title: Disruption of heparan sulfate proteoglycan conformation perturbs B-cell maturation and APRIL-mediated plasma cell survival.
abstract: The development and antigen-dependent differentiation of B lymphocytes are orchestrated by an array of growth factors, cytokines, and chemokines that require tight spatiotemporal regulation. Heparan sulfate proteoglycans specifically bind and regulate the bioavailability of soluble protein ligands, but their role in the immune system has remained largely unexplored. Modification of heparan sulfate by glucuronyl C5-epimerase (Glce) controls heparan sulfate-chain flexibility and thereby affects ligand binding. Here we show that Glce deficiency impairs B-cell maturation, resulting in decreased plasma cell numbers and immunoglobulin levels. We demonstrate that C5-epimerase modification of heparan sulfate is critical for binding of a proliferation inducing ligand (APRIL) and that Glce-deficient plasma cells fail to respond to APRIL-mediated survival signals. Our results identify heparan sulfate proteoglycans as novel players in B-cell maturation and differentiation and suggest that heparan sulfate conformation is crucial for recruitment of factors that control plasma cell survival.
authors.affiliation: Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Rogier M
authors.initials: RM
authors.lastname: Reijmers
authors.forename: Richard W J
authors.initials: RW
authors.lastname: Groen
authors.forename: Annemieke
authors.initials: A
authors.lastname: Kuil
authors.forename: Kees
authors.initials: K
authors.lastname: Weijer
authors.forename: Fiona C
authors.initials: FC
authors.lastname: Kimberley
authors.forename: Jan Paul
authors.initials: JP
authors.lastname: Medema
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Li
authors.forename: Marcel
authors.initials: M
authors.lastname: Spaargaren
authors.forename: Steven T
authors.initials: ST
authors.lastname: Pals
mesh_terms: D000818:Animals; D002238:Carbohydrate Epimerases / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010950:Plasma Cells / Q000201:enzymology / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D019812:Heparan Sulfate Proteoglycans; C491959:Tnfsf13 protein, mouse; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D002238:Carbohydrate Epimerases