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Protective role of B cells in sterile particulate–induced lung injury
Shaikh M. Atif, Douglas G. Mack, Amy S. McKee, Javier Rangel-Moreno, Allison K. Martin, Andrew Getahun, Lisa A. Maier, John C. Cambier, Rubin Tuder, Andrew P. Fontenot
Shaikh M. Atif, Douglas G. Mack, Amy S. McKee, Javier Rangel-Moreno, Allison K. Martin, Andrew Getahun, Lisa A. Maier, John C. Cambier, Rubin Tuder, Andrew P. Fontenot
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Research Article Immunology Pulmonology

Protective role of B cells in sterile particulate–induced lung injury

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Abstract

Susceptibility to chronic beryllium (Be) disease (CBD) is linked to HLA-DP molecules possessing a glutamic acid at the 69th position of the β-chain (βGlu69), with the most prevalent βGlu69-containing molecule being HLA-DP2. We have previously shown that HLA-DP2–transgenic (HLA-DP2–Tg) mice exposed to Be oxide (BeO) develop mononuclear infiltrates in a peribronchovascular distribution and a beryllium-specific, HLA-DP2–restricted CD4+ T cell response. In addition to T cells, B cells constituted a major portion of infiltrated leukocytes in the lung of BeO-exposed HLA-DP2–Tg mice and sequester BeO particles within ectopic lymphoid aggregates and granulomas. B cell depletion was associated with a loss of lymphoid aggregates and granulomas as well as a significant increase in lung injury in BeO-exposed mice. The protective role of B cells was innate in origin, and BeO-induced B cell recruitment to the lung was dependent on MyD88 signaling. Similar to BeO-exposed HLA-DP2–Tg mice, B cells also accumulate in the lungs of CBD subjects, located at the periphery and surrounding the granuloma. Overall, our data suggest what we believe is a novel modulatory role for B cells in the protection of the lung against sterile particulate exposure, with B cell recruitment to the inflamed lung occurring in an antigen-independent and MyD88-dependent manner.

Authors

Shaikh M. Atif, Douglas G. Mack, Amy S. McKee, Javier Rangel-Moreno, Allison K. Martin, Andrew Getahun, Lisa A. Maier, John C. Cambier, Rubin Tuder, Andrew P. Fontenot

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Figure 3

BeO exposure of HLA-DP2–Tg mice induced the formation of ectopic lymphoid aggregates (ELAs).

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BeO exposure of HLA-DP2–Tg mice induced the formation of ectopic lymphoi...
Representative multicolor immunofluorescence lung images of serial sections from HLA-DP2–Tg mice exposed to either BeO (A–D) or PBS (E–H) are shown. Original magnification, ×200. (A and E) Lung sections were stained for CXCL13 (red), FDC-M1 (green), and nuclei were stained with DAPI (blue). (A) FDC-M1+ cells with branched stromal cell morphology were not present; however, CXCL13+ cells with stromal cell morphology (white arrows) were located inside lymphoid aggregates of BeO-exposed mice. (E) CXCL13+ cells with monocyte/macrophage–like morphology (white arrows) were present in PBS-treated HLA-DP2–Tg mice in the absence of ELAs. (B and F) Lung sections were stained for expression of CXCL12 (green), PNAd/high endothelial venule (HEV) cells (red), lymphatic vessels/Lyve-1 (white), and with DAPI (blue). (B) ELAs with CXCL12+ (green) PNAd+ HEVs (orange asterisk), and Lyve-1+ lymphatics were present in BeO-treated HLA-DP2–Tg mice. (F) A small PNAd+ HEV and Lyve-1+ lymphatics in PBS-treated HLA-DP2–Tg mice are shown. (C and G) Lung sections were stained for expression of IgG (green), CD3 (red), B220 (white), and with DAPI (blue). (C) CD3+ T cells outside and inside of B220+ B cell aggregates in the lungs of BeO-treated HLA-DP2–Tg–mice are shown. (G) Few dispersed B220+ B cells and CD3+ T cells were seen in the PBS-treated HLA-DP2–Tg mice. (D and H) Lung sections were stained for expression of PCNA (red), PNA (green), B220 (white), and with DAPI (blue). (D) Large B cell blasts (PCNA+PNA+B220lo, yellow arrowheads) were present in B cell aggregates of BeO-treated HLA-DP2–Tg mice. (H) Rare B220+ B cells were seen in the small ELAs observed in PBS-treated HLA-DP2–Tg mice and were not expressing PCNA or PNA. Yellow scale bars: 100 μm.

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