Infection of the airways is a major cause of death worldwide and a persistent problem in critical care medicine. Mortality from airway infection is on the rise and thus there is an urgent need to develop alternative treatments. Innate response activator (IRA) B cells are a unique B cell population we recently discovered that protects against microbial sepsis. In a mouse abdominal sepsis model, peritoneal B1a B cells recognize bacteria with pattern recognition receptors, migrate to the spleen, differentiate to IRA B cells, and protect against overwhelming infection by mechanisms that involve the cytokine and growth factor GM-CS. IRA B cells, which we also identified in humans, are vital to how the host clears bacteria. We have now shown in preliminary experiments that B1a B cells and IRA B cells also reside in the pleural cavity. Mice lacking IRA B cells rapidly succumb to bacterial airway infection, fail to accumulate IgM-producing cells in the lungs, and fail to generate secretory IgM. Moreover, the pleural cavity is the source of IgMhigh B cells that accumulate in the lungs, whereas injection of pleural cavity IRA B cell precursors to the pleura of IRA B cell knockouts restores IgM responses and protects against bacterial infection. Here we will test the hypothesis that pleural cavity-derived IRA B cells control the generation and accumulation of natural antibody producing cells in the lung. IRA B cells, we propose, are essential coordinators of immune defense and protect against airway infection. The project is important because it is based on a strong phenotype and has clear translational potential and it is innovative because it explores the biology of a newly- discovered cell, identifies a previously unknown GM-CSF-IgM axis, and identifies the pleural cavity as an important hub for immune cells.

Public Health Relevance

Airway infection is a very serious condition that has a high mortality and is on the rise. Innate response activator (IRA) B cells are a newly discovered population of cells that protect against bacterial infection. IRA B cells develop in the pleural space, a region surrounding the lung that helps in respiration but that has unknown function in immunity. Experiments proposed in this grant will aim to unravel the role of pleural space IRA B cells in airway infection and will test whether IRA B cells can be used therapeutically.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI104695-01
Application #
8727137
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Davidson, Wendy F
Project Start
2013-09-05
Project End
2014-08-31
Budget Start
2013-09-05
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$402,747
Indirect Cost
$167,747
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Nahrendorf, Matthias; Swirski, Filip K (2014) Regulating repair: regulatory T cells in myocardial infarction. Circ Res 115:7-9
Pittet, Mikael J; Nahrendorf, Matthias; Swirski, Filip K (2014) The journey from stem cell to macrophage. Ann N Y Acad Sci 1319:1-18
Swirski, Filip K (2014) Monocyte recruitment and macrophage proliferation in atherosclerosis. Kardiol Pol 72:311-4
Kobzik, Lester; Swirski, Filip K (2014) MARCOing monocytes for elimination. Sci Transl Med 6:219fs4
Hilgendorf, Ingo; Gerhardt, Louisa M S; Tan, Timothy C et al. (2014) Ly-6Chigh monocytes depend on Nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium. Circ Res 114:1611-22
Nahrendorf, Matthias; Swirski, Filip K (2014) Fluorescent leukocytes enter plaque on the microscope stage. Circ Res 114:740-1
Swirski, Filip K; Nahrendorf, Matthias (2014) Do vascular smooth muscle cells differentiate to macrophages in atherosclerotic lesions? Circ Res 115:605-6
Weber, Georg F; Chousterman, Benjamin G; Hilgendorf, Ingo et al. (2014) Pleural innate response activator B cells protect against pneumonia via a GM-CSF-IgM axis. J Exp Med 211:1243-56