title: Toll-Like Receptor 9 Stimulation Induces Aberrant Expression of a Proliferation-Inducing Ligand by Tonsillar Germinal Center B Cells in IgA Nephropathy.
abstract: The TNF family member a proliferation-inducing ligand (APRIL; also known as TNFSF13), produced by myeloid cells, participates in the generation and survival of antibody-producing plasma cells. We studied the potential role of APRIL in the pathogenesis of IgA nephropathy (IgAN). We found that a significant proportion of germinal centers (GCs) in tonsils of patients with IgAN contained cells aberrantly producing APRIL, contributing to an overall upregulation of tonsillar APRIL expression compared with that in tonsils of control patients with tonsillitis. In IgAN GC, antigen-experienced IgD-CD38+/-CD19+B cells expressing a switched IgG/IgA B cell receptor produced APRIL. Notably, these GC B cells expressed mRNA encoding the common cleavable APRIL-αbut also, the less frequent APRIL-δ/ζmRNA, which encodes a protein that lacks a furin cleavage site and is, thus, the uncleavable membrane-bound form. Significant correlation between TLR9 and APRIL expression levels existed in tonsils from patients with IgAN.In vitro, repeated TLR9 stimulation induced APRIL expression in tonsillar B cells from control patients with tonsillitis. Clinically, aberrant APRIL expression in tonsillar GC correlated with greater proteinuria, and patients with IgAN and aberrant APRIL overexpression in tonsillar GC responded well to tonsillectomy, with parallel decreases in serum levels of galactose-deficient IgA1. Taken together, our data indicate that antibody disorders in IgAN associate with TLR9-induced aberrant expression of APRIL in tonsillar GC B cells.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Muto
authors.affiliation: Analytical Immunology for Chronic Pathologies, Albert Bonniot Institute, Institut National de la Santé et de la Recherche Médicale/University Joseph Fourier U823, Grenoble, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Manfroi
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Joh
authors.affiliation: Division of Nephrology and Diabetology, Narita Memorial Hospital, Toyohashi, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Nagai
authors.affiliation: Department of Internal Medicine, Tokyo Metropolitan Health and Medical Treatment Corporation, Okubo Hospital, Tokyo, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Wakai
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Grenoble University Hospital, Grenoble, France; and.
authors.forename: Christian
authors.initials: C
authors.lastname: Righini
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Maiguma
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
authors.forename: Shozo
authors.initials: S
authors.lastname: Izui
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tomino
authors.affiliation: Analytical Immunology for Chronic Pathologies, Albert Bonniot Institute, Institut National de la Santé et de la Recherche Médicale/University Joseph Fourier U823, Grenoble, France; yusuke@juntendo.ac.jp bertrand.huard@ujf-grenoble.fr.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Huard
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Juntendo University, Tokyo, Japan; yusuke@juntendo.ac.jp bertrand.huard@ujf-grenoble.fr.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Suzuki
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000378:metabolism*; D005260:Female; D018858:Germinal Center / Q000166:cytology* / Q000378:metabolism*; D005922:Glomerulonephritis, IGA / Q000209:etiology* / Q000378:metabolism*; D006801:Humans; D008297:Male; D014066:Palatine Tonsil; D051217:Toll-Like Receptor 9 / Q000502:physiology*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000096:biosynthesis*
chemical_list: C495371:TLR9 protein, human; C114631:TNFSF13 protein, human; D051217:Toll-Like Receptor 9; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13
keywords: IgA nephropathy; cytokines; immunology