{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T23:14:23Z","timestamp":1784934863419,"version":"3.55.0"},"reference-count":124,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T00:00:00Z","timestamp":1658707200000},"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><jats:bold>Review<\/jats:bold>: Interleukin-18 (IL-18) is a proinflammatory cytokine that promotes various innate immune processes related to infection, inflammation, and autoimmunity. Patients with systemic juvenile idiopathic arthritis and adult-onset Still\u2019s disease exhibit chronic excess of serum IL-18, which is associated with a high incidence of macrophage activation syndrome (MAS), although the mechanisms of IL-18 regulation in such diseases remain largely unknown. Similar elevation of serum IL-18 and susceptibility to MAS\/hemophagocytic lymphohistiocytosis (HLH) have been reported in monogenic diseases such as X-linked inhibitor of apoptosis deficiency (i.e., X-linked lymphoproliferative syndrome type 2) and NLRC4-associated autoinflammatory disease. Recent advances in molecular and cellular biology allow the identification of other genetic defects such as defects in <jats:italic>CDC42<\/jats:italic>, <jats:italic>PSTPIP1<\/jats:italic>, and <jats:italic>WDR1<\/jats:italic> that result in high serum IL-18 levels and hyperinflammation. Among these diseases, chronic excess of serum IL-18 appears to be linked with severe hyperinflammation and\/or predisposition to MAS\/HLH. In this review, we focus on recent findings in inflammatory diseases associated with and probably attributable to chronic excess of serum IL-18 and describe the clinical and therapeutical relevance of understanding the pathology of this group of diseases.<\/jats:p>","DOI":"10.3389\/fimmu.2022.930141","type":"journal-article","created":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T13:00:23Z","timestamp":1658754023000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Immune-mediated inflammatory diseases with chronic excess of serum interleukin-18"],"prefix":"10.3389","volume":"13","author":[{"given":"Hanae","family":"Miyazawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taizo","family":"Wada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0000000000000634","article-title":"Interleukin-18 in pediatric rheumatic diseases","volume":"31","author":"Prencipe","year":"2019","journal-title":"Curr Opin Rheumatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12616","article-title":"Interleukin-18: Biological properties and role in disease pathogenesis","volume":"281","author":"Kaplanski","year":"2018","journal-title":"Immunol Rev"},{"key":"B3","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1111\/imr.12621","article-title":"Overview of the IL-1 family in innate inflammation and acquired immunity","volume":"281","author":"Dinarello","year":"2018","journal-title":"Immunol Rev"},{"key":"B4","doi-asserted-by":"publisher","first-page":"6160","DOI":"10.1038\/s41598-019-42661-5","article-title":"An innate interaction between IL-18 and the propeptide that inactivates its precursor form","volume":"9","author":"Tsutsumi","year":"2019","journal-title":"Sci Rep"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01840","article-title":"Human autoinflammatory diseases mediated by NLRP3-, pyrin-, NLRP1-, and NLRC4-inflammasome dysregulation updates on diagnosis, treatment, and the respective roles of IL-1 and IL-18","volume":"11","author":"Alehashemi","year":"2020","journal-title":"Front Immunol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"5340","DOI":"10.1038\/ncomms6340","article-title":"The structural basis for receptor recognition of human interleukin-18","volume":"5","author":"Tsutsumi","year":"2014","journal-title":"Nat Commun"},{"key":"B7","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1111\/imr.12606","article-title":"The family of the interleukin-1 receptors","volume":"281","author":"Boraschi","year":"2018","journal-title":"Immunol Rev"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-06-789552","article-title":"Unopposed IL-18 signaling leads to severe TLR9-induced macrophage activation syndrome in mice","volume":"131","author":"Girard-Guyonvarc'h","year":"2018","journal-title":"Blood"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.696605","article-title":"Current understanding of IL-37 in human health and disease","volume":"12","author":"Su","year":"2021","journal-title":"Front Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019000936","article-title":"Pediatric hemophagocytic lymphohistiocytosis","volume":"135","author":"Canna","year":"2020","journal-title":"Blood"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0000000000000526","article-title":"Systemic juvenile idiopathic arthritis and macrophage activation syndrome: update on pathogenesis and treatment","volume":"30","author":"Yasin","year":"2018","journal-title":"Curr Opin Rheumatol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1007\/s12026-014-8561-9","article-title":"Pathogenesis of adult-onset still\u2019s disease: new insights from the juvenile counterpart","volume":"61","author":"Jamilloux","year":"2015","journal-title":"Immunol