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Single-cell transcriptome mapping identifies a local, innate B cell population driving chronic rejection after lung transplantation
Natalia F. Smirnova, … , Nirmal S. Sharma, Oliver Eickelberg
Natalia F. Smirnova, … , Nirmal S. Sharma, Oliver Eickelberg
Published September 22, 2022
Citation Information: JCI Insight. 2022;7(18):e156648. https://doi.org/10.1172/jci.insight.156648.
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Resource and Technical Advance Pulmonology Transplantation

Single-cell transcriptome mapping identifies a local, innate B cell population driving chronic rejection after lung transplantation

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Abstract

Bronchiolitis obliterans syndrome (BOS) is the main reason for poor outcomes after lung transplantation (LTx). We and others have recently identified B cells as major contributors to BOS after LTx. The extent of B cell heterogeneity and the relative contributions of B cell subpopulations to BOS, however, remain unclear. Here, we provide a comprehensive analysis of cell population changes and their gene expression patterns during chronic rejection after orthotopic LTx in mice. Of 11 major cell types, Mzb1-expressing plasma cells (PCs) were the most prominently increased population in BOS lungs. These findings were validated in 2 different cohorts of human BOS after LTx. A Bhlhe41, Cxcr3, and Itgb1 triple-positive B cell subset, also expressing classical markers of the innate-like B-1 B cell population, served as the progenitor pool for Mzb1+ PCs. This subset accounted for the increase in IgG2c production within BOS lung grafts. A genetic lack of Igs decreased BOS severity after LTx. In summary, we provide a detailed analysis of cell population changes during BOS. IgG+ PCs and their progenitors — an innate B cell subpopulation — are the major source of local Ab production and a significant contributor to BOS after LTx.

Authors

Natalia F. Smirnova, Kent Riemondy, Marta Bueno, Susan Collins, Pavan Suresh, Xingan Wang, Kapil N. Patel, Carlyne Cool, Melanie Königshoff, Nirmal S. Sharma, Oliver Eickelberg

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Figure 7

Genetic deficiency in Ab production partially protects murine lungs against the development of BOS signs.

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Genetic deficiency in Ab production partially protects murine lungs agai...
Lung grafts from HLA donors were orthotopically transplanted into Aicda+/+ and Aicda–/– littermates on a B6 background (HLA→Aicda+/+ and HLA→Aicda–/–) and analyzed 1 month later. Naive nontransplanted Aicda+/– mice were used as baseline controls. (A) Measurement of the lung function of the left lung grafts after clamping the right bronchus. (B) Representative histology after Masson trichrome (MTC) staining and quantification of the peribronchial fibrosis area, normalized to the basement membrane (BM) length. Scale bars, 100 μm. (C) Immunofluorescence staining for MZB1+ and CC10+ (club cell 10 kDa protein-positive) cells, and quantification of CC10+ cells normalized to the basement membrane length. Scale bars, 100 μm. Data are expressed as mean ± SEM and analyzed with a 1-way ANOVA followed by a Tukey’s multiple comparisons test. *P < 0.05, **P < 0.01. px, pixel.

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ISSN 2379-3708

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