Dissecting Integrin Expression and Function on Memory B Cells in Mice and Humans in Autoimmunity

Camponeschi, Alessandro; Gerasimčik, Natalija; Wang, Ying; Fredriksson, Timothy; Chen, Dongfeng; Farroni, Chiara; Thorarinsdottir, Katrin; Ottsjo, Louise Sjökvist; Aranburu, Alaitz; Cardell, Susanna; Carsetti, Rita; Gjertsson, Inger; Mårtensson, Inga‐Lill; Grimsholm, Ola

doi:10.3389/fimmu.2019.00534

Cited by 16 publications

(14 citation statements)

References 34 publications

(37 reference statements)

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“…To further characterize the extravasation potential of human neonatal monocytes, we measured the cell surface expression of CD11b, CD31, CD49d, CD54, CD50 and LFA-1. These molecules represent the most ubiquitously reported adhesion molecules used by human monocytes to extravasate [37][38][39][40][41][42][43] . Among these markers, CD31 and CD11b demonstrated significantly lower levels on both the CD16− and CD16+ neonatal monocytes, as compared to their adult counterparts ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Considering that newborn monocytes could express a divergent set of surface anchoring molecules, used selectively to colonize healthy non-inflamed tissues, we assessed CD11b, CD31 (PECAM-1), CD49d, CD50 (ICAM-3), CD54 (ICAM-1) and LFA-1 (CD11a/CD18). These markers are important mediators of human monocyte extravasation [37][38][39][40][41][42][43] and are constitutively expressed on the surface of monocytes 60 . CD49d pairs with β1-integrin CD29 to form VLA-4, and CD11a and CD11b couple with β2 integrin CD18 to form LFA-1 and CR3, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Neonatal monocytes demonstrate impaired homeostatic extravasation into a microphysiological human vascular model

Sánchez-Schmitz

Morrocchi

Cooney

et al. 2020

Sci Rep

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Infections are most frequent at the extremes of life, especially among newborns, reflecting age-specific differences in immunity. Monocytes maintain tissue-homeostasis and defence-readiness by escaping circulation in the absence of inflammation to become tissue-resident antigen presenting cells in vivo. Despite equivalent circulating levels, neonates demonstrate lower presence of monocytes inside peripheral tissues as compared to adults. To study the ability of monocytes to undergo autonomous transendothelial extravasation under biologically accurate circumstances we engineered a three-dimensional human vascular-interstitial model including collagen, fibronectin, primary endothelial cells and autologous untreated plasma. This microphysiological tissue construct enabled age-specific autonomous extravasation of monocytes through a confluent human endothelium in the absence of exogenous chemokines and activation. Both CD16− and CD16+ newborn monocytes demonstrated lower adherence and extravasation as compared to adults. In contrast, pre-activated tissue constructs were colonized by newborn monocytes at the same frequency than adult monocytes, suggesting that neonatal monocytes are capable of colonizing inflamed tissues. The presence of autologous plasma neither improved newborn homeostatic extravasation nor shaped age-specific differences in endothelial cytokines that could account for this impairment. Newborn monocytes demonstrated significantly lower surface expression of CD31 and CD11b, and mechanistic experiments using blocking antibodies confirmed a functional role for CD31 and CD54 in neonatal homeostatic extravasation. Our data suggests that newborn monocytes are intrinsically impaired in extravasation through quiescent endothelia, a phenomenon that could contribute to the divergent immune responsiveness to vaccines and susceptibility to infection observed during early life.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Neonatal monocytes demonstrate impaired homeostatic extravasation into a microphysiological human vascular model

Sánchez-Schmitz

Morrocchi

Cooney

et al. 2020

Sci Rep

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“…We identified the likely cellular origin of PCs in rejected lung grafts using trajectory and pseudotime analysis. These PC progenitors were defined by a set of transcripts, encoding the cell surface markers integrin beta 1 ( Itgb1 ) and Cxcr3 (known to regulate cell adhesion (36) and chemotaxis (37, 38)), as well as the transcription factors Bhlhe41, Zbtb20, and Zbtb32. In murine lung grafts, both the PC cluster, as well as their putative progenitors, were the only intragraft B cells positive for genes encoding IgA, IgG 1 , IgG 2b , IgG 2c and IgG 3 .…”

Section: Discussionmentioning

confidence: 99%

Single cell transcriptome mapping identifies a local innate B cell population driving local antibody production and chronic rejection after lung transplantation

