{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T01:03:34Z","timestamp":1791594214952,"version":"4.3.4"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,12]],"date-time":"2022-09-12T00:00:00Z","timestamp":1662940800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Patients with STAT1 gain-of-function (GOF) mutations suffer from an inborn error of immunity hallmarked by chronic mucocutaneous candidiasis (CMC). The pathogenesis behind this complex and heterogeneous disease is still incompletely understood. Beyond the well-recognized Th17 failure, linked to the STAT1\/STAT3 dysbalance-driven abrogation of antifungal defense, only little is known about the consequences of augmented STAT1 signaling in other cells, including, interestingly, the innate immune cells. STAT1-mediated signaling was previously shown to be increased in STAT1 GOF CD14+ monocytes. Therefore, we hypothesized that monocytes might represent important co-orchestrators of antifungal defense failure, as well as various immunodysregulatory phenomena seen in patients with STAT1 GOF CMC, including autoimmunity. In this article, we demonstrate that human STAT1 GOF monocytes are characterized by proinflammatory phenotypes and a strong inflammatory skew of their secretory cytokine profile. Moreover, they exhibit diminished CD16 expression, and reduction of classical (CD14++C16-) and expansion of intermediate (CD14++16+) subpopulations. Amongst the functional aberrations, a selectively enhanced responsiveness to TLR7\/8 stimulation, but not to other TLR ligands, was noted, which might represent a contributing mechanism in the pathogenesis of STAT1 GOF-associated autoimmunity. Importantly, some of these features extend to STAT1 GOF monocyte-derived dendritic cells and to STAT1 GOF peripheral myeloid dendritic cells, suggesting that the alterations observed in monocytes are, in fact, intrinsic due to STAT1 mutation, and not mere bystanders of chronic inflammatory environment. Lastly, we observe that the proinflammatory bias of STAT1 GOF monocytes may be ameliorated with JAK inhibition. Taken together, we show that monocytes likely play an active role in both the microbial susceptibility and autoimmunity in STAT1 GOF CMC.<\/jats:p>","DOI":"10.3389\/fimmu.2022.983977","type":"journal-article","created":{"date-parts":[[2022,9,12]],"date-time":"2022-09-12T07:28:18Z","timestamp":1662967698000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Immunoprofiling of monocytes in STAT1 gain-of-function chronic mucocutaneous candidiasis"],"prefix":"10.3389","volume":"13","author":[{"given":"Marketa","family":"Bloomfield","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irena","family":"Zentsova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Milota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Sediva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuzana","family":"Parackova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1084\/JEM.20110958","article-title":"Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis","volume":"208","author":"Liu","year":"2011","journal-title":"J Exp Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-11-679902","article-title":"Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype","volume":"127","author":"Toubiana","year":"2016","journal-title":"Blood"},{"key":"B3","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1007\/S10875-015-0214-9","article-title":"The extended clinical phenotype of 26 patients with chronic mucocutaneous candidiasis due to gain-of-Function mutations in STAT1","volume":"36","author":"Depner","year":"2016","journal-title":"J Clin Immunol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1056\/NEJMOA1100102\/SUPPL_FILE\/NEJMOA1100102_DISCLOSURES.PDF","article-title":"STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis","volume":"365","author":"van de Veerdonk","year":"2011","journal-title":"N Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/EJI.201445344","article-title":"Gain-of-function STAT1 mutations impair STAT3 activity in patients with chronic mucocutaneous candidiasis (CMC)","volume":"45","author":"Zheng","year":"2015","journal-title":"Eur J Immunol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1007\/s10875-018-0519-6","article-title":"Utility of ruxolitinib in a child with chronic mucocutaneous candidiasis caused by a novel STAT1 gain-of-function mutation","volume":"38","author":"Bloomfield","year":"2018","journal-title":"J Clin Immunol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/S10875-022-01257-X\/FIGURES\/2","article-title":"Impact of JAK inhibitors in pediatric patients with STAT1 gain of function (GOF) mutations\u201310 children and review of the literature","volume":"12","author":"Dey\u00e0-Mart\u00ednez","year":"2022","journal-title":"J Clin Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1126\/SCIENCE.8197455","article-title":"Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins","volume":"264","author":"Darnell","year":"1994","journal-title":"Science"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1039\/B606246F","article-title":"Structure, function, and regulation of STAT proteins","volume":"2","author":"Lim","year":"2006","journal-title":"Mol Biosyst"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/NRM909","article-title":"Stats: transcriptional control and biological impact","volume":"3","author":"Levy","year":"2002","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1074\/JBC.R700016200","article-title":"JAK-STAT signaling: From interferons to cytokines","volume":"282","author":"Schindler","year":"2007","journal-title":"J Biol Chem"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1073\/PNAS.0501063102","article-title":"Implications of an