title: Long-Lived Plasma Cells Are Contained within the CD19(-)CD38(hi)CD138(+) Subset in Human Bone Marrow.
abstract: Antibody responses to viral infections are sustained for decades by long-lived plasma cells (LLPCs). However, LLPCs have yet to be characterized in humans. Here we used CD19, CD38, and CD138 to identify four PC subsets in human bone marrow (BM). We found that the CD19(-)CD38(hi)CD138(+) subset was morphologically distinct, differentially expressed PC-associated genes, and exclusively contained PCs specific for viral antigens to which the subjects had not been exposed for more than 40 years. Protein sequences of measles- and mumps-specific circulating antibodies were encoded for by CD19(-)CD38(hi)CD138(+) PCs in the BM. Finally, we found that CD19(-)CD38(hi)CD138(+) PCs had a distinct RNA transcriptome signature and human immunoglobulin heavy chain (VH) repertoire that was relatively uncoupled from other BM PC subsets and probably represents the B cell response's "historical record" of antigenic exposure. Thus, our studies define human LLPCs and provide a mechanism for the life-long maintenance of anti-viral antibodies in the serum.
authors.affiliation: Divisions of Pulmonary, Allergy, & Critical Care Medicine, Emory University, Atlanta, GA 30322, USA; Pulmonary & Critical Care Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Halliley
authors.affiliation: Division of Rheumatology, Emory University, Atlanta, GA 30322, USA; Lowance Center for Human Immunology in the Departments of Medicine and Pediatrics, Emory University, Atlanta, GA 30322, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Tipton
authors.affiliation: Divisions of Hematology/Oncology/James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Liesveld
authors.affiliation: Division of Allergy, Immunology, and Rheumatology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Rosenberg
authors.affiliation: Cell Signaling Technology, Inc., Danvers, MA 01923, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Darce
authors.affiliation: Cell Signaling Technology, Inc., Danvers, MA 01923, USA.
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Gregoretti
authors.affiliation: Cell Signaling Technology, Inc., Danvers, MA 01923, USA.
authors.forename: Lana
authors.initials: L
authors.lastname: Popova
authors.affiliation: Division of Allergy, Immunology, and Rheumatology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Kaminiski
authors.affiliation: Division of Allergy, Immunology, and Rheumatology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Fucile
authors.affiliation: Divisions of Pulmonary, Allergy, & Critical Care Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Albizua
authors.affiliation: Divisions of Pulmonary, Allergy, & Critical Care Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Shuya
authors.initials: S
authors.lastname: Kyu
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA 30322, USA.
authors.forename: Kuang-Yueh
authors.initials: KY
authors.lastname: Chiang
authors.affiliation: Department of Pathology & Laboratory Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Kyle T
authors.initials: KT
authors.lastname: Bradley
authors.affiliation: Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Burack
authors.affiliation: Oregon Health & Sciences University, Beaverton, OR 97006, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Slifka
authors.affiliation: Oregon Health & Sciences University, Beaverton, OR 97006, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Hammarlund
authors.affiliation: Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA 30322, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA 30322, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Division of Infectious Diseases, University of Rochester Medical Center & Rochester General Hospital, Rochester, NY 14621, USA.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Walsh
authors.affiliation: Division of Infectious Diseases, University of Rochester Medical Center & Rochester General Hospital, Rochester, NY 14621, USA.
authors.forename: Ann R
authors.initials: AR
authors.lastname: Falsey
authors.affiliation: Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Troy D
authors.initials: TD
authors.lastname: Randall
authors.affiliation: Cell Signaling Technology, Inc., Danvers, MA 01923, USA.
authors.forename: Wan Cheung
authors.initials: WC
authors.lastname: Cheung
authors.affiliation: Division of Rheumatology, Emory University, Atlanta, GA 30322, USA; Lowance Center for Human Immunology in the Departments of Medicine and Pediatrics, Emory University, Atlanta, GA 30322, USA.
authors.forename: Iñaki
authors.initials: I
authors.lastname: Sanz
authors.affiliation: Divisions of Pulmonary, Allergy, & Critical Care Medicine, Emory University, Atlanta, GA 30322, USA; Lowance Center for Human Immunology in the Departments of Medicine and Pediatrics, Emory University, Atlanta, GA 30322, USA. Electronic address: f.e.lee@emory.edu.
authors.forename: F Eun-Hyung
authors.initials: FE
authors.lastname: Lee
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology*; D018941:Antigens, CD19 / Q000378:metabolism; D001854:Bone Marrow Cells / Q000276:immunology*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D008459:Measles virus / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D009109:Mumps virus / Q000276:immunology*; D010950:Plasma Cells / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D053668:Syndecan-1 / Q000378:metabolism; D055815:Young Adult
chemical_list: D000914:Antibodies, Viral; D018941:Antigens, CD19; D007143:Immunoglobulin Heavy Chains; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C508241:SDC1 protein, human; D053668:Syndecan-1; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1
keywords: antibody secreting cells; bone marrow; heterogeneity; human; long-lived plasma cells; measles; mumps infection; next generation sequencing; plasma cells; plasmablasts; proteomics; vaccine