title: Modeling the dynamics and migratory pathways of virus-specific antibody-secreting cell populations in primary influenza infection.
abstract: The B cell response to influenza infection of the respiratory tract contributes to viral clearance and establishes profound resistance to reinfection by related viruses. Numerous studies have measured virus-specific antibody-secreting cell (ASC) frequencies in different anatomical compartments after influenza infection and provided a general picture of the kinetics of ASC formation and dispersion. However, the dynamics of ASC populations are difficult to determine experimentally and have received little attention. Here, we applied mathematical modeling to investigate the dynamics of ASC growth, death, and migration over the 2-week period following primary influenza infection in mice. Experimental data for model fitting came from high frequency measurements of virus-specific IgM, IgG, and IgA ASCs in the mediastinal lymph node (MLN), spleen, and lung. Model construction was based on a set of assumptions about ASC gain and loss from the sampled sites, and also on the directionality of ASC trafficking pathways. Most notably, modeling results suggest that differences in ASC fate and trafficking patterns reflect the site of formation and the expressed antibody class. Essentially all early IgA ASCs in the MLN migrated to spleen or lung, whereas cell death was likely the major reason for IgM and IgG ASC loss from the MLN. In contrast, the spleen contributed most of the IgM and IgG ASCs that migrated to the lung, but essentially none of the IgA ASCs. This finding points to a critical role for regional lymph nodes such as the MLN in the rapid generation of IgA ASCs that seed the lung. Results for the MLN also suggest that ASC death is a significant early feature of the B cell response. Overall, our analysis is consistent with accepted concepts in many regards, but it also indicates novel features of the B cell response to influenza that warrant further investigation.
authors.affiliation: Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Miao
authors.affiliation: David H. Smith Center for Vaccine Biology & Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Mark Y
authors.initials: MY
authors.lastname: Sangster
authors.affiliation: David H. Smith Center for Vaccine Biology & Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Livingstone
authors.affiliation: Department of Medicine, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Shannon P
authors.initials: SP
authors.lastname: Hilchey
authors.affiliation: Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Le
authors.initials: L
authors.lastname: Zhang
authors.affiliation: David H. Smith Center for Vaccine Biology & Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Topham
authors.affiliation: David H. Smith Center for Vaccine Biology & Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Tim R
authors.initials: TR
authors.lastname: Mosmann
authors.affiliation: Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Holden-Wiltse
authors.affiliation: Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Perelson
authors.affiliation: Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Hulin
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Medicine, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Zand
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D000921:Antibody-Producing Cells / Q000166:cytology / Q000276:immunology* / Q000821:virology; D002465:Cell Movement; D003198:Computer Simulation; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000821:virology; D008198:Lymph Nodes / Q000276:immunology / Q000821:virology; D051379:Mice / Q000276:immunology / Q000821:virology*; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D009975:Orthomyxoviridae / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000662:veterinary; D013154:Spleen / Q000276:immunology / Q000821:virology
chemical_list: D000914:Antibodies, Viral; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M