antiparallel dimeric structure of nonphosphorylated STAT1 for the activation-inactivation cycle","volume":"102","author":"Zhong","year":"2005","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2019.01433\/BIBTEX","article-title":"STAT1 gain-of-function mutations cause high total STAT1 levels with normal dephosphorylation","volume":"10","author":"Zimmerman","year":"2019","journal-title":"Front Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/J.JID.2017.09.035","article-title":"STAT1 gain-of-Function and dominant negative STAT3 mutations impair IL-17 and IL-22 immunity associated with CMC","volume":"138","author":"Hiller","year":"2018","journal-title":"J Invest Dermatol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41525-021-00196-7","article-title":"STAT1 gain-of-function heterozygous cell models reveal diverse interferon-signature gene transcriptional responses","volume":"6","author":"Scott","year":"2021","journal-title":"NPJ Genomic Med 2021 61"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2021.654406\/BIBTEX","article-title":"Clinical relevance of gain- and loss-of-Function germline mutations in STAT1: A systematic review","volume":"12","author":"Zhang","year":"2021","journal-title":"Front Immunol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"2142","DOI":"10.1016\/J.JACI.2017.08.040","article-title":"Ruxolitinib partially reverses functional NK cell deficiency in patients with STAT1 gain-of-function mutations","volume":"141","author":"Vargas-Hern\u00e1ndez","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1016\/J.JACI.2016.10.051","article-title":"Impaired natural killer cell functions in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations","volume":"140","author":"Tabellini","year":"2017","journal-title":"J Allergy Clin Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.10.005","article-title":"Immunity review developmental and functional heterogeneity of monocytes","volume":"49","author":"Guilliams","year":"2018","journal-title":"Immunity"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1182\/BLOOD-2010-02-258558","article-title":"Nomenclature of monocytes and dendritic cells in blood","volume":"116","author":"Ziegler-Heitbrock","year":"2010","journal-title":"Blood"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01140","article-title":"The role of monocytes and macrophages in autoimmune diseases: A comprehensive review","volume":"10","author":"Ma","year":"2019","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1189\/JLB.0513250","article-title":"Simple diagnosis of STAT1 gain-of-function alleles in patients with chronic mucocutaneous candidiasis","volume":"95","author":"Mizoguchi","year":"2014","journal-title":"J Leukoc Biol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2019.01761\/BIBTEX","article-title":"Five-marker alternative to CD16-CD14 gating to identify the three human monocyte subsets","volume":"10","author":"Ong","year":"2019","journal-title":"Front Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1126\/SCIENCE.AAH4573\/SUPPL_FILE\/AAH4573_VILLANI_SM.PDF","article-title":"Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors","volume":"356","author":"Villani","year":"2017","journal-title":"Science (80-)"},{"key":"B25","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1016\/J.IMMUNI.2019.08.008","article-title":"Single-cell analysis of human mononuclear phagocytes reveals subset-defining markers and identifies circulating inflammatory dendritic cells","volume":"51","author":"Dutertre","year":"2019","journal-title":"Immunity"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/INTIMM\/11.7.1075","article-title":"STAT1 activation during monocyte to macrophage maturation: Role of adhesion molecules","volume":"11","author":"Coccia","year":"1999","journal-title":"Int Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1007\/S10753-014-9922-1","article-title":"STAT1 regulates MD-2 expression in monocytes of sepsis via miR-30a","volume":"37","author":"Wang","year":"2014","journal-title":"Inflammation"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1007\/S10875-018-0557-0\/FIGURES\/1","article-title":"Increased STAT1 amounts correlate with the phospho-STAT1 level in STAT1 gain-of-function defects","volume":"38","author":"Bernasconi","year":"2018","journal-title":"J Clin Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/J.GENE.2016.04.006","article-title":"Common variable immunodeficiency, impaired neurological development and reduced numbers of T regulatory cells in a 10-year-old boy with a STAT1 gain-of-function mutation","volume":"586","author":"Kobbe","year":"2016","journal-title":"Gene"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PPAT.1007850","article-title":"The protective effect of inflammatory monocytes during systemic c. albicans infection is dependent on collaboration between c-type lectin-like receptors","volume":"15","author":"Thompson","year":"2019","journal-title":"PloS Pathog"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/EJI.201141418","article-title":"The classical CD14++CD16\u2013 monocytes, but not the patrolling CD14+CD16+ monocytes, promote Th17 responses to candida albicans","volume":"41","author":"Smeekens","year":"2011","journal-title":"Eur J Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/SREP34310","article-title":"CD16 is indispensable for antibody-dependent cellular cytotoxicity by human monocytes","volume":"6","author":"Yeap","year":"2016","journal-title":"Sci Rep"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1083\/JCB.201712085\/VIDEO-4","article-title":"Shedding of CD16 disassembles the NK cell immune synapse and boosts serial engagement of target cells","volume":"217","author":"Srpan","year":"2018","journal-title":"J