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Blood, 1 October 2007, Vol. 110, No. 7, pp. 2381-2389.
Prepublished online as a Blood First Edition Paper on July 9, 2007; DOI 10.1182/blood-2007-02-075143.
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HEMATOPOIESIS
Constitutive alternative NF- B signaling promotes marginal zone B-cell development but disrupts the marginal sinus and induces HEV-like structures in the spleen
Feng Guo1,
Debra Weih1,
Elke Meier1, and
Falk Weih1,2
1 Leibniz-Institute for Age Research—Fritz-Lipmann-Institute, Jena; and
2 Friedrich-Schiller-University, Jena, Germany
Nuclear factor- B (NF-B) 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-B 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-B2 (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-B pathway favors MZ B-cell development and accumulation but leads to a disorganized spleen microarchitecture.
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