Long-lived plasma cells (LLPC) sustain protective antibody production for a lifetime but the identity of the cellular source of human LLPC has eluded us for decades. In our lab, we have definitively linked the long-lived viral serum antibody source to a single cellular compartment within the human bone marrow (BM). The PC specificities concentrate in these unique long-lived viral specificities from exposures that occurred over 40-60 years ago. In this application, we will study the survival mechanisms of human BM LLPC by (1) understanding the ontogeny and survival of the short-lived PC and the LLPC, (2) testing the intrinsic molecular mechanisms of LLPC survival, and (3) defining the unique metabolic signatures of LLPC. The significance of this work is several-fold from understanding the means of generation to the mechanisms of maintenance (or survival) of human LLPC. It will provide insights to designing vaccine adjuvants, developing novel targets of pathogenic plasma cells in diseases such as autoimmunity, allergy, and transplantation (sparing protective LLPC), and offering novel diagnostic testing and drug pathways to treat multiple myeloma (oncology).

Public Health Relevance

Long-lived plasma cells (LLPC) sustain protective antibody production for a lifetime but the identity of the cellular source of human LLPC has eluded us for decades; but in our lab, we have definitively linked the long- lived viral serum antibody source to a single cellular compartment within the human bone marrow (BM) CD19- CD138+CD38hi. The long-lived viral specificities from exposures that occurred over 40-60 years ago concentrate in these PC compartments. In this application, we will study the survival mechanisms of these newly identified human BM LLPC by (1) understanding the ontogeny and survival of the short-lived PC compared to the LLPC, (2) testing the intrinsic molecular mechanisms of LLPC survival, and (3) defining the unique metabolic signatures of LLPC.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI121252-01
Application #
9008805
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Ferguson, Stacy E
Project Start
2016-01-01
Project End
2020-12-31
Budget Start
2016-01-01
Budget End
2016-12-31
Support Year
1
Fiscal Year
2016
Total Cost
$390,000
Indirect Cost
$140,000
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Nguyen, Doan C; Lewis, Holly C; Joyner, Chester et al. (2018) Extracellular vesicles from bone marrow-derived mesenchymal stromal cells support ex vivo survival of human antibody secreting cells. J Extracell Vesicles 7:1463778
Jenks, Scott A; Cashman, Kevin S; Zumaquero, Esther et al. (2018) Distinct Effector B Cells Induced by Unregulated Toll-like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus. Immunity 49:725-739.e6
Forrest, Osric A; Ingersoll, Sarah A; Preininger, Marcela K et al. (2018) Frontline Science: Pathological conditioning of human neutrophils recruited to the airway milieu in cystic fibrosis. J Leukoc Biol 104:665-675
Nguyen, Doan C; Garimalla, Swetha; Xiao, Haopeng et al. (2018) Factors of the bone marrow microniche that support human plasma cell survival and immunoglobulin secretion. Nat Commun 9:3698
Roumanes, D; Falsey, A R; Quataert, S et al. (2018) T-Cell Responses in Adults During Natural Respiratory Syncytial Virus Infection. J Infect Dis 218:418-428
Upadhyay, Amit A; Kauffman, Robert C; Wolabaugh, Amber N et al. (2018) BALDR: a computational pipeline for paired heavy and light chain immunoglobulin reconstruction in single-cell RNA-seq data. Genome Med 10:20
Kuruvilla, Merin E; Lee, F Eun-Hyung; Lee, Gerald B (2018) Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease. Clin Rev Allergy Immunol :
Corrado, Alessia; Battle, Monica; Wise, Sarah K et al. (2018) Endocannabinoid receptor CB2R is significantly expressed in aspirin-exacerbated respiratory disease: a pilot study. Int Forum Allergy Rhinol 8:1184-1189
D'Angio, Carl T; Wyman, Claire P; Misra, Ravi S et al. (2017) Plasma cell and serum antibody responses to influenza vaccine in preterm and full-term infants. Vaccine 35:5163-5171