Res"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-210324","article-title":"Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications","volume":"76","author":"Ombrello","year":"2017","journal-title":"Ann Rheum Dis"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1520779112","article-title":"HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis","volume":"112","author":"Ombrello","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.03089","article-title":"Natural killer cells in systemic autoinflammatory diseases: a focus on systemic juvenile idiopathic arthritis and macrophage activation syndrome","volume":"10","author":"Vandenhaute","year":"2020","journal-title":"Front Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-12-820852","article-title":"Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome","volume":"131","author":"Weiss","year":"2018","journal-title":"Blood"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kez282","article-title":"IL-18 as a biomarker linking systemic juvenile idiopathic arthritis and macrophage activation syndrome","volume":"59","author":"Yasin","year":"2020","journal-title":"Rheumatol (Oxford)"},{"key":"B18","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.clim.2016.05.010","article-title":"Cytokine profile in adult-onset still\u2019s disease: Comparison with systemic juvenile idiopathic arthritis","volume":"169","author":"Inoue","year":"2016","journal-title":"Clin Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keq133","article-title":"Distinct cytokine profiles of systemic-onset juvenile idiopathic arthritis-associated macrophage activation syndrome with particular emphasis on the role of interleukin-18 in its pathogenesis","volume":"49","author":"Shimizu","year":"2010","journal-title":"Rheumatol (Oxf)"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keaa634","article-title":"Clinical significance of interleukin-18 for the diagnosis and prediction of disease course in systemic juvenile idiopathic arthritis","volume":"60","author":"Mizuta","year":"2021","journal-title":"Rheumatol (Oxf)"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kew300","article-title":"Elevated serum levels of free interleukin-18 in adult-onset still\u2019s disease","volume":"55","author":"Girard","year":"2016","journal-title":"Rheumatol (Oxford)."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2015-209020","article-title":"Elevated circulating levels of interferon-\u03b3 and interferon-\u03b3-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis","volume":"76","author":"Bracaglia","year":"2017","journal-title":"Ann Rheum Dis"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keu524","article-title":"Cytokines in systemic juvenile idiopathic arthritis and haemophagocytic lymphohistiocytosis: tipping the balance between interleukin-18 and interferon-\u03b3","volume":"54","author":"Put","year":"2015","journal-title":"Rheumatol (Oxf)"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kep418","article-title":"Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis","volume":"49","author":"Vastert","year":"2010","journal-title":"Rheumatol (Oxford)"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/art.38793","article-title":"Whole-exome wequencing reveals overlap between macrophage activation syndrome in systemic juvenile idiopathic arthritis and familial hemophagocytic lymphohistiocytosis","volume":"66","author":"Kaufman","year":"2014","journal-title":"Arthritis Rheumatol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/art.24750","article-title":"Defective phosphorylation of interleukin-18 receptor beta causes impaired natural killer cell function in systemic-onset juvenile idiopathic arthritis","volume":"60","author":"de Jager","year":"2009","journal-title":"Arthritis Rheumatol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/art.39933","article-title":"Inflammatory gene expression profile and defective interferon-\u03b3 and granzyme K in natural killer cells from systemic juvenile idiopathic arthritis patients","volume":"69","author":"Put","year":"2017","journal-title":"Arthritis Rheumatol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1111\/ped.13679","article-title":"Transient natural killer cell dysfunction associated with interleukin-18 overproduction in systemic juvenile idiopathic arthritis","volume":"60","author":"Takakura","year":"2018","journal-title":"Pediatr Int"},{"key":"B29","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.cytogfr.2014.05.005","article-title":"Cytokine balance and cytokine-driven natural killer cell dysfunction in systemic juvenile idiopathic arthritis","volume":"26","author":"Avau","year":"2015","journal-title":"Cytokine Growth Factor Rev"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/art.39295","article-title":"Inhibition of natural killer cell cytotoxicity by interleukin-6: implications for the pathogenesis of macrophage activation syndrome","volume":"67","author":"Cifaldi","year":"2015","journal-title":"Arthritis Rheumatol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keg074","article-title":"Reduced perforin expression in systemic juvenile idiopathic arthritis is restored by autologous stem-cell