Detection of interferon alpha protein reveals differential levels and cellular sources in disease

Rodero, Mathieu P; Decalf, Jérémie; Bondet, Vincent; Hunt, David; Rice, Gillian I.; Werneke, Scott; McGlasson, Sarah; Alyanakian, Marie‐Alexandra; Bader-Meunier, Brigitte; Barnérias, Christine; Bellon, N.; Belot, Alexandre; Bodemer, Christine; Briggs, Tracy A; Desguerre, Isabelle; Frémond, Marie-Louise; Hully, Marie; Maagdenberg, Arn M. J. M. van den; Melki, Isabelle; Meyts, Isabelle; Musset, Lucile; Pelzer, Nadine; Quartier, Pierre; Terwindt, Gisela M.; Wardlaw, Joanna M.; Wiseman, Stewart; Rieux-Laucat, Frédéric; Rose, Y; Neven, Bénédicte; Hertel, Christina; Hayday, Adrian; Albert, Matthew L.; Rozenberg, Flore; Crow, Yanick J.; Duffy, Darragh

doi:10.1084/jem.20161451

Cited by 293 publications

(289 citation statements)

References 24 publications

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“…The lack of significant elevation of type I IFN in pDCs (Fig. 2A) is consistent with the recent finding that, in SLE, type I IFN expression in circulating pDCs was not elevated compared to B cells (20). The identity of sorted cells was verified by high expression of the Cd19 gene in B cells and Cd317 in pDCs (Fig.…”

Section: Resultssupporting

confidence: 92%

Cutting Edge: Endogenous IFN-β Regulates Survival and Development of Transitional B Cells

Hamilton

Yang

et al. 2017

The Journal of Immunology

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The transitional stage of B-cell development is a formative stage in the spleen where autoreactive specificities are censored as B cells gain immune-competence, but the intrinsic and extrinsic factors regulating survival of transitional stage 1 (T1) B cells are unknown. We report that B-cell expression of IFNβ is required for optimal survival and TLR7 responses of transitional B cells in the spleen and was over-expressed in T1 B cells from BXD2 lupus-prone mice. Single-cell gene expression analysis of B6 Ifnb+/+ vs. B6 Ifnb−/− T1 B cells revealed heterogeneous expression of Ifnb in WT B cells and distinct gene expression patterns associated with endogenous IFNβ. Single cell analysis of BXD2 T1 B cells revealed that Ifnb is expressed in early T1 B-cell development with subsequent upregulation of Tlr7 and Ifna1. Together these data suggest that T1 B-cell expression of IFNβ plays a key role in regulating responsiveness to external factors.

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Section: Resultssupporting

confidence: 92%

Cutting Edge: Endogenous IFN-β Regulates Survival and Development of Transitional B Cells

Hamilton

Yang

et al. 2017

The Journal of Immunology

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“…C). This concentration is considerably less than those observed in patients with interferonopathies or SLE, two diseases with a known IFN signature . Follow‐up of IFN‐α serum levels in one of the patients showed substantial fluctuations of IFN‐α levels, including the samples that were drawn only 1 week apart (Fig.…”

Section: Resultsmentioning

confidence: 90%

Interferon signature in patients with STAT1 gain‐of‐function mutation is epigenetically determined

et al. 2019

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STAT1 gain‐of‐function (GOF) variants lead to defective Th17 cell development and chronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. Stimulation of cells with STAT1 inducing cytokines like interferons (IFN) result in hyperphosphorylation and delayed dephosphorylation of GOF STAT1. However, the mechanism how the delayed dephosphorylation exactly causes the increased expression of STAT1‐dependent genes, and how the intracellular signal transduction from cytokine receptors is affected, remains unknown. In this study we show that the circulating levels of IFN‐α were not persistently elevated in STAT1 GOF patients. Nevertheless, the expression of interferon signature genes was evident even in the patient with low or undetectable serum IFN‐α levels. Chromatin immunoprecipitation (ChIP) experiments revealed that the active chromatin mark trimethylation of lysine 4 of histone 3 (H3K4me3), was significantly enriched in areas associated with interferon‐stimulated genes in STAT1 GOF cells in comparison to cells from healthy donors. This suggests that the chromatin binding of GOF STAT1 variant promotes epigenetic changes compatible with higher gene expression and elevated reactivity to type I interferons, and possibly predisposes for interferon‐related autoimmunity. The results also suggest that epigenetic rewiring may be responsible for treatment failure of Janus kinase 1/2 (JAK1/2) inhibitors in certain patients.

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“…First, it is possible that low levels of IFN-I continue to be produced in chronic infection and this residual IFN-I (below the limits of detection) sustains this ISG signature. Newer, more sensitive IFN-I detection assays 65 may be able to address this question. Second, other cytokines might sustain the ISG signature initially induced by IFN-I.…”

Section: Cd4+ T Responses In Mouse Models Of Chronic Infectionmentioning

confidence: 99%

CD4+ T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective

Vella

Herati

Wherry

2017

Trends in Molecular Medicine

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CD4+ T cells play a critical role in the response to chronic viral infections during the acute phase and in the partial containment of infections once chronic infection is established. As infection persists, the virus-specific CD4+ T cell response begins to shift in phenotype. The predominant change described in both mouse and human studies of chronic viral infection is a decrease in detectable Th1 responses. Some Th1 loss is due to decreased proliferative potential and decreased cytokine production in the setting of chronic antigen exposure. However, recent data suggest that Th1 dysfunction is accompanied by a shift in the differentiation pathway of virus-specific CD4+ T cells, with enrichment for cells with a T follicular helper cell (Tfh) phenotype. A Tfh-like program during chronic infection has now been identified in virus-specific CD8+ T cells as well. In this review, we discuss what is known about CD4+ T cell differentiation in chronic viral infections, with a focus on the emergence of the Tfh program and the implications of this shift with respect to Tfh function and the host-pathogen interaction.

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Detection of interferon alpha protein reveals differential levels and cellular sources in disease

Cited by 293 publications

References 24 publications

Cutting Edge: Endogenous IFN-β Regulates Survival and Development of Transitional B Cells

Cutting Edge: Endogenous IFN-β Regulates Survival and Development of Transitional B Cells

Interferon signature in patients with STAT1 gain‐of‐function mutation is epigenetically determined

CD4+ T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective

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