Constitutive alternative NF-κB signaling promotes marginal zone B-cell development but disrupts the marginal sinus and induces HEV-like structures in the spleen

• Published in: Blood Vol. 110; no. 7; pp. 2381 - 2389
• Main Authors: Guo, Feng, Weih, Debra, Meier, Elke, Weih, Falk
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.10.2007; The Americain Society of Hematology
• Subjects: Biological and medical sciences; Hematologic and hematopoietic diseases; Medical sciences; Spleen; Marginal zone; Signal transduction; Hematology; B-Lymphocyte; Transcription factor NFκB; Paranasal sinus; Structure
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-02-075143

Nuclear factor-κB (NF-κB) plays a crucial role in B-cell and lymphoid organ development. Here, we studied the consequences of constitutive, signal-independent activation of the alternative NF-κB pathway for the splenic marginal zone (MZ). In contrast to nfkb2−/− mice, which lack both p100 and p52, mice that lack only the inhibitory p100 precursor but still express the p52 subunit of NF-κB2 (p100−/−) had markedly elevated MZ B-cell numbers. Both cell-intrinsic mechanisms and increased stromal expression of vascular cell adhesion molecule-1 (VCAM-1) contributed to the accumulation of MZ B cells in p100−/− spleens. While migration of p100−/− MZ B cells toward the lysophospholipid sphingosine-1 phosphate (S1P) was not affected, CXCL13-stimulated chemotaxis was impaired, correlating with reduced migration of MZ B cells into follicles in response to lipopolysaccharide (LPS). Strikingly, p100 deficiency resulted in the absence of a normal marginal sinus, strongly induced expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and glycosylated cell adhesion molecule-1 (GlyCAM-1), and the formation of nonfunctional ectopic high endothelial venule (HEV)–like structures in the red pulp. Thus, constitutive activation of the alternative NF-κB pathway favors MZ B-cell development and accumulation but leads to a disorganized spleen microarchitecture.