transplantation","volume":"42","author":"Wulffraat","year":"2003","journal-title":"Rheumatol (Oxford)"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/art.41073","article-title":"Systemic juvenile idiopathic arthritis\u2013associated lung disease: characterization and risk factors","volume":"71","author":"Schulert","year":"2019","journal-title":"Arthritis Rheumatol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2019-216040","article-title":"Emergent high fatality lung disease in systemic juvenile arthritis","volume":"78","author":"Saper","year":"2019","journal-title":"Ann Rheum Dis"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1172\/JCI129301","article-title":"Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases","volume":"130","author":"de Jesus","year":"2020","journal-title":"J Clin Invest"},{"key":"B35","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.clim.2018.10.016","article-title":"Targeting cytokines to treat autoinflammatory diseases","volume":"206","author":"Hausmann","year":"2019","journal-title":"Clin Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2017-212608","article-title":"Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset still\u2019s disease","volume":"77","author":"Gabay","year":"2018","journal-title":"Ann Rheum Dis"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keab673","article-title":"Interfering with interferons: targeting the JAK-STAT pathway in complications of systemic juvenile idiopathic arthritis (SJIA)","volume":"61","author":"Verweyen","year":"2022","journal-title":"Rheumatol (Oxford)"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2015.01.015","article-title":"XIAP deficiency syndrome in humans","volume":"39","author":"Latour","year":"2015","journal-title":"Semin Cell Dev Biol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2021.660520","article-title":"Evolution of our understanding of XIAP deficiency","volume":"9","author":"Mudde","year":"2021","journal-title":"Front Pediatr"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2015-310382","article-title":"Impaired antibacterial autophagy links granulomatous intestinal inflammation in niemann\u2013pick disease type C1 and XIAP deficiency with NOD2 variants in crohn\u2019s disease","volume":"66","author":"Schwerd","year":"2017","journal-title":"Gut"},{"key":"B41","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1038\/s41419-018-0508-y","article-title":"Inhibitor of apoptosis proteins are required for effective fusion of autophagosomes with lysosomes","volume":"9","author":"Gradzka","year":"2018","journal-title":"Cell Death Dis"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/nature05257","article-title":"XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome","volume":"444","author":"Rigaud","year":"2006","journal-title":"Nature"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-01-256099","article-title":"XIAP deficiency: A unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease","volume":"116","author":"Marsh","year":"2010","journal-title":"Blood."},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2013.09.007","article-title":"Sustained elevation of serum interleukin-18 and its association with hemophagocytic lymphohistiocytosis in XIAP deficiency","volume":"65","author":"Wada","year":"2014","journal-title":"Cytokine"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1956","DOI":"10.1016\/j.jaci.2018.04.033","article-title":"Autoinflammatory mutation in NLRC4 reveals a leucine-rich repeat (LRR)\u2013 LRR oligomerization interface","volume":"142","author":"Moghaddas","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02162","article-title":"Rapamycin as an adjunctive therapy for NLRC4 associated macrophage activation syndrome","volume":"9","author":"Barsalou","year":"2018","journal-title":"Front Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3066","article-title":"Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation","volume":"46","author":"Romberg","year":"2014","journal-title":"Nat Genet"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3089","article-title":"An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome","volume":"46","author":"Canna","year":"2014","journal-title":"Nat Genet"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2016.10.022","article-title":"Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition","volume":"139","author":"Canna","year":"2017","journal-title":"J Allergy Clin Immunol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-019-00611-w","article-title":"Autoinflammation with infantile enterocolitis associated with recurrent perianal abscesses","volume":"39","author":"Siahanidou","year":"2019","journal-title":"J Clin Immunol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2019.108328","article-title":"A novel de novo NLRC4 mutation reinforces the likely pathogenicity of specific LRR domain mutation","volume":"211","author":"Chear","year":"2020","journal-title":"Clin Immunol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10194369","article-title":"NLRC4 GOF mutations, a challenging diagnosis from neonatal age to adulthood","volume":"10","author":"Bardet","year":"2021","journal-title":"J Clin