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Pleural innate response activator B cells protect against pneumonia via a GM-CSF-IgM axis.

Weber GF, Chousterman BG, Hilgendorf I, Robbins CS, Theurl I, Gerhardt LM, Iwamoto Y, Quach TD, Ali M, Chen JW, Rothstein TL, Nahrendorf M, Weissleder R, Swirski FK - J. Exp. Med. (2014)

Bottom Line: We show that in response to lung infection, B1a B cells migrate from the pleural space to the lung parenchyma to secrete polyreactive emergency immunoglobulin M (IgM).The strategic location of these cells, coupled with the capacity to produce GM-CSF-dependent IgM, ensures effective early frontline defense against bacteria invading the lungs.The study describes a previously unrecognized GM-CSF-IgM axis and positions IRA B cells as orchestrators of protective IgM immunity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 Department of Visceral, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany fswirski@mgh.harvard.edu georg.weber@uniklinikum-dresden.de.

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IRA B cells in humans. (A) Human pleural B cells were placed in vitro for 2 d and stimulated with anti-Ig and IL-2. Data show the appearance of GM-CSF–producing, IRA-like B cells. (B) Fluorescence-minus-one (FMO) and isotype controls of stimulated human B cells. (C) Total B cells were collected from human pleural space, cord blood, and peripheral blood and cultured for 2 d either in medium or with anti-Ig and IL-2 stimulation. Data show quantity of IRA-like B cells appearing in each condition. (D) Total B cells from the pleural space were cultured as in C, and with anti–GM-CSF, anti-CD116, or a Stat5 inhibitor. Data show quantity of IRA-like B cells appearing in each condition (n = 4–15). Relevant data are presented as mean ± SD. ***, P < 0.001. (E) Model for the function of IRA B cells in mouse pneumonia. During airway infection pleural space B1a cells recognize bacteria or its components (1). This leads to the generation (2) of IRA B cells which produce GM-CSF and express the GM-CSF receptor. GM-CSF acts on its receptor in an autocrine (3) manner. The signaling orchestrates generation of IgM-producing cells (4) which relocate to the lung (5). IgM derived from pleural space B cells is essential to the control of bacteremia (6).
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fig10: IRA B cells in humans. (A) Human pleural B cells were placed in vitro for 2 d and stimulated with anti-Ig and IL-2. Data show the appearance of GM-CSF–producing, IRA-like B cells. (B) Fluorescence-minus-one (FMO) and isotype controls of stimulated human B cells. (C) Total B cells were collected from human pleural space, cord blood, and peripheral blood and cultured for 2 d either in medium or with anti-Ig and IL-2 stimulation. Data show quantity of IRA-like B cells appearing in each condition. (D) Total B cells from the pleural space were cultured as in C, and with anti–GM-CSF, anti-CD116, or a Stat5 inhibitor. Data show quantity of IRA-like B cells appearing in each condition (n = 4–15). Relevant data are presented as mean ± SD. ***, P < 0.001. (E) Model for the function of IRA B cells in mouse pneumonia. During airway infection pleural space B1a cells recognize bacteria or its components (1). This leads to the generation (2) of IRA B cells which produce GM-CSF and express the GM-CSF receptor. GM-CSF acts on its receptor in an autocrine (3) manner. The signaling orchestrates generation of IgM-producing cells (4) which relocate to the lung (5). IgM derived from pleural space B cells is essential to the control of bacteremia (6).

Mentions: Previously, we demonstrated that the human spleen contains a population of GM-CSF–producing IRA B-like cells (Rauch et al., 2012). To determine whether humans also contain, or can develop, IRA B-like cells in the pleural space, we obtained human pleural fluid by thoracentesis, and cultured B cells in either medium or a classical human B cell stimulation cocktail containing anti-Ig and IL-2. After 2 d of culture, human pleural CD19+ CD20+ IgM+ B cells produced GM-CSF (Fig. 10, A–C). The GM-CSF producers clustered in a single rather than bimodal distribution, suggesting indiscriminate activation in this in vitro setting. To reveal whether the appearance of IRA B-like cells was unique to the pleural space, we also cultured B cells from cord and peripheral blood. In the cord blood, which contains predominantly naive and transitional cells, a large GM-CSF–producing population likewise arose (Fig. 10 C). In contrast, culturing peripheral blood B cell did not stimulate GM-CSF production (Fig. 10 C), a result which supports the concept that IRA B cells arise in specific locations. Adding nontoxic doses of anti–GM-CSF, anti-CD116, or a STAT5 inhibitor to the culture containing pleural cells prevented the appearance of IRA B-like cells, further indicating an important role of the GM-CSF pathway (Fig. 10 D). Although further work is required to elucidate the similarities and differences between murine and human IRA B cells, these data nevertheless illustrate our current findings’ potential translatability. In sum, the production of GM-CSF by IRA B cells orchestrates the generation of protective IgM, which is critical in the early defense to infection (Fig. 10 E).


