Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria

Rosain, Jérémie; Neehus, Anna-Lena; Manry, Jérémy; Yang, Rui; Pen, Jérémie Le; Daher, Wassim; Li, Yong; Chan, Yi‐Hao; Tahuil, Natalia; Türel, Özden; Bourgey, Mathieu; Ogishi, Masato; Doisne, Jean‐Marc; Izquierdo, Helena M.; Shirasaki, Takayoshi; Voyer, Tom Le; Guérin, Antoine; Bastard, Paul; Moncada-Vélez, Marcela; Han, Ji Eun; Khan, Taushif; Rapaport, Franck; Hong, Seon-Hui; Cheung, Andrew; Haake, Kathrin; Mindt, Barbara C.; Pérez, Laura; Philippot, Quentin; Lee, Danyel; Zhang, Peng; Rinchai, Darawan; Ali, Fatima; Ata, Manar; Rahman, Mahbuba; Peel, Jessica N.; Heissel, Søren; Molina, Henrik; Kendir-Demirkol, Yasemin; Bailey, Rasheed; Zhao, Shuxiang; Bohlen, Jonathan; Mancini, Mathieu; Seeleuthner, Yoann; Roelens, Marie; Lorenzo, Lazaro; Soudée, Camille; Paz, María Elvira Josefina; González, María Laura; Jeljeli, Mohamed; Soulier, Jean; Romana, Serge; L’Honneur, Anne-Sophie; Materna, Marie; Martı́nez-Barricarte, Rubén; Pochon, Mathieu; Oleaga-Quintas, Carmen; Michev, Alexandre; Migaud, Mélanie; Lévy, Romain; Alyanakian, Marie‐Alexandra; Rozenberg, Flore; Croft, Carys A.; Vogt, Guillaume; Émile, Jean-François; Kremer, Laurent; Cindy, S.; Fritz, Jörg H.; Lemon, Stanley M.; Spaan, András N.; Manel, Nicolas; Abel, Laurent; MacDonald, Margaret R.; Boisson–Dupuis, Stéphanie; Marr, Nico; Tangye, Stuart G.; Santo, James P. Di; Zhang, Qian; Zhang, Shen-Ying; Rice, Charles M.; Béziat, Vivien; Lachmann, Nico; Langlais, David; Casanova, Jean‐Laurent; Gros, Philippe; Bustamante, Jacinta

doi:10.1016/j.cell.2022.12.038

Cited by 42 publications

(29 citation statements)

References 214 publications

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“…From the therapeutic perspective, additional simple and sensitive biomarkers should be identified to evaluate disease activity and forecast the disease course of patients with anti-MDA5+ DM. The selection of IFI44, Mx1, and IRF1 as targeted genes in this study was based on several considerations, including their previous identification as highly upregulated and specific interferonstimulated genes (21)(22)(23), the need to differentiate between IFN-I and IFN-II signaling pathways, and the importance of selecting genes with close expression and designing non-mutually exclusive primers for accurate and reliable detection using multiplex RT-qPCR assays. The application of multiplex RT-qPCR in this study of IFN-I scores in patients with anti-MDA5+ DM was innovative.…”

Section: Discussionmentioning

confidence: 99%

Type I interferon score is associated with the severity and poor prognosis in anti-MDA5 antibody-positive dermatomyositis patients

Qian

Chen

et al. 2023

Front. Immunol.

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ObjectivesTo investigate the clinical significance of the interferon (IFN) score, especially the IFN-I score, in patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (anti-MDA5+ DM).MethodsWe enrolled 262 patients with different autoimmune diseases, including idiopathic inflammatory myopathy, systemic lupus erythematosus, rheumatoid arthritis, adult-onset Still’s disease, and Sjögren’s syndrome, as well as 58 healthy controls. Multiplex quantitative real-time polymerase chain reaction (RT-qPCR) using four TaqMan probes was used to evaluate type I IFN-stimulated genes (IFI44 and MX1), one type II IFN-stimulated gene (IRF1), and one internal control gene (HRPT1), which were used to determine the IFN-I score. The clinical features and disease activity index were compared between the high and low IFN-I score groups in 61 patients with anti-MDA5+ DM. The associations between laboratory findings and the predictive value of the baseline IFN-I score for mortality were analyzed.ResultsThe IFN score was significantly higher in patients with anti-MDA5+ DM than in healthy controls. The IFN-I score was positively correlated with the serum IFN-α concentration, ferritin concentration, and Myositis Disease Activity Assessment Visual Analogue Scale (MYOACT) score. Compared with patients with a low IFN-I score, patients with a high IFN-I score showed a higher MYOACT score, C-reactive protein concentration, aspartate transaminase concentration, ferritin concentration, plasma cell percentage, and CD3+ T-cell percentage, as well as lower lymphocyte, natural killer cell, and monocyte counts. The 3-month survival rate was significantly lower in patients with an IFN-I score of >4.9 than in those with an IFN-I score of ≤4.9 (72.9% vs. 100%, respectively; P = 0.044).ConclusionThe IFN score, especially the IFN-I score, measured by multiplex RT-qPCR is a valuable tool to monitor disease activity and predict mortality in patients with anti-MDA5+ DM.