Cell Biol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2019.01902\/BIBTEX","article-title":"ADAM17-mediated reduction in CD14++ CD16+ monocytes ex vivo and reduction in intermediate monocytes with immune paresis in acute pancreatitis and acute alcoholic hepatitis","volume":"10","author":"Waller","year":"2019","journal-title":"Front Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2016.00384\/BIBTEX","article-title":"Sustained immune complex-mediated reduction in CD16 expression after vaccination regulates NK cell function","volume":"7","author":"Goodier","year":"2016","journal-title":"Front Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.4049\/JIMMUNOL.1100244","article-title":"CD16 regulates TRIF-dependent TLR4 response in human monocytes and their subsets","volume":"188","author":"Shalova","year":"2012","journal-title":"J Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1111\/SJI.12883","article-title":"Pattern of human monocyte subpopulations in health and disease","volume":"92","author":"O\u017ca\u0144ska","year":"2020","journal-title":"Scand J Immunol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1111\/CEI.12160","article-title":"Aicardi\u2013gouti\u00e8res syndrome: A model disease for systemic autoimmunity","volume":"175","author":"Lee-Kirsch","year":"2014","journal-title":"Clin Exp Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1007\/S10875-020-00847-X\/FIGURES\/2","article-title":"Human STAT1 gain-of-Function heterozygous mutations: Chronic mucocutaneous candidiasis and type I interferonopathy","volume":"40","author":"Okada","year":"2020","journal-title":"J Clin Immunol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1691","DOI":"10.1016\/J.JACI.2013.01.004","article-title":"Gain-of-function STAT1 mutations are associated with PD-L1 overexpression and a defect in b-cell survival","volume":"131","author":"Romberg","year":"2013","journal-title":"J Allergy Clin Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2019.00768\/BIBTEX","article-title":"Impaired STAT3-dependent upregulation of IL2R\u03b1 in b cells of a patient with a STAT1 gain-of-Function mutation","volume":"10","author":"van Zelm","year":"2019","journal-title":"Front Immunol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1111\/J.1600-065X.2008.00739.X","article-title":"Innate immunity to pathogens: Diversity in receptors for microbial recognition","volume":"227","author":"Akira","year":"2009","journal-title":"Immunol Rev"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1126\/SCIENCE.1124978\/SUPPL_FILE\/PISITKUN.SOM.PDF","article-title":"Autoreactive b cell responses to RNA-related antigens due to TLR7 gene duplication","volume":"312","author":"Pisitkun","year":"2006","journal-title":"Science (80-)"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2021.777197\/BIBTEX","article-title":"Anti-TLR7 antibody protects against lupus nephritis in NZBWF1 mice by targeting b cells and patrolling monocytes","volume":"12","author":"Murakami","year":"2021","journal-title":"Front Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/J.IMMUNI.2010.08.012","article-title":"Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors","volume":"33","author":"Cros","year":"2010","journal-title":"Immunity"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1073\/PNAS.1507052112\/SUPPL_FILE\/PNAS.201507052SI.PDF","article-title":"RNA Sensing by conventional dendritic cells is central to the development of lupus nephritis","volume":"112","author":"Celhar","year":"2015","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1084\/JEM.20110654","article-title":"Type I interferon negatively controls plasmacytoid dendritic cell numbers in vivo","volume":"208","author":"Swiecki","year":"2011","journal-title":"J Exp Med"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1182\/BLOOD-2006-08-038422","article-title":"Functional specialization of human circulating CD16 and CD1c myeloid dendritic-cell subsets","volume":"109","author":"Piccioli","year":"2007","journal-title":"Blood"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1172\/JCI.INSIGHT.96101","article-title":"A type of human skin dendritic cell marked by CD5 is associated with the development of inflammatory skin disease","volume":"2","author":"Korenfeld","year":"2017","journal-title":"JCI Insight"},{"key":"B50","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1097\/SHK.0000000000001078","article-title":"Immunophenotyping of monocytes during human sepsis shows impairment in antigen presentation: A shift toward nonclassical differentiation and upregulation of FC\u03b3Ri-receptor","volume":"50","author":"Ferreira da Mota","year":"2018","journal-title":"Shock"},{"key":"B51","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/cells9102206","article-title":"Disharmonic inflammatory signatures in COVID-19: Augmented neutrophils\u2019 but impaired monocytes\u2019 and dendritic cells\u2019 responsiveness","volume":"9","author":"Parackova","year":"2020","journal-title":"Cells"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2021.778830\/BIBTEX","article-title":"Development of exhausted memory monocytes and underlying mechanisms","volume":"12","author":"Pradhan","year":"2021","journal-title":"Front Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.983977\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,12]],"date-time":"2022-09-12T07:28:23Z","timestamp":1662967703000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.983977\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,12]]},"references-count":52,"alternative-id":["10.3389\/fimmu.2022.983977"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.983977","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,12]]},"article-number":"983977"}}