免疫学
细胞因子
炎症
CD86
CD40
炎症性肠病
细胞毒性T细胞
免疫系统
T细胞
B细胞
医学
生物
抗体
体外
内科学
疾病
生物化学
作者
Iana Gadjalova,Julia M. Heinze,Marie Christine Goess,Julian Hofmann,Annalisa Buck,Marie-Christin Weber,Birgit Blissenbach,Maximilian Kampick,Oleg Krut,Katja Steiger,Klaus‐Peter Janssen,Philipp‐Alexander Neumann,Jürgen Ruland,Selina J. Keppler
标识
DOI:10.1016/j.mucimm.2023.10.005
摘要
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 provide evidence for the detrimental role of activated B cells during the onset of autoimmune intestinal inflammation. Using Wiskott-Aldrich Syndrome interacting protein deficient (Wipf1−/−) mice as a mouse model of chronic colitis, we identified clusters of differentiation (CD)86 expression on activated B cells as a crucial factor exacerbating pro-inflammatory cytokine production of intestinal CD4 T cells. Depleting B cells through anti-CD20 antibody treatment or blocking costimulatory signals mediated by CD86 through cytotoxic T lymphocyte antigen-4-immunoglobulin (CTLA-4-Ig) diminished intestinal inflammation in our mouse model of chronic IBD at the onset of disease. This was due to a reduction in aberrant humoral immune responses and reduced CD4 T cell pro-inflammatory cytokine production, especially interferon-g (IFN-g) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Interestingly, in addition to B cells isolated from the inflamed colon of Wipf1−/− mice, we also found CD86 mRNA and protein expression upregulated on activated B cells isolated from inflamed tissue of human patients with IBD. B cell activation and CD86 expression were boosted by soluble CD40L in vitro, which we found in the serum of mice and human patients with IBD. In summary, our data provides detailed insight into the contribution of B cells to intestinal inflammation, with implications for the treatment of IBD. 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 provide evidence for the detrimental role of activated B cells during the onset of autoimmune intestinal inflammation. Using Wiskott-Aldrich Syndrome interacting protein deficient (Wipf1−/−) mice as a mouse model of chronic colitis, we identified clusters of differentiation (CD)86 expression on activated B cells as a crucial factor exacerbating pro-inflammatory cytokine production of intestinal CD4 T cells. Depleting B cells through anti-CD20 antibody treatment or blocking costimulatory signals mediated by CD86 through cytotoxic T lymphocyte antigen-4-immunoglobulin (CTLA-4-Ig) diminished intestinal inflammation in our mouse model of chronic IBD at the onset of disease. This was due to a reduction in aberrant humoral immune responses and reduced CD4 T cell pro-inflammatory cytokine production, especially interferon-g (IFN-g) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Interestingly, in addition to B cells isolated from the inflamed colon of Wipf1−/− mice, we also found CD86 mRNA and protein expression upregulated on activated B cells isolated from inflamed tissue of human patients with IBD. B cell activation and CD86 expression were boosted by soluble CD40L in vitro, which we found in the serum of mice and human patients with IBD. In summary, our data provides detailed insight into the contribution of B cells to intestinal inflammation, with implications for the treatment of IBD.
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