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Network analysis identifies proinflammatory plasma cell polarization for secretion of ISG15 in human autoimmunity

ABSTRACT: Plasma cells (PCs) as effectors of humoral immunity produce immunoglobulins to match pathogenic insult. However, emerging data suggests more diverse roles for PCs as regulators of immune and inflammatory responses via secretion of factors other than immunoglobulins. The extent to which such responses are pre-programmed in B-lineage cells or can be induced in PCs by the microenvironment is unknown. Here we dissect the impact of IFNs on the regulatory networks of human plasma cells. We show that core PC programs are unaffected, while PCs respond to IFNs with distinctive transcriptional responses. The ISG15-system emerges as a major transcriptional output induced in a sustained fashion by IFN-α in PCs and linked both to intracellular conjugation and ISG15 secretion. This leads to the identification of ISG15-secreting plasmablasts/PCs in patients with active SLE. Thus ISG15-secreting PCs represent a distinct pro-inflammatory PC subset providing an immunoglobulin-independent mechanism of PC action in human autoimmunity

ORGANISM(S): Homo sapiens

PROVIDER: GSE75007 | GEO | 2016/07/22

SECONDARY ACCESSION(S): PRJNA302173

REPOSITORIES: GEO

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Network analysis identifies proinflammatory plasma cell polarization for secretion of ISG15 in human autoimmunity

Project description:Plasma cells (PCs) as effectors of humoral immunity produce immunoglobulins to match pathogenic insult. However, emerging data suggests more diverse roles for PCs as regulators of immune and inflammatory responses via secretion of factors other than immunoglobulins. The extent to which such responses are pre-programmed in B-lineage cells or can be induced in PCs by the microenvironment is unknown. Here we dissect the impact of IFNs on the regulatory networks of human plasma cells. We show that core PC programs are unaffected, while PCs respond to IFNs with distinctive transcriptional responses. The ISG15-system emerges as a major transcriptional output induced in a sustained fashion by IFN-Î± in PCs and linked both to intracellular conjugation and ISG15 secretion. This leads to the identification of ISG15-secreting plasmablasts/PCs in patients with active SLE. Thus ISG15-secreting PCs represent a distinct pro-inflammatory PC subset providing an immunoglobulin-independent mechanism of PC action in human autoimmunity B-cells were isolated from the peripheral blood of three adult donors and differentiated in vitro (see individual samples for culture conditions)

2016-07-22 | E-GEOD-75007 | biostudies-arrayexpress

Transcriptional profiling of the maturation of human in vivo-generated plasma cells

Project description:In vivo antigen (Ag)-induced differentiation of B lymphocytes into plasma cells (PCs) takes place in extra-follicular foci and germinal centers of the secondary lymphoid organs (SLOs). Most of these SLO PCs are short-living and only relatively few PCs, characterized by secreting high-affinity antibodies (Ab), travel through the circulation and finally home in specialized survival niches of the bone marrow (BM) and, at a lesser extent, in the SLOs, where they become long-living Ab-secreting PCs. Initially, we have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to distinguish between human circulating Ag-induced PCs in comparison with tonsil and BM PCs distinctively regulate genes involved in cell proliferation. Now, moreover, to characterize further the B-cell transition into PC, transcriptomes from human naïve B lymphocytes were also included in the analysis, and genes showing significant changes in the comparison between B lymphocytes and every of the three PC subsets were selected as the PC signature.

2017-09-12 | GSE81589 | GEO

Gene expression signatures of human plasma cells isolated from different territories

Project description:In vivo antigen (Ag)-induced differentiation of B lymphocytes into plasma cells (PCs) takes place in extra-follicular foci and germinal centers of the secondary lymphoid organs (SLOs). Most of these SLO PCs are short-living and only relatively few PCs, characterized by secreting high-affinity antibodies (Ab), travel through the circulation and finally home in specialized survival niches of the bone marrow (BM) and, at a lesser extent, in the SLOs, where they become long-living Ab-secreting PCs. We have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to distinguish between human circulating Ag-induced PCs in comparison with tonsil and BM PCs distinctively regulate genes involved in cell proliferation. Gene expressions in human plasma cells isolated from tonsil (7 samples), blood (6 samples) and bone marrow (7samples) were measured. Each sample was isolated from a different donor.

