Nfkb2 deficiency and its impact on plasma cells and immunoglobulin expression in murine small intestinal mucosa

Abstract

Background & Aims: The alternative (non-canonical) nuclear factor-kB (NF-kB) signalling pathway predominantly regulates the function of the p52/RelB heterodimer. Germline Nfkb2 deficiency in mice leads to loss of p100/p52 protein and offers protection against a variety of gastrointestinal conditions, including azoxymethane/dextran sulfate sodium (DSS)-induced colitis-associated cancer and lipopolysaccharide (LPS)-induced small intestinal epithelial apoptosis. However, the common underlying protective mechanisms have not yet been fully elucidated. Methods: We applied high throughput RNASeq and proteomic analyses to characterise the transcriptional and protein signatures of the small intestinal mucosa of naïve adult Nfkb2-/- mice. Those data were validated by immunohistochemistry and quantitative ELISA using both small intestinal tissue lysates and serum. Results: We identified a B-lymphocyte defect as a major transcriptional signature in the small intestinal mucosa and immunoglobulin A as the most downregulated protein by proteomic analysis in Nfkb2-/- mice. Small intestinal immunoglobulins were dramatically dysregulated, with undetectable levels of immunoglobulin A and greatly increased amounts of immunoglobulin M being detected. The numbers of IgA-producing, CD138+ve plasma cells were also reduced in the lamina propria of the small intestinal villi of Nfkb2-/- mice. This phenotype was even more striking in the small intestinal mucosa of RelB-/- mice, although these mice were equally sensitive to LPS-induced intestinal apoptosis as their RelB+/+ wild-type counterparts. Conclusions: NF-kB2/p52 deficiency confers resistance to LPS-induced small intestinal apoptosis and also appears to regulate the plasma cell population and immunoglobulin levels within the gut.

The NFκB signaling system in the generation of B-cell subsets: from germinal center B cells to memory B cells and plasma cells

“…NFκB2-deficient mice show IgA downregulation and significantly elevated IgM in the small intestine mucosa. The lamina propria of the small intestine of NFκB2 deficient mice had fewer CD138 + PCs that produced IgA ( 148 ). Almaden et al.…”

“…NFkB2-deficient mice show IgA downregulation and significantly elevated IgM in the small intestine mucosa. The lamina propria of the small intestine of NFkB2 deficient mice had fewer CD138 + PCs that produced IgA (148). Almaden et al showed that germline NFkB2 heterozygosity enhanced antibody production and proposed that NFkB2 heterozygosity leads to disruption of IkBd and sustains cRel activity leading to enhance B cell proliferation and subsequent antibody production (16).…”