New human combined immunodeficiency caused by interferon regulatory factor 4 (IRF4) deficiency inherited by uniparental isodisomy

García-Morato, María Bravo; Santos, Francisco Javier Aracil; Briones, Alejandro C.; Moreno, Alfonso Blázquez; Maté, Ángela del Pozo; Domínguez-Soto, Ángeles; Merino, María J.; Molina, Lucía del Pino; Canizales, Juan Torres; Marín, Ana V.; García, Elena Vallespín; Rodríguez, Marta Feito; Sabando, Diego Plaza López; Jiménez-Reinoso, Anaïs; Castillo, Yasmina Mozo del; Santaeufemia, F.J. Sanz; Lucas-Laguna, R. de; Cárdenas, Paula P.; Polo, Luz; Díaz, María Coronel; Valés‐Gómez, Mar; Santiago, ER de; Cerdán, Antonio Ferreira; Blanco, Julián Nevado; Corbí, Ángel L.; Reyburn, Hugh; Regueiro, José R.; López‐Granados, Eduardo; Pena, Rebeca Rodríguez

doi:10.1016/j.jaci.2017.12.995

Cited by 18 publications

(16 citation statements)

References 25 publications

(4 reference statements)

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“…5 B ). Motifs of other TFs, including many critical to B cell development (ETS1, RUNX1, RUNX2, EBF1, SPIB, and GABPA) and/or already implicated in human primary immunodeficiencies (TCF3, IRF3, IRF4, and IRF8; Hambleton et al, 2011 ; Boisson et al, 2013 ; Andersen et al, 2015 ; Bravo García-Morato et al, 2018 ; Tangye et al, 2020 ), were also significantly overrepresented. Hence, PU.1 haploinsufficiency specifically limits the access of nonpioneer TFs, including those relevant to B cell development and/or associated with primary immunodeficiencies, to pro–B cell open chromatin.…”

Section: Resultsmentioning

confidence: 99%

Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients

Coz

Nguyen

et al. 2021

Journal of Experimental Medicine

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The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro–B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro– to pre–B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1’s critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.

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Section: Resultsmentioning

confidence: 99%

Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients

Coz

Nguyen

et al. 2021

Journal of Experimental Medicine

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“…IRF4 is a suppressor of innate immune signaling, by inhibiting TLR/MyD88 signaling (32). The relevance of this inhibitory function is underscored by enhanced susceptibility to septic shock in mice and an autoinflammatory immune-defective disease in IRF4-defective inherited humans (32, 33). Likewise, in the acute phase of IRI, IRF4 acts as an endogenous regulator of myeloid cell activation, i.e., dendritic cells, suppresses TNF-α release from intrarenal myeloid cells, and thereby limits tubular cell necrosis, tissue inflammation, and acute renal failure 24 h and 5 days post-IRI (19).…”

Section: Discussionmentioning

confidence: 99%

IFN Regulatory Factor 4 Controls Post-ischemic Inflammation and Prevents Chronic Kidney Disease

Lorenz

Moschovaki-Filippidou

Würf

et al. 2019

Front. Immunol.

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Ischemia reperfusion injury (IRI) of the kidney results in interferon regulatory factor 4 (IRF4)–mediated counter-regulation of the acute inflammatory response. Beyond that, IRF4 exerts important functions in controlling the cytokine milieu, T-cell differentiation, and macrophage polarization. The latter has been implicated in tissue remodeling. It therefore remains elusive what the role of IRF4 is in terms of long-term outcome following IRI. We hypothesized that an inability to resolve chronic inflammation in Irf4−/− mice would promote chronic kidney disease (CKD) progression. To evaluate the effects of IRF4 in chronic upon acute injury in vivo, a mouse model of chronic injury following acute IRI was employed. The expression of Irf4 increased within 10 days after IRI in renal tissue. Both mRNA and protein levels remained high up to 5 weeks upon IRI, suggesting a regulatory function in the chronic phase. Mice deficient in IRF4 display increased tubular cell loss and defective clearance of infiltrating macrophages. These phenomena were associated with increased expression of pro-inflammatory macrophage markers together with reduced expression of alternatively activated macrophage markers. In addition, IRF4-deficient mice showed defective development of alternatively activated macrophages. Hints of a residual M1 macrophage signature were further observed in human biopsy specimens of patients with hypertensive nephropathy vs. living donor specimens. Thus, IRF4 restricts CKD progression and kidney fibrosis following IRI, potentially by enabling M2 macrophage polarization and restricting a Th1 cytokine response. Deteriorated alternative macrophage subpopulations in Irf4−/− mice provoke chronic intrarenal inflammation, tubular epithelial cell loss, and renal fibrosis in the long course after IRI in mice. The clinical significance of these finding for human CKD remains uncertain at present and warrants further studies.

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“…Notable examples include the interferon regulatory factor 4 (IRF4), the α chain of the interleukin 2 receptor (IL-2Rα/CD25), the cytotoxic T lymphocyte protein 4 and the glycoprotein A repetitions predominant (GARP). [16][17][18][19][20][21][22] Genetic variants affecting the function or the expression of these molecules have been reported to underlie monogenic inborn errors of immunity, which cause immune dysregulation [18][19][20][21][22] or to confer susceptibility for autoimmune diseases. [23][24][25] An imbalance between proinflammatory CD4 + T helper (Th) cell subsets, that is, Th1 and Th17 cells, and Tregs is thought to be involved in the pathogenesis of GCA.…”

Section: Vasculitismentioning

confidence: 99%

Novel aspects of regulatory T cell dysfunction as a therapeutic target in giant cell arteritis

et al. 2021

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ObjectivesGiant cell arteritis (GCA) is the most common primary vasculitis, preferentially affecting the aorta and its large-calibre branches. An imbalance between proinflammatory CD4+ T helper cell subsets and regulatory T cells (Tregs) is thought to be involved in the pathogenesis of GCA and Treg dysfunction has been associated with active disease. Our work aims to explore the aetiology of Treg dysfunction and the way it is affected by remission-inducing immunomodulatory regimens.MethodsA total of 41 GCA patients were classified into active disease (n=14) and disease in remission (n=27). GCA patients’ and healthy blood donors’ (HD) Tregs were sorted and subjected to transcriptome and phenotypic analysis.ResultsTranscriptome analysis revealed 27 genes, which were differentially regulated between GCA-derived and HD-derived Tregs. Among those, we identified transcription factors, glycolytic enzymes and IL-2 signalling mediators. We confirmed the downregulation of forkhead box P3 (FOXP3) and interferon regulatory factor 4 (IRF4) at protein level and identified the ineffective induction of glycoprotein A repetitions predominant (GARP) and CD25 as well as the reduced T cell receptor (TCR)-induced calcium influx as correlates of Treg dysfunction in GCA. Inhibition of glycolysis in HD-derived Tregs recapitulated most identified dysfunctions of GCA Tregs, suggesting the central pathogenic role of the downregulation of the glycolytic enzymes. Separate analysis of the subgroup of tocilizumab-treated patients identified the recovery of the TCR-induced calcium influx and the Treg suppressive function to associate with disease remission.ConclusionsOur findings suggest that low glycolysis and calcium signalling account for Treg dysfunction and inflammation in GCA.

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New human combined immunodeficiency caused by interferon regulatory factor 4 (IRF4) deficiency inherited by uniparental isodisomy

Cited by 18 publications

References 25 publications

Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients

Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients

IFN Regulatory Factor 4 Controls Post-ischemic Inflammation and Prevents Chronic Kidney Disease

Novel aspects of regulatory T cell dysfunction as a therapeutic target in giant cell arteritis

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