Long-Lived Plasma Cells Are Contained within the CD19(-)CD38(hi)CD138(+) Subset in Human Bone Marrow.

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.

[1]  F. Mora-López,et al.  Increased survival is a selective feature of human circulating antigen-induced plasma cells synthesizing high-affinity antibodies. , 2008, Blood.

[2]  S. Tangye,et al.  Increased Expression of CD27 on Activated Human Memory B Cells Correlates with Their Commitment to the Plasma Cell Lineage1 , 2005, The Journal of Immunology.

[3]  M. Zand,et al.  CpG DNA activation and plasma-cell differentiation of CD27- naive human B cells. , 2007, Blood.

[4]  R. Scheuermann,et al.  Elucidation of seventeen human peripheral blood B‐cell subsets and quantification of the tetanus response using a density‐based method for the automated identification of cell populations in multidimensional flow cytometry data , 2010, Cytometry. Part B, Clinical cytometry.

[5]  Nichole E Carlson,et al.  Duration of humoral immunity to common viral and vaccine antigens. , 2007, The New England journal of medicine.

[6]  Kenneth G. C. Smith,et al.  Competence and competition: the challenge of becoming a long-lived plasma cell , 2006, Nature Reviews Immunology.

[7]  R. Ahmed,et al.  Long-lived plasma cells: a mechanism for maintaining persistent antibody production. , 1998, Current opinion in immunology.

[8]  Mark M. Davis,et al.  Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells , 1994, Cell.

[9]  Andreas Radbruch,et al.  Chemotactic Responsiveness Toward Ligands for CXCR3 and CXCR4 Is Regulated on Plasma Blasts During the Time Course of a Memory Immune Response1 , 2002, The Journal of Immunology.

[10]  D. Tough,et al.  B-cell kinetics in humans: rapid turnover of peripheral blood memory cells. , 2005, Blood.

[11]  F. Miller.  THE INDUCED DEVELOPMENT AND HISTOGENESIS OF PLASMA CELLS , 1931, The Journal of experimental medicine.

[12]  Andreas Radbruch,et al.  Plasma Cell Survival Is Mediated by Synergistic Effects of Cytokines and Adhesion-Dependent Signals1 , 2003, The Journal of Immunology.

[13]  E. Walsh,et al.  Peak frequencies of circulating human influenza-specific antibody secreting cells correlate with serum antibody response after immunization. , 2010, Vaccine.

[14]  A. Campos-Caro,et al.  The heterogeneity shown by human plasma cells from tonsil, blood, and bone marrow reveals graded stages of increasing maturity, but local profiles of adhesion molecule expression. , 2002, Blood.

[15]  R. Lamb,et al.  Orthomyxoviridae: The Viruses and Their Replication. , 1996 .

[16]  K. Fairfax,et al.  Plasma cell development: from B-cell subsets to long-term survival niches. , 2008, Seminars in immunology.

[17]  K. Tarte,et al.  Characterization of a Transitional Preplasmablast Population in the Process of Human B Cell to Plasma Cell Differentiation , 2011, The Journal of Immunology.

[18]  A. Chanan-Khan,et al.  Sustained antibody responses depend on CD28 function in bone marrow–resident plasma cells , 2011, The Journal of experimental medicine.

[19]  S. Casola,et al.  Plasma cells require autophagy for sustainable immunoglobulin production , 2013, Nature Immunology.

[20]  G. Morgan,et al.  Flow cytometric disease monitoring in multiple myeloma: the relationship between normal and neoplastic plasma cells predicts outcome after transplantation. , 2002, Blood.

[21]  Patrice Duroux,et al.  IMGT/HIGHV-QUEST: THE IMGT® WEB PORTAL FOR IMMUNOGLOBULIN (IG) OR ANTIBODY AND T CELL RECEPTOR (TR) ANALYSIS FROM NGS HIGH THROUGHPUT AND DEEP SEQUENCING , 2012 .

[22]  R. Geha,et al.  Cutting Edge: The Dependence of Plasma Cells and Independence of Memory B Cells on BAFF and APRIL1 , 2008, The Journal of Immunology.

[23]  R. Mcmillan,et al.  Immunoglobulin synthesis by human lymphoid tissues: normal bone marrow as a major site of IgG production. , 1972, Journal of immunology.

[24]  Sean A Beausoleil,et al.  Proteomics-directed cloning of circulating antiviral human monoclonal antibodies , 2012, Nature Biotechnology.

