title: APRIL secreted by neutrophils binds to heparan sulfate proteoglycans to create plasma cell niches in human mucosa.
abstract: The bone marrow constitutes a favorable environment for long-lived antibody-secreting plasma cells, providing blood-circulating antibody. Plasma cells are also present in mucosa-associated lymphoid tissue (MALT) to mediate local frontline immunity, but how plasma cell survival there is regulated is not known. Here we report that a proliferation-inducing ligand (APRIL) promoted survival of human upper and lower MALT plasma cells by upregulating expression of the antiapoptotic proteins bcl-2, bcl-xL, and mcl-1. The in situ localization of APRIL was consistent with such a prosurvival role in MALT. In upper MALT, tonsillar epithelium produced APRIL. Upon infection, APRIL production increased considerably when APRIL-secreting neutrophils recruited from the blood infiltrated the crypt epithelium. Heparan sulfate proteoglycans (HSPGs) retained secreted APRIL in the subepithelium of the infected zone to create APRIL-rich niches, wherein IgG-producing plasma cells accumulated. In lower MALT, neutrophils were the unique source of APRIL, giving rise to similar niches for IgA-producing plasmocytes in villi of lamina propria. Furthermore, we found that mucosal humoral immunity in APRIL-deficient mice is less persistent than in WT mice. Hence, production of APRIL by inflammation-recruited neutrophils may create plasma cell niches in MALT to sustain a local antibody production.
authors.affiliation: Division of Hematology, Geneva University Hospital, Department of Patho-Immunology, Geneva University Medical Center, Geneva, Switzerland. bertrand.huard@medecine.unige.ch
authors.forename: Bertrand
authors.initials: B
authors.lastname: Huard
authors.forename: Thomas
authors.initials: T
authors.lastname: McKee
authors.forename: Carine
authors.initials: C
authors.lastname: Bosshard
authors.forename: Stéphane
authors.initials: S
authors.lastname: Durual
authors.forename: Thomas
authors.initials: T
authors.lastname: Matthes
authors.forename: Samir
authors.initials: S
authors.lastname: Myit
authors.forename: Olivier
authors.initials: O
authors.lastname: Donze
authors.forename: Christophe
authors.initials: C
authors.lastname: Frossard
authors.forename: Carlo
authors.initials: C
authors.lastname: Chizzolini
authors.forename: Christiane
authors.initials: C
authors.lastname: Favre
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zubler
authors.forename: Jean Philippe
authors.initials: JP
authors.lastname: Guyot
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.forename: Eddy
authors.initials: E
authors.lastname: Roosnek
mesh_terms: D002460:Cell Line; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology; D009092:Mucous Membrane / Q000276:immunology*; D009504:Neutrophils / Q000378:metabolism*; D010950:Plasma Cells / Q000276:immunology*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000378:metabolism*
chemical_list: D019812:Heparan Sulfate Proteoglycans; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13