Network Analysis Identifies Proinflammatory Plasma Cell Polarization for Secretion of ISG15 in Human Autoimmunity

Care, Matthew A.; Stephenson, Sophie; Barnes, Nicholas A.; Fan, Im; Zougman, Alexandre; El-Sherbiny, Yasser M.; Vital, Edward M; Westhead, David R.; Tooze, Reuben; Doody, Gina M.

doi:10.4049/jimmunol.1600624

Cited by 51 publications

(66 citation statements)

References 78 publications

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“…, ; Care et al. ) those involved immunoproteasomal degradation ( PSME1 , PSME2, PSMB10 ), or those not previously reported in retroviral infection ( HERC6 and PSMB10 ). Expression of all transcripts was confirmed to be up‐regulated by qPCR in the livers from SIV‐infected animals compared to controls (3.2–91.9 fold), with P ≤ 0.001 (Table ).…”

Section: Resultsmentioning

confidence: 99%

“…Multiple genes that were significantly up-regulated in livers of SIV infected macaques (3.5-14.2-fold), are also up-regulated in tissues of patients with SLE, including MX1, (Feng et al 2006;Aranow et al 2015 (Feng et al 2006;Care et al 2016) and USP18 (Coit et al 2013) (Tables 2, 3). A DAVID pathway analysis for the 138 differentially expressed genes in liver tissue revealed five pathways that were altered by SIV infection: genes dysregulated in SLE, as well as immunoproteasomal degradation, antigen presentation, RIG-I-like receptor signaling, and ISGylation (Table 3).…”

Section: Hepatic Expression: Sle-associated Genes and Other Pathwaysmentioning

confidence: 99%

“…Validation by qPCR was performed for selected pathway genes, to include key genes overexpressed in patients with SLE (HERC5 and ISG15), (Feng et al 2006Care et al 2016) those involved immunoproteasomal degradation (PSME1, PSME2, PSMB10), or those not previously reported in retroviral infection (HERC6 and PSMB10). Expression of all transcripts was confirmed to be up-regulated by qPCR in the livers from SIV-infected animals compared to controls (3.2-91.9 fold), with P ≤ 0.001 (Table S2).…”

Section: Hepatic Expression: Sle-associated Genes and Other Pathwaysmentioning

confidence: 99%

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Hepatic expression profiles in retroviral infection: relevance to drug hypersensitivity risk

Wong¹,

Johnson

Friedrich

et al. 2017

Pharmacology Res & Perspec

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HIV‐infected patients show a markedly increased risk of delayed hypersensitivity (HS) reactions to potentiated sulfonamide antibiotics (trimethoprim/sulfamethoxazole or TMP/SMX). Some studies have suggested altered SMX biotransformation in HIV infection, but hepatic biotransformation pathways have not been evaluated directly. Systemic lupus erythematosus (SLE) is another chronic inflammatory disease with a higher incidence of sulfonamide HS, but it is unclear whether retroviral infection and SLE share risk factors for drug HS. We hypothesized that retroviral infection would lead to dysregulation of hepatic pathways of SMX biotransformation, as well as pathway alterations in common with SLE that could contribute to drug HS risk. We characterized hepatic expression profiles and enzymatic activities in an SIV‐infected macaque model of retroviral infection, and found no evidence for dysregulation of sulfonamide drug biotransformation pathways. Specifically, NAT1,NAT2,CYP2C8,CYP2C9,CYB5R3,MARC1/2, and glutathione‐related genes (GCLC,GCLM,GSS,GSTM1, and GSTP1) were not differentially expressed in drug naïve SIVmac239‐infected male macaques compared to age‐matched controls, and activities for SMX N‐acetylation and SMX hydroxylamine reduction were not different. However, multiple genes that are reportedly over‐expressed in SLE patients were also up‐regulated in retroviral infection, to include enhanced immunoproteasomal processing and presentation of antigens as well as up‐regulation of gene clusters that may be permissive to autoimmunity. These findings support the hypothesis that pathways downstream from drug biotransformation may be primarily important in drug HS risk in HIV infection.

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Section: Resultsmentioning

confidence: 99%

Section: Hepatic Expression: Sle-associated Genes and Other Pathwaysmentioning

confidence: 99%

Section: Hepatic Expression: Sle-associated Genes and Other Pathwaysmentioning

confidence: 99%

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Hepatic expression profiles in retroviral infection: relevance to drug hypersensitivity risk

Wong¹,

Johnson

Friedrich

et al. 2017

Pharmacology Res & Perspec

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“…For example, B cells are a key mediator in SLE (15,16). IFN-I stimulates B cells to differentiate into plasmablasts which are expanded in SLE and correlate with disease activity (17,18). We previously demonstrated that the rate of plasmablast regeneration post-rituximab predicts clinical outcome (19).…”

Section: Introductionmentioning

confidence: 99%

B cell tetherin: a flow-cytometric cell-specific assay for response to Type-I interferon predicts clinical features and flares in SLE

El-Sherbiny

Yusof

Psarras

et al. 2019

Preprint

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Objective: Type I interferon (IFN-I) responses are broadly associated with autoimmune disease including SLE. Given the cardinal role of autoantibodies in SLE, we investigated whether a B lineage cell-specific IFN assay might correlate with SLE activity. Methods: B cells and PBMCs were stimulated with IFN-I and IFN-II. Gene expression was scrutinised for pathway-related membrane protein expression. A flow-cytometric assay for tetherin (CD317), an IFN-induced protein ubiquitously expressed on leucocytes, was validated in vitro then clinically against SLE diagnosis, plasmablast expansion, and BILAG-2004 score in a discovery cohort (156 SLE; 30 RA; 22 healthy controls). A second longitudinal validation cohort of 80 patients was also evaluated for SLE flare prediction. Results: In vitro, a close cell-specific and dose-responsive relationship between IFN-I responsive genes and cell surface tetherin in all immune subsets existed. Tetherin expression was selectively responsive to the IFN-I compared to IFN-II and -III. In the discovery cohort memory B-cell tetherin was best associated with diagnosis (SLE/HC: effect size=0.11, p=0.003;SLE/RA: effect size=0.17, p<0.001); plasmablast numbers in rituximab-treated patients (Rho=0.38, p=0.047) and BILAG-2004.Association were equivalent or stronger than interferon score or monocyte tetherin.The validation cohort confirmed this relationship with memory B-cell tetherin predictive of future clinical flares ), p=0.022).Conclusion: Memory B cell surface tetherin, a reflection of cell-specific IFN response in a convenient flow cytometric assay, was associated with SLE diagnosis, disease activity and predicted flares better than other cell subsets or whole blood assays in independent validation cohorts.

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“…New insights into disease mechanisms of relevance to SLE research* Phenotype and function of pathogenic and regulatory cells B cells and plasma cells(13,(53)(54)(55)(56)(57)(58) …”

mentioning

confidence: 99%

New Perspectives in Rheumatology: May You Live in Interesting Times: Challenges and Opportunities in Lupus Research

Sanz

2017

Arthritis & Rheumatology

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Network Analysis Identifies Proinflammatory Plasma Cell Polarization for Secretion of ISG15 in Human Autoimmunity

Cited by 51 publications

References 78 publications

Hepatic expression profiles in retroviral infection: relevance to drug hypersensitivity risk

Hepatic expression profiles in retroviral infection: relevance to drug hypersensitivity risk

B cell tetherin: a flow-cytometric cell-specific assay for response to Type-I interferon predicts clinical features and flares in SLE

New Perspectives in Rheumatology: May You Live in Interesting Times: Challenges and Opportunities in Lupus Research

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