2015-01-05 | E-GEOD-59697 | biostudies-arrayexpress

ISG15 in regulation of interferon responses

Project description:We assessed how lack of ISG15 influences the levels of transcripts after IFNa stimulation. Expression data from ISG15 deficient patients (P1, P2, P3) and control (C1, C6, C16) hTert fibroblasts

2014-12-01 | GSE60359 | GEO

Gene expression profile at single cell level of plasma cells (PCs) from human bone marrow

Project description:Antibody-secreting plasma cells (PCs) are generated in secondary lymphoid organs, but are reported to reside in an emerging range of anatomical sites. Analysis of the transcriptome of different tissue-resident (Tr)PC populations revealed that they each have their own transcriptional signature indicative of functional adaptation to the host tissue environment. In contrast to expectation, all TrPCs were extremely long-lived, regardless of their organ of residence, with the longevity influenced by intrinsic factors like the immunoglobulin isotype. Analysis at single-cell resolution revealed that the bone marrow is unique in housing a compendium of PCs generated all over the body that retain aspects of the transcriptional program indicative of their tissue of origin.

2023-11-12 | GSE229957 | GEO

ISG15 counteracts Listeria monocytogenes infection

Project description:ISG15 is primarily documented as an interferon-stimulated, ubiquitin-like protein (ubl), which has anti-viral activity. Although ISG15 was the founding member of the ubl protein family, very little is known about its function. We have found that ISG15 expression in non-phagocytic cells is dramatically induced upon Listeria infection and that surprisingly this induction can be Type I Interferon independent. Listeria-mediated ISG15 induction depends on the cytosolic surveillance pathway, which senses bacterial DNA and signals through STING, TBK1, IRF3 and IRF7. Most importantly, we observed that ISG15 expression restricts Listeria infection both in vitro and in vivo. We then made use of Stable Isotope Labeling in tissue culture (SILAC) to identify the ISGylated proteins that could be responsible for the ISG15-mediated protective effect. Our SILAC analysis revealed that overexpression of ISG15 leads to a striking ISGylation of integral membrane proteins of the endoplasmic reticulum and Golgi apparatus, which correlates with increased canonical secretion of cytokines. Taken together, our data reveal a previously uncharacterized signaling pathway that restricts Listeria infection and acts via ISGylation, reinforcing the view that ISG15 is a key component of the innate immune arsenal of the mammalian host.

2017-03-29 | MSV000080750 | MassIVE

ISG15 counteracts Listeria monocytogenes infection

2015-07-24 | PXD001805 | Pride

Gene expression signatures of human plasma cells isolated from different territories

Project description:In vivo antigen (Ag)-induced differentiation of B lymphocytes into plasma cells (PCs) takes place in extra-follicular foci and germinal centers of the secondary lymphoid organs (SLOs). Most of these SLO PCs are short-living and only relatively few PCs, characterized by secreting high-affinity antibodies (Ab), travel through the circulation and finally home in specialized survival niches of the bone marrow (BM) and, at a lesser extent, in the SLOs, where they become long-living Ab-secreting PCs. We have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to distinguish between human circulating Ag-induced PCs in comparison with tonsil and BM PCs distinctively regulate genes involved in cell proliferation.

2015-01-05 | GSE59697 | GEO

Transcriptome analysis of human colonic IgA+ plasma cell subsets and naïve B cells

Project description:Immunoglobulin A (IgA) is the most abundant antibody in the intestinal tract. Recent studies show that discrete subsets of gut human plasma cells (PCs) release IgA, which contributes to the maintenance of gut homeostasis. To better characterize the properties of these PC subsets, we performed global transcriptome analysis in naïve B cells as well as immature CD19+IgA+CD138- PCs, mature CD19+IgA+CD138+ PCs and late CD19-IgA+CD138+ PCs after their purification from human colon samples.

2020-03-29 | GSE141005 | GEO

Mature IgM+ plasma cells sense antigen and develop competence for cytokine production upon antigenic challenge

Project description:Dogma holds that plasma cells (PC), as opposed to B cells, cannot bind antigen (Ag) because they have switched from expression of membrane-bound immunoglobulins that constitute the B cell Ag receptor (BCR) to production of the secreted form of immunoglobulins. We have compared the phenotypical and functional attributes of PC generated by the T-cell-dependent and T-cell-independent forms of the hapten NP. We unexpectedly found that the nature of the secreted Ig isotype rather than the chemical structure of the immunizing Ag defines two functionally distinct populations of PC. Fully mature IgM-expressing bone marrow PC retain expression of a functional BCR while their IgG+ counterparts do not. We show that Ag boost modifies the gene expression profile of IgM+ PC and initiates a cytokine production program, characterized by upregulation of CCL5 and IL-10. Our results demonstrate that IgM-expressing PC can sense Ag and acquire competence for cytokine production upon antigenic challenge.

2016-11-01 | GSE80216 | GEO

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