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

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 2

BeO exposure resulted in the formation of ectopic lymphoid aggregates (ELAs) and granulomatous inflammation in HLA-DP2–Tg mice.

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BeO exposure resulted in the formation of ectopic lymphoid aggregates (E...
HLA-DP2–Tg mice were exposed to BeO as described in Methods, lungs were harvested on day 21, and serial sections were analyzed by H&E and reticulin staining (A–D) or were analyzed by immunohistochemical staining for CD4 and B220 (E and F). BeO exposure of HLA-DP2–Tg mice induced ELAs (A and B) and granuloma formation (C and D) in the lungs of HLA-DP2–Tg mice (H&E stained in A and B; reticulin stained in C and D; original magnification, ×40). Yellow arrows in B and D depict the distribution of type IV collagen within the aggregates and granulomas, respectively. The yellow arrow in C depicts a multinucleated giant cell. (E) Immunohistochemical staining of CD4+ cells and (F) B220+ cells infiltrating the lungs of BeO-exposed HLA-DP2–Tg mice. Original magnification (E and F), ×2 (left) and ×20 (right). Histology images are representative of 5 to 6 animals per group from 3 independent experiments. Scale bars: 20 μm. The average size (G) and number (H) of ELAs in the lungs of BeO-exposed HLA-DP2–Tg mice are shown. Statistical significance was determined using a Student’s t test (2 tailed), and the solid lines and error bars depict the mean ± SEM. A P value of <0.05 was considered statistically significant.