek, Ria; Blissenbach, Birgit; Buck, Annalisa; Weber, Marie-Christin; Scherer, Emely; Kampick, Maximilian; Öllinger, Rupert; Krut, Oleg; Rad, Roland; Steiger, Katja; Winter, Christof; Janssen, Klaus-Peter; Neumann, Philipp-Alexander; Geha, Raif S. ... & Keppler, Selina J.
