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Extrafollicular IgD^-CD27^-CXCR5^-CD11c^- DN3 B cells infiltrate inflamed tissues in autoimmune fibrosis and in severe COVID-19.

ABSTRACT: Although therapeutic B cell depletion dramatically resolves inflammation in many diseases in which antibodies appear not to play a central role, distinct extrafollicular pathogenic B cell subsets that accumulate in disease lesions have hitherto not been identified. The circulating immunoglobulin D (IgD)^-CD27^-CXCR5^-CD11c⁺ DN2 B cell subset has been previously studied in some autoimmune diseases. A distinct IgD^-CD27^-CXCR5^-CD11c^- DN3 B cell subset accumulates in the blood both in IgG4-related disease, an autoimmune disease in which inflammation and fibrosis can be reversed by B cell depletion, and in severe COVID-19. These DN3 B cells prominently accumulate in the end organs of IgG4-related disease and in lung lesions in COVID-19, and double-negative B cells prominently cluster with CD4⁺ T cells in these lesions. Extrafollicular DN3 B cells may participate in tissue inflammation and fibrosis in autoimmune fibrotic diseases, as well as in COVID-19.

SUBMITTER: Allard-Chamard H

PROVIDER: S-EPMC10227203 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Extrafollicular IgD-CD27-CXCR5-CD11c- DN3 B cells infiltrate inflamed tissues in autoimmune fibrosis and in severe COVID-19.

Allard-Chamard Hugues H Kaneko Naoki N Bertocchi Alice A Sun Na N Boucau Julie J Kuo Hsiao-Hsuan HH Farmer Jocelyn R JR Perugino Cory C Mahajan Vinay S VS Murphy Samuel J H SJH Premo Katherine K Diefenbach Thomas T Ghebremichael Musie M Yuen Grace G Kotta Alekhya A Akman Zafer Z Lichterfeld Mathias M Walker Bruce D BD Yu Xu G XG Moriyama Masafumi M Maehara Takashi T Nakamura Seiji S Stone John H JH Padera Robert F RF Pillai Shiv S

Cell reports 20230530 6

Although therapeutic B cell depletion dramatically resolves inflammation in many diseases in which antibodies appear not to play a central role, distinct extrafollicular pathogenic B cell subsets that accumulate in disease lesions have hitherto not been identified. The circulating immunoglobulin D (IgD)-CD27-CXCR5-CD11c+ DN2 B cell subset has been previously studied in some autoimmune diseases. A distinct IgD-CD27-CXCR5-</sup ...[more]

PMID: 37300833

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Project description:The origin and function of blood IgM+IgD+CD27+ B cells is controversial, and they are considered a heterogeneous population. Previous staining of circulating B cells of healthy donors with rotavirus fluorescent virus-like particles allowed us to differentiate two subsets of IgM+IgD+CD27+: IgMhi and IgMlo B cells. Here, we confirmed this finding and compared the phenotype, transcriptome, in vitro function, and Ig gene repertoire of these two subsets. Eleven markers phenotypically discriminated both subsets (CD1c, CD69, IL21R, CD27, MTG, CD45RB, CD5, CD184, CD23, BAFFR, and CD38) with the IgMhi phenotypically resembling previously reported marginal zone B cells and the IgMlo resembling both naïve and memory B cells. Transcriptomic analysis showed that both subpopulations clustered close to germinal center-experienced IgM only B cells with a Principal Component Analysis, but differed in expression of 78 genes. Moreover, IgMhi B cells expressed genes characteristic of previously reported marginal zone B cells. After stimulation with CpG and cytokines, significantly (p < 0.05) higher frequencies (62.5%) of IgMhi B cells proliferated, compared with IgMlo B cells (35.37%), and differentiated to antibody secreting cells (14.22% for IgMhi and 7.19% for IgMlo). IgMhi B cells had significantly (p < 0.0007) higher frequencies of mutations in IGHV and IGKV regions, IgMlo B cells had higher usage of IGHJ6 genes (p < 0.0001), and both subsets differed in their HCDR3 properties. IgMhi B cells shared most of their shared IGH clonotypes with IgM only memory B cells, and IgMlo B cells with IgMhi B cells. These results support the notion that differential expression of IgM and IgD discriminates two subpopulations of human circulating IgM+IgD+CD27+ B cells, with the IgMhi B cells having similarities with previously described marginal zone B cells that passed through germinal centers, and the IgMlo B cells being the least differentiated amongst the IgM+CD27+ subsets.

Dataset Information

Extrafollicular IgD^-CD27^-CXCR5^-CD11c^- DN3 B cells infiltrate inflamed tissues in autoimmune fibrosis and in severe COVID-19.

Publications

Extrafollicular IgD<sup>-</sup>CD27<sup>-</sup>CXCR5<sup>-</sup>CD11c<sup>-</sup> DN3 B cells infiltrate inflamed tissues in autoimmune fibrosis and in severe COVID-19.

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