[25]  D. Isenberg,et al.  B cell depletion therapy in systemic lupus erythematosus: effect on autoantibody and antimicrobial antibody profiles. , 2006, Arthritis and rheumatism.

[26]  John D. Storey.  A direct approach to false discovery rates , 2002 .

[27]  Hongmei Yang,et al.  Frequencies of human influenza-specific antibody secreting cells or plasmablasts post vaccination from fresh and frozen peripheral blood mononuclear cells. , 2009, Journal of immunological methods.

[28]  James E. Crowe,et al.  Neutralizing antibodies derived from the B cells of 1918 influenza pandemic survivors , 2008, Nature.

[29]  J. Grün,et al.  A unique population of IgG-expressing plasma cells lacking CD19 is enriched in human bone marrow. , 2015, Blood.

[30]  M. Hibbs,et al.  Plasma cell development and survival , 2010, Immunological reviews.

[31]  D. Skowronski,et al.  Rapid decline of influenza vaccine-induced antibody in the elderly: is it real, or is it relevant? , 2008, The Journal of infectious diseases.

[32]  Patrick C. Wilson,et al.  Rapid cloning of high-affinity human monoclonal antibodies against influenza virus , 2008, Nature.

[33]  Steven J. M. Jones,et al.  Circos: an information aesthetic for comparative genomics. , 2009, Genome research.

[34]  L. Medeiros,et al.  Immunophenotypic heterogeneity of normal plasma cells: comparison with minimal residual plasma cell myeloma , 2012, Journal of Clinical Pathology.

[35]  G. Jiménez-Gómez,et al.  Immunization-Induced Perturbation of Human Blood Plasma Cell Pool: Progressive Maturation, IL-6 Responsiveness, and High PRDI-BF1/BLIMP1 Expression Are Critical Distinctions between Antigen-Specific and Nonspecific Plasma Cells1 , 2006, The Journal of Immunology.

[36]  D. Kelly,et al.  CRM197-conjugated serogroup C meningococcal capsular polysaccharide, but not the native polysaccharide, induces persistent antigen-specific memory B cells. , 2006, Blood.

[37]  C. Berek,et al.  Generation of migratory antigen-specific plasma blasts and mobilization of resident plasma cells in a secondary immune response. , 2005, Blood.

[38]  Sean A Beausoleil,et al.  A proteomics approach for the identification and cloning of monoclonal antibodies from serum , 2012, Nature Biotechnology.

[39]  M. Slifka,et al.  Mechanisms that determine plasma cell lifespan and the duration of humoral immunity , 2010, Immunological reviews.

[40]  T. Waldmann,et al.  Metabolic properties of IgG subclasses in man. , 1970, The Journal of clinical investigation.

[41]  Andreas Radbruch,et al.  Lifetime of plasma cells in the bone marrow , 1997, Nature.

[42]  F. E. Lee,et al.  Antibodies Against Conserved Antigens Provide Opportunities for Reform in Influenza Vaccine Design , 2011, Front. Immun..

[43]  S. Rudikoff,et al.  Interleukin 6 is essential for in vivo development of B lineage neoplasms , 1995, The Journal of experimental medicine.

[44]  Mark J. Shlomchik,et al.  Maintenance of the plasma cell pool is independent of memory B cells , 2008, Proceedings of the National Academy of Sciences.

[45]  Kenneth G. C. Smith,et al.  FcγRIIb controls bone marrow plasma cell persistence and apoptosis , 2007, Nature Immunology.

[46]  J. Cyster,et al.  A Coordinated Change in Chemokine Responsiveness Guides Plasma Cell Movements , 2001, The Journal of experimental medicine.

[47]  Kenneth G. C. Smith,et al.  FcgammaRIIb controls bone marrow plasma cell persistence and apoptosis. , 2007, Nature immunology.

[48]  E. Walsh,et al.  Circulating Human Antibody-Secreting Cells during Vaccinations and Respiratory Viral Infections Are Characterized by High Specificity and Lack of Bystander Effect , 2011, The Journal of Immunology.

[49]  Antonio Lanzavecchia,et al.  Maintenance of Serological Memory by Polyclonal Activation of Human Memory B Cells , 2002, Science.

[50]  Dan R. Littman,et al.  The Role of CXCR4 in Maintaining Peripheral B Cell Compartments and Humoral Immunity , 2004, The Journal of experimental medicine.

[51]  S. Ely,et al.  CDK inhibitor p18(INK4c) is required for the generation of functional plasma cells. , 2002, Immunity.