Pleural innate response activator B cells protect against pneumonia via a GM-CSF-IgM axis.

Weber GF, Chousterman BG, Hilgendorf I, Robbins CS, Theurl I, Gerhardt LM, Iwamoto Y, Quach TD, Ali M, Chen JW, Rothstein TL, Nahrendorf M, Weissleder R, Swirski FK - J. Exp. Med. (2014)

IRA B cells in humans. (A) Human pleural B cells were placed in vitro for 2 d and stimulated with anti-Ig and IL-2. Data show the appearance of GM-CSF–producing, IRA-like B cells. (B) Fluorescence-minus-one (FMO) and isotype controls of stimulated human B cells. (C) Total B cells were collected from human pleural space, cord blood, and peripheral blood and cultured for 2 d either in medium or with anti-Ig and IL-2 stimulation. Data show quantity of IRA-like B cells appearing in each condition. (D) Total B cells from the pleural space were cultured as in C, and with anti–GM-CSF, anti-CD116, or a Stat5 inhibitor. Data show quantity of IRA-like B cells appearing in each condition (n = 4–15). Relevant data are presented as mean ± SD. ***, P < 0.001. (E) Model for the function of IRA B cells in mouse pneumonia. During airway infection pleural space B1a cells recognize bacteria or its components (1). This leads to the generation (2) of IRA B cells which produce GM-CSF and express the GM-CSF receptor. GM-CSF acts on its receptor in an autocrine (3) manner. The signaling orchestrates generation of IgM-producing cells (4) which relocate to the lung (5). IgM derived from pleural space B cells is essential to the control of bacteremia (6).
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4042649&req=5

fig10: IRA B cells in humans. (A) Human pleural B cells were placed in vitro for 2 d and stimulated with anti-Ig and IL-2. Data show the appearance of GM-CSF–producing, IRA-like B cells. (B) Fluorescence-minus-one (FMO) and isotype controls of stimulated human B cells. (C) Total B cells were collected from human pleural space, cord blood, and peripheral blood and cultured for 2 d either in medium or with anti-Ig and IL-2 stimulation. Data show quantity of IRA-like B cells appearing in each condition. (D) Total B cells from the pleural space were cultured as in C, and with anti–GM-CSF, anti-CD116, or a Stat5 inhibitor. Data show quantity of IRA-like B cells appearing in each condition (n = 4–15). Relevant data are presented as mean ± SD. ***, P < 0.001. (E) Model for the function of IRA B cells in mouse pneumonia. During airway infection pleural space B1a cells recognize bacteria or its components (1). This leads to the generation (2) of IRA B cells which produce GM-CSF and express the GM-CSF receptor. GM-CSF acts on its receptor in an autocrine (3) manner. The signaling orchestrates generation of IgM-producing cells (4) which relocate to the lung (5). IgM derived from pleural space B cells is essential to the control of bacteremia (6).
Mentions: Previously, we demonstrated that the human spleen contains a population of GM-CSF–producing IRA B-like cells (Rauch et al., 2012). To determine whether humans also contain, or can develop, IRA B-like cells in the pleural space, we obtained human pleural fluid by thoracentesis, and cultured B cells in either medium or a classical human B cell stimulation cocktail containing anti-Ig and IL-2. After 2 d of culture, human pleural CD19+ CD20+ IgM+ B cells produced GM-CSF (Fig. 10, A–C). The GM-CSF producers clustered in a single rather than bimodal distribution, suggesting indiscriminate activation in this in vitro setting. To reveal whether the appearance of IRA B-like cells was unique to the pleural space, we also cultured B cells from cord and peripheral blood. In the cord blood, which contains predominantly naive and transitional cells, a large GM-CSF–producing population likewise arose (Fig. 10 C). In contrast, culturing peripheral blood B cell did not stimulate GM-CSF production (Fig. 10 C), a result which supports the concept that IRA B cells arise in specific locations. Adding nontoxic doses of anti–GM-CSF, anti-CD116, or a STAT5 inhibitor to the culture containing pleural cells prevented the appearance of IRA B-like cells, further indicating an important role of the GM-CSF pathway (Fig. 10 D). Although further work is required to elucidate the similarities and differences between murine and human IRA B cells, these data nevertheless illustrate our current findings’ potential translatability. In sum, the production of GM-CSF by IRA B cells orchestrates the generation of protective IgM, which is critical in the early defense to infection (Fig. 10 E).

Bottom Line: We show that in response to lung infection, B1a B cells migrate from the pleural space to the lung parenchyma to secrete polyreactive emergency immunoglobulin M (IgM).The strategic location of these cells, coupled with the capacity to produce GM-CSF-dependent IgM, ensures effective early frontline defense against bacteria invading the lungs.The study describes a previously unrecognized GM-CSF-IgM axis and positions IRA B cells as orchestrators of protective IgM immunity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 Department of Visceral, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany fswirski@mgh.harvard.edu georg.weber@uniklinikum-dresden.de.

Show MeSH
Related in: MedlinePlus