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Section: Discussionmentioning

confidence: 99%

Type I interferon score is associated with the severity and poor prognosis in anti-MDA5 antibody-positive dermatomyositis patients

Qian

Chen

et al. 2023

Front. Immunol.

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“…Raw FASTQ files were aligned to the GRCh38 reference genome and count matrices for cell barcodes and UMIs were generated for each sample by CellRanger (v3.0.1). Using the Seurat (v4.3.0) R package, samples were filtered from cells expressing any two lineage markers ( CD79A , CD3G , CD14 , and LILRA4 ) as these were considered doublets 70,71 . In the HC-INS dataset, doublet and nonviable cells were removed by excluding cells expressing <200 or <3000 genes, >10% mitochondrial genes, and <10% ribosomal protein genes.…”

Section: Methodsmentioning

confidence: 99%

The extrafollicular B cell response is a hallmark of childhood idiopathic nephrotic syndrome

Al-Aubodah,

Aoudjit,

Pascale

et al. 2023

Preprint

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An autoimmune B cell origin for childhood idiopathic nephrotic syndrome (INS) is predicted based on the efficacy of rituximab (RTX) at maintaining long-term remission from proteinuria. Knowledge regarding the nature of the culprit B cell response is very limited. Using single-cell RNA-sequencing, we demonstrate that a B cell transcriptional program poised for effector functions represents the major immune perturbation in the blood of children with active INS. This was conferred by the engagement of an extrafollicular B cell response marked by the expansion of atypical B cells (atBCs), marginal zone-like B cells, and antibody-secreting cells (ASCs). In flow-based analyses of blood from 13 children with active INS and 24 healthy donors, this was reflected by the proliferation of RTX-sensitive extrafollicular (CXCR5—) CD21low T-bet+ CD11c+ atBCs, and short-lived T-bet+ ASCs. Together, our study provides evidence for an extrafollicular origin for humoral immunity in active INS.

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“…In conclusion, while mice lacking IFN-γ were shown to be susceptible to infection by both viruses and bacterial pathogens capable of surviving macrophage-mediated phagocytosis [ 180 , 181 ], the study of MSMD patients has shown that human IFN-γ is primarily a macrophage-activating factor and appears less important for anti-viral immunity. Notably, while both type I and II IFNs induce the transcription factor IRF1, in vitro studies of cells obtained from unrelated children with inherited complete IRF1 deficiency and multiple, life-threatening diseases in early life caused by weakly virulent mycobacteria and related intra-macrophagic pathogens but no history of severe viral disease demonstrated that IRF1 is essential for IFN-γ-dependent macrophage immunity to mycobacteria, but largely redundant for type I IFN-dependent anti-viral immunity [ 182 ]. A recent study of a patient with inherited PD-1 deficiency and TB, who died of pulmonary autoimmunity, has also highlighted the indispensable role of human PD1 in governing both anti-mycobacterial immunity and self-tolerance and provided important mechanistic insights relevant for the treatment of cancer patients who receive immunotherapy with PD-1-directed checkpoint inhibitors, thereby exhibiting a high vulnerability to tuberculosis for previously unknown reasons.…”

Section: Defects In the Interferon Pathwaysmentioning

confidence: 99%

Interferons and Resistance Mechanisms in Tumors and Pathogen-Driven Diseases—Focus on the Major Histocompatibility Complex (MHC) Antigen Processing Pathway

Massa

Wang

Marr

et al. 2023

IJMS

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Interferons (IFNs), divided into type I, type II, and type III IFNs represent proteins that are secreted from cells in response to various stimuli and provide important information for understanding the evolution, structure, and function of the immune system, as well as the signaling pathways of other cytokines and their receptors. They exert comparable, but also distinct physiologic and pathophysiologic activities accompanied by pleiotropic effects, such as the modulation of host responses against bacterial and viral infections, tumor surveillance, innate and adaptive immune responses. IFNs were the first cytokines used for the treatment of tumor patients including hairy leukemia, renal cell carcinoma, and melanoma. However, tumor cells often develop a transient or permanent resistance to IFNs, which has been linked to the escape of tumor cells and unresponsiveness to immunotherapies. In addition, loss-of-function mutations in IFN signaling components have been associated with susceptibility to infectious diseases, such as COVID-19 and mycobacterial infections. In this review, we summarize general features of the three IFN families and their function, the expression and activity of the different IFN signal transduction pathways, and their role in tumor immune evasion and pathogen clearance, with links to alterations in the major histocompatibility complex (MHC) class I and II antigen processing machinery (APM). In addition, we discuss insights regarding the clinical applications of IFNs alone or in combination with other therapeutic options including immunotherapies as well as strategies reversing the deficient IFN signaling. Therefore, this review provides an overview on the function and clinical relevance of the different IFN family members, with a specific focus on the MHC pathways in cancers and infections and their contribution to immune escape of tumors.

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Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria

Cited by 42 publications

References 214 publications

Type I interferon score is associated with the severity and poor prognosis in anti-MDA5 antibody-positive dermatomyositis patients

Type I interferon score is associated with the severity and poor prognosis in anti-MDA5 antibody-positive dermatomyositis patients

The extrafollicular B cell response is a hallmark of childhood idiopathic nephrotic syndrome

Interferons and Resistance Mechanisms in Tumors and Pathogen-Driven Diseases—Focus on the Major Histocompatibility Complex (MHC) Antigen Processing Pathway

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