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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 protect against pneumonia. (A) Clinical score of WT, WT receiving anti-CD116, µMT, WT/µMT, GM/WT, and GM/µMT mice 9 h after infection with E. coli (n = 5–10 mice). (B) Body temperature of the groups above. (C) Bacterial titer in BAL after E. coli infection of WT, WT receiving anti-CD116, µMT, WT/µMT, GM/WT, and GM/µMT mice (n = 5–10 mice). (D) Kaplan-Meier survival curves after S. pneumoniae i.t. infection for WT/µMT, GM/WT, and GM/µMT mice (n = 8–10). Relevant data are presented as mean ± SD and tested by ANOVA; *, P < 0.05; **, P < 0.01; ***, P < 0.001.
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fig5: IRA B cells protect against pneumonia. (A) Clinical score of WT, WT receiving anti-CD116, µMT, WT/µMT, GM/WT, and GM/µMT mice 9 h after infection with E. coli (n = 5–10 mice). (B) Body temperature of the groups above. (C) Bacterial titer in BAL after E. coli infection of WT, WT receiving anti-CD116, µMT, WT/µMT, GM/WT, and GM/µMT mice (n = 5–10 mice). (D) Kaplan-Meier survival curves after S. pneumoniae i.t. infection for WT/µMT, GM/WT, and GM/µMT mice (n = 8–10). Relevant data are presented as mean ± SD and tested by ANOVA; *, P < 0.05; **, P < 0.01; ***, P < 0.001.

Mentions: After reconstitution, we infected GM/µMT, WT/µMT, and GM/WT mice with Escherichia coli. Although E. coli are not the predominant pneumonia-causing pathogen, they are Gram-negative, LPS-bearing bacteria and are responsible for a significant proportion of hospital-acquired pneumonias (Williams et al., 2002; Klevens et al., 2007; Scott et al., 2008; Esperatti et al., 2010; Jones, 2010; Magret et al., 2011; Venkatachalam et al., 2011). We monitored infected mice for morbidity and bacterial titer. As additional controls, we infected WT, B cell–deficient µMT mice (i.e., nonirradiated, nonchimeric), and WT mice that received anti-CD116 intrapleurally (i.e., anti–GM-CSFRα, the subunit of the GM-CSF receptor which is specific to GM-CSF; the antibody has been reported to be neutralizing). Three groups of mice—µMT, WT receiving anti-CD116, and chimeric GM/µMT (i.e., IRA KO)—became very morbid (Fig. 5 A), hypothermic (Fig. 5 B), and had increased bacterial counts in the BAL (Fig. 5 C). In contrast, WT mice and the two chimeric controls were more resistant to infection. The data show that B cell–derived GM-CSF is important and beneficial to the early response to airway infection. The similarity between µMT and GM/µMT mice in failing to protect against infection illustrates that GM-CSF production by B cells is an essential component of the overall B cell response at this early time point. Blocking CD116, GM-CSF’s specific receptor subunit, confirmed that GM-CSF signaling is important in WT mice in vivo. We also wondered whether the key finding that IRA B cells are protective was specific to E. coli or might also apply to other bacterial pathogens. GM/µMT mice infected with Streptococcus pneumoniae, a major cause of disease in humans worldwide and the primary pathogen responsible for pneumonia (Mizgerd, 2008), died earlier and in larger numbers than controls (Fig. 5 D). These data underscore the importance of IRA B cells in pneumonia, thereby prompting us to delve further into these protective processes.


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 protect against pneumonia. (A) Clinical score of WT, WT receiving anti-CD116, µMT, WT/µMT, GM/WT, and GM/µMT mice 9 h after infection with E. coli (n = 5–10 mice). (B) Body temperature of the groups above. (C) Bacterial titer in BAL after E. coli infection of WT, WT receiving anti-CD116, µMT, WT/µMT, GM/WT, and GM/µMT mice (n = 5–10 mice). (D) Kaplan-Meier survival curves after S. pneumoniae i.t. infection for WT/µMT, GM/WT, and GM/µMT mice (n = 8–10). Relevant data are presented as mean ± SD and tested by ANOVA; *, P < 0.05; **, P < 0.01; ***, P < 0.001.
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Related In: Results  -  Collection

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fig5: IRA B cells protect against pneumonia. (A) Clinical score of WT, WT receiving anti-CD116, µMT, WT/µMT, GM/WT, and GM/µMT mice 9 h after infection with E. coli (n = 5–10 mice). (B) Body temperature of the groups above. (C) Bacterial titer in BAL after E. coli infection of WT, WT receiving anti-CD116, µMT, WT/µMT, GM/WT, and GM/µMT mice (n = 5–10 mice). (D) Kaplan-Meier survival curves after S. pneumoniae i.t. infection for WT/µMT, GM/WT, and GM/µMT mice (n = 8–10). Relevant data are presented as mean ± SD and tested by ANOVA; *, P < 0.05; **, P < 0.01; ***, P < 0.001.
Mentions: After reconstitution, we infected GM/µMT, WT/µMT, and GM/WT mice with Escherichia coli. Although E. coli are not the predominant pneumonia-causing pathogen, they are Gram-negative, LPS-bearing bacteria and are responsible for a significant proportion of hospital-acquired pneumonias (Williams et al., 2002; Klevens et al., 2007; Scott et al., 2008; Esperatti et al., 2010; Jones, 2010; Magret et al., 2011; Venkatachalam et al., 2011). We monitored infected mice for morbidity and bacterial titer. As additional controls, we infected WT, B cell–deficient µMT mice (i.e., nonirradiated, nonchimeric), and WT mice that received anti-CD116 intrapleurally (i.e., anti–GM-CSFRα, the subunit of the GM-CSF receptor which is specific to GM-CSF; the antibody has been reported to be neutralizing). Three groups of mice—µMT, WT receiving anti-CD116, and chimeric GM/µMT (i.e., IRA KO)—became very morbid (Fig. 5 A), hypothermic (Fig. 5 B), and had increased bacterial counts in the BAL (Fig. 5 C). In contrast, WT mice and the two chimeric controls were more resistant to infection. The data show that B cell–derived GM-CSF is important and beneficial to the early response to airway infection. The similarity between µMT and GM/µMT mice in failing to protect against infection illustrates that GM-CSF production by B cells is an essential component of the overall B cell response at this early time point. Blocking CD116, GM-CSF’s specific receptor subunit, confirmed that GM-CSF signaling is important in WT mice in vivo. We also wondered whether the key finding that IRA B cells are protective was specific to E. coli or might also apply to other bacterial pathogens. GM/µMT mice infected with Streptococcus pneumoniae, a major cause of disease in humans worldwide and the primary pathogen responsible for pneumonia (Mizgerd, 2008), died earlier and in larger numbers than controls (Fig. 5 D). These data underscore the importance of IRA B cells in pneumonia, thereby prompting us to delve further into these protective processes.

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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Related in: MedlinePlus