title: B-cell signaling in persistent polyclonal B lymphocytosis (PPBL).
abstract: Persistent polyclonal B lymphocytosis (PPBL) is a benign hematological disorder characterized by a selective expansion of circulating polyclonal marginal zone (MZ)-like B cells. Previous reports demonstrated that cases of PPBL showed poor activation, proliferation and survival of B cells in vitro, yet the underlying defect remains unknown. Here we report for the first time an attenuated activation of the canonical NF-κB (nuclear factor of kappa light polypeptide gene enhancer in B cells) and mitogen-activated protein kinase/extracellular signal-regulated kinase pathway after CD40 stimulation. This defect was selective, as alternative NF-κB signaling after CD40 stimulation and both B-cell receptor- and Toll-like receptor 9-mediated activation remained unaffected. Reduced canonical NF-κB activation resulted in decreased IκBα and CD40 expression in resting cells. In PPBL patients, expression of Bcl-xL in MZ-like B cells did not increase upon activation, consistent with the high apoptosis rates of PPBL-derived B cells that were observed in vitro. The B-cell phenotype of mice with selective knockouts of early components of the CD40 signaling pathway resembles PPBL, but sequencing corresponding genes in sorted MZ-like B cells of PPBL patients did not reveal relevant genetic alterations. Nevertheless, the frequently observed mutations in early signaling components of the NF-κB pathway in MZ lymphomas underline the relevance of our findings for the pathogenesis of PPBL.
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Voelxen
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.|Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wehr
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Gutenberger
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Baerbel
authors.initials: B
authors.lastname: Keller
authors.affiliation: Division of Pediatric Hematology and Oncology, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Erlacher
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Dominguez-Conde
authors.affiliation: Division of Pediatric Hematology and Oncology, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bertele
authors.affiliation: Institute for Cell and Gene Therapy, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Emmerich
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Milena
authors.initials: M
authors.lastname: Pantic
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Jennings
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Mirzokhid
authors.initials: M
authors.lastname: Rakhmanov
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Foerster
authors.affiliation: Department of Hematology and Oncology, SLK-Klinikum am Gesundbrunnen, Heilbronn, Germany.
authors.forename: Uwe M
authors.initials: UM
authors.lastname: Martens
authors.affiliation: University Medical Center and Polyclinic I, Dresden, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Platzbecker
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Hans-Hartmut
authors.initials: HH
authors.lastname: Peter
authors.affiliation: Institute of Pathology, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Fisch
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Kaan
authors.initials: K
authors.lastname: Boztug
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Eibel
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Salzer
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Warnatz
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism; D002675:Child, Preschool; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008218:Lymphocytosis / Q000235:genetics / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D019013:CD40 Antigens; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell; D048049:Extracellular Signal-Regulated MAP Kinases