Med"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20190147","article-title":"A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function","volume":"216","author":"Lam","year":"2019","journal-title":"J Exp Med"},{"key":"B54","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1016\/j.jaci.2019.06.017","article-title":"Severe autoinflammation in 4 patients with c-terminal variants in cell division control protein 42 homolog (CDC42) successfully treated with IL-1\u03b2 inhibition","volume":"144","author":"Gernez","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-020-00778-7","article-title":"Infantile myelofibrosis and myeloproliferation with CDC42 dysfunction","volume":"40","author":"Verboon","year":"2020","journal-title":"J Clin Immunol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-020-00786-7","article-title":"A new patient with NOCARH syndrome due to CDC42 defect","volume":"40","author":"He","year":"2020","journal-title":"J Clin Immunol"},{"key":"B57","doi-asserted-by":"publisher","first-page":"1201","DOI":"10.1016\/j.jaci.2020.03.020","article-title":"A toxic palmitoylation of Cdc42 enhances NF-\u03baB signaling and drives a severe autoinflammatory syndrome","volume":"146","author":"Bekhouche","year":"2020","journal-title":"J Allergy Clin Immunol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1111\/jdv.13856","article-title":"High level of serum human interleukin-18 in a patient with pyogenic arthritis, pyoderma gangrenosum and acne syndrome","volume":"31","author":"Kanameishi","year":"2017","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1002\/art.41976","article-title":"Excess serum interleukin-18 distinguishes patients with pathogenic mutations in PSTPIP1","volume":"74","author":"Stone","year":"2022","journal-title":"Arthritis Rheumatol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-03-706028","article-title":"Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency","volume":"128","author":"Kuhns","year":"2016","journal-title":"Blood."},{"key":"B61","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1084\/jem.20161228","article-title":"Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1","volume":"214","author":"Standing","year":"2017","journal-title":"J Exp Med"},{"key":"B62","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.1016\/j.jaci.2018.04.023","article-title":"Mutations affecting the actin regulator WD repeat\u2013containing protein 1 lead to aberrant lymphoid immunity","volume":"142","author":"Pfajfer","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.05.008","article-title":"XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation","volume":"7","author":"Yabal","year":"2014","journal-title":"Cell Rep"},{"key":"B64","doi-asserted-by":"publisher","first-page":"6282","DOI":"10.1038\/ncomms7282","article-title":"RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL","volume":"6","author":"Lawlor","year":"2015","journal-title":"Nat Commun"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.01.012","article-title":"Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation","volume":"36","author":"Vince","year":"2012","journal-title":"Immunity"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.06.073","article-title":"XIAP loss triggers RIPK3- and caspase-8-driven IL-1\u03b2 activation and cell death as a consequence of TLR-MyD88-induced cIAP1-TRAF2 degradation","volume":"20","author":"Lawlor","year":"2017","journal-title":"Cell Rep"},{"key":"B67","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1038\/s41419-019-1938-x","article-title":"TNFR2 induced priming of the inflammasome leads to a RIPK1-dependent cell death in the absence of XIAP","volume":"10","author":"Knop","year":"2019","journal-title":"Cell Death Dis"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-06-432500","article-title":"Allogeneic hematopoietic cell transplantation for XIAP deficiency: an international survey reveals poor outcomes","volume":"121","author":"Marsh","year":"2013","journal-title":"Blood"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-07-298372","article-title":"Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1\/SAP deficiency) versus type 2 (XLP-2\/XIAP deficiency)","volume":"117","author":"Pachlopnik Schmid","year":"2011","journal-title":"Blood"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-022-01236-2","article-title":"A case of XIAP deficiency successfully managed with tadekinig alfa (rhIL-18BP)","volume":"42","author":"Geerlinks","year":"2022","journal-title":"J Clin Immunol"},{"key":"B71","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1111\/imr.12906","article-title":"Molecular mechanisms activating the NAIP-NLRC4 inflammasome: Implications in infectious disease, autoinflammation, and cancer","volume":"297","author":"Kay","year":"2020","journal-title":"Immunol Rev"},{"key":"B72","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1097\/ACI.0000000000000396","article-title":"NLRC4 inflammasomopathies","volume":"17","author":"Romberg","year":"2017","journal-title":"Curr Opin Allergy Clin Immunol"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20141091","article-title":"An inherited mutation in NLRC4 causes autoinflammation in human and mice","volume