Structure and function of the immune system in the spleen

Lewis, Steven M.; Williams, Adam; Eisenbarth, Stephanie C.

doi:10.1126/sciimmunol.aau6085

Cited by 728 publications

(613 citation statements)

References 125 publications

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“…Different populations of dendritic cells reside in the spleen; the role of specific subsets of these cells in the development of FVIII inhibitors has not yet been explored. In contrast to that of the mouse spleen, the cellular architecture of the human spleen has not yet been fully elucidated (36,37). In human spleen the border between the white and red pulp is formed by a perifollicular zone whose cellular composition has not yet been fully characterized.…”

Section: Fviii Uptake Processing and Presentationmentioning

confidence: 99%

“…The architecture of the spleen promotes intimate contact between blood borne antigens and antigen capturing and presenting cells that are localized in the marginal zone (36,37). Fenestrated splenic endothelial cells are well-positioned to filter blood borne antigens like FVIII and von Willebrand factor (VWF) from the circulating blood, thus promoting capture of antigens via scavenger receptors such as stabilin-2 (42).…”

Section: Fviii Uptake Processing and Presentationmentioning

confidence: 99%

“…Fenestrated splenic endothelial cells are well-positioned to filter blood borne antigens like FVIII and von Willebrand factor (VWF) from the circulating blood, thus promoting capture of antigens via scavenger receptors such as stabilin-2 (42). Marginal zone macrophages, marginal zone B cells and populations of marginal zone-located dendritic cells are also capable of capturing and/or processing blood borne antigens (36,37). Transfer of antigens from marginal zone macrophages and endothelial cells to more dynamic marginal zone B cells and marginal zone-residing dendritic cells is most likely required for their transport to the T cell-enriched white pulp.…”

Section: Fviii Uptake Processing and Presentationmentioning

confidence: 99%

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Tolerating Factor VIII: Recent Progress

et al. 2020

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Development of neutralizing antibodies against biotherapeutic agents administered to prevent or treat various clinical conditions is a longstanding and growing problem faced by patients, medical providers and pharmaceutical companies. The hemophilia A community has deep experience with attempting to manage such deleterious immune responses, as the lifesaving protein drug factor VIII (FVIII) has been in use for decades. Hemophilia A is a bleeding disorder caused by genetic mutations that result in absent or dysfunctional FVIII. Prophylactic treatment consists of regular intravenous FVIII infusions. Unfortunately, 1/4 to 1/3 of patients develop neutralizing anti-FVIII antibodies, referred to clinically as "inhibitors," which result in a serious bleeding diathesis. Until recently, the only therapeutic option for these patients was "Immune Tolerance Induction," consisting of intensive FVIII administration, which is extraordinarily expensive and fails in ∼30% of cases. There has been tremendous recent progress in developing novel potential clinical alternatives for the treatment of hemophilia A, ranging from encouraging results of gene therapy trials, to use of other hemostatic agents (either promoting coagulation or slowing down anti-coagulant or fibrinolytic pathways) to "bypass" the need for FVIII or supplement FVIII replacement therapy. Although these approaches are promising, there is widespread agreement that preventing or reversing inhibitors remains a high priority. Risk profiles of novel therapies are still unknown or incomplete, and FVIII will likely continue to be considered the optimal hemostatic agent to support surgery and manage trauma, or to combine with other therapies. We describe here recent exciting studies, most still pre-clinical, that address FVIII immunogenicity and suggest novel interventions to prevent or reverse inhibitor development. Studies of FVIII uptake, processing and presentation on antigen-presenting cells, epitope mapping, and the roles of complement, heme, von Willebrand factor, glycans, and the microbiome in FVIII immunogenicity are elucidating mechanisms of primary and secondary immune responses and suggesting additional novel targets. Promising tolerogenic therapies include development of FVIII-Fc fusion proteins, nanoparticle-based therapies, oral tolerance, and engineering of regulatory or cytotoxic T cells to render them FVIII-specific. Importantly, these studies are highly applicable to other scenarios where establishing immune tolerance to a defined antigen is a clinical priority.

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Section: Fviii Uptake Processing and Presentationmentioning

confidence: 99%

Section: Fviii Uptake Processing and Presentationmentioning

confidence: 99%

Section: Fviii Uptake Processing and Presentationmentioning

confidence: 99%

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Tolerating Factor VIII: Recent Progress

et al. 2020

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“…It is responsible for filtration of pathogens and foreign antigens including abnormal cells. These functions are mediated mainly through T& B lymphocytes (Steven et al, 2019).…”

Section: A B C Dmentioning

confidence: 99%

Toxic Effects of Formaldehyde on Cellular Immunity and Possible Relationship to Its Risk of Carcinogenesis: An Experimental Study

El-Nagdy

Elgezawy

Nasif³

2020

Zagazig Journal of Forensic Medicine

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“…This approach allowed us to identify genes with significant gradients of expression within one or several clusters, and we used these results to further annotate the atlas. Overall, we identified 30 cell populations, comprising most of the known splenic cell types 16,17 (Fig. 1a).…”

Section: A High-quality Cite-seq Atlas Of the Murine Spleenmentioning

confidence: 99%

Single-Cell Transcriptomic Analysis of mIHC Images via Antigen Mapping

Govek

Troisi

Woodhouse

et al. 2019

Preprint

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Highly-multiplexed immunohistochemistry (mIHC) enables the staining and quantification of dozens of antigens in a tissue section with single-cell resolution. However, annotating cell populations that differ little in the profiled antigens or for which the antibody panel does not include specific markers is challenging. To overcome this obstacle, we have developed an approach for enriching mIHC images with single-cell RNA-seq data, building upon recent experimental procedures for augmenting single-cell transcriptomes with concurrent antigen measurements. Spatially-resolved Transcriptomics via Epitope Anchoring (STvEA) performs transcriptome-guided annotation of highly-multiplexed cytometry datasets. It increases the level of detail in histological analyses by enabling annotation of subtle cell populations, spatial patterns of transcription, and interactions between cell types. More generally, it enables the systematic annotation of cell populations in cytometry data. We demonstrate the utility of STvEA by uncovering the architecture of poorly characterized cell types in the murine spleen using published highly-multiplexed cytometry and mIHC data.

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Structure and function of the immune system in the spleen

Cited by 728 publications

References 125 publications

Tolerating Factor VIII: Recent Progress

Tolerating Factor VIII: Recent Progress

Toxic Effects of Formaldehyde on Cellular Immunity and Possible Relationship to Its Risk of Carcinogenesis: An Experimental Study

Single-Cell Transcriptomic Analysis of mIHC Images via Antigen Mapping

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