Smirnova

Riemondy

Collins

et al. 2021

Preprint

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Bronchiolitis obliterans syndrome (BOS) due to chronic rejection 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, however, as well as those B cell populations that determine chronic rejection of the lung, remain entirely unclear. Here, we provide a map of cell population heterogeneity and their gene expression patterns during chronic rejection after orthotopic LTx in mice. Out of a total of 14 major comprehensive cell clusters, corresponding to 11 known major cell subpopulations, Mzb1-expressing plasma cells (PCs) were the most prominently increased cell population in lungs with BOS. Scgb1a1-expressing bronchial epithelial cells were depleted, while Cd14-expressing monocytes and Pdgfra-expressing fibroblasts were enriched in BOS grafts. These findings were validated in two different cohorts of human BOS after LTx. MZB1-IgG-double positive PCs infiltrated the airways of patients with BOS, while they were absent from healthy lungs. IgG, but not IgA, IgD, IgE or IgM, were significantly increased in bronchoalveolar lavage from BOS patients, compared with LTx patients who did not develop BOS. Pseudotime and trajectory analysis revealed that a Bhlhe41, Cxcr3, 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 progenitor B cell subset accounted for the increase in IgG2c expression and production in BOS lung grafts. Importantly, Aicda-/- mice, which lack all isotypes of Ig (except IgM) were protected from the onset of BOS after LTx. In summary, we provide a detailed atlas of cell population changes of chronic rejection after LTx. We have identified IgG-positive PCs and their progenitors - an innate B cell subpopulation characterized by a specific subset of markers - as the major source of local antibody production and a major contributor to both mouse and human BOS after LTx.

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“…For instance, within the 6 GBM signature genes, ITGB2 has not been widely associated with the pathogenesis of GBM. ITGB2 encodes for cell surface protein that is important in regulating cell adhesion and cell-surface mediated signalling [50]. Hence overexpression of this protein is relevant in promoting cancer growth possibly by modulating cancer cells adhesive and migratory properties, and the pro-oncogenic signalling cascades.…”

Section: Discussionmentioning

confidence: 99%

Integration of RNA-Seq and proteomics data identifies glioblastoma multiforme surfaceome signature

Syafruddin

Nazarie

Moidu

et al. 2020

Preprint

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Background: Glioblastoma multiforme (GBM) is a highly lethal, stage IV brain tumour with a prevalence of approximately 2 per 10000 people globally. The cell surface proteins or surfaceome serve as an information gateway in many oncogenic signalling pathways and are important in modulating cancer phenotypes. Dysregulation of surfaceome expression and activity have been shown to promote tumorigenesis. The expression of GBM surfaceome is a case in point; OMICS screening in cell-based system identified that this sub-proteome is largely perturbed in GBM. Additionally, since these cell surface proteins have ‘direct’ access to drugs, they are appealing targets for cancer therapy. However, a comprehensive aberrant GBM surfaceome landscape has not been fully defined. Thus, this study aimed to define GBM-specific surfaceome genes and identify key cell-surface genes that could potentially be developed as novel GBM biomarkers for therapeutic purposes. Methods: We integrated the RNA-Seq data from TCGA GBM (n=166) and GTEx normal brain cortex (n=408) databases to identify the significantly dysregulated surfaceome in GBM. This was followed by integrative analysis that combines transcriptomics, proteomics and protein-protein interaction network data to prioritize the high-confidence GBM surfaceome signature. Results: Of the 2,381 significantly dysregulated genes in GBM, 395 genes were classified as surfaceome. Via the integrative analysis, we identified 6 high-confidence GBM molecular signature, HLA-DRA, CD44, SLC1A5, EGFR, ITGB2, PTPRJ, which were significantly upregulated in GBM. The expression of these genes were validated in an independent transcriptomics database, which confirmed their upregulated expression in GBM. Importantly, high expression of CD44, PTPRJ and HLA-DRA is significantly associated with poor disease-free survival. Last, using the Drugbank database, we identified several clinically-approved drugs targeting the GBM molecular signature suggesting potential drug repurposing. Conclusions: In summary, we identified and highlighted the key GBM surface-enriched repertoires that could be biologically relevant in supporting GBM pathogenesis. These genes could be further interrogated experimentally in future studies that could lead to efficient diagnostic/prognostic markers or potential treatment options for GBM.

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Dissecting Integrin Expression and Function on Memory B Cells in Mice and Humans in Autoimmunity

Cited by 16 publications

References 34 publications

Neonatal monocytes demonstrate impaired homeostatic extravasation into a microphysiological human vascular model

Neonatal monocytes demonstrate impaired homeostatic extravasation into a microphysiological human vascular model

Single cell transcriptome mapping identifies a local innate B cell population driving local antibody production and chronic rejection after lung transplantation

Integration of RNA-Seq and proteomics data identifies glioblastoma multiforme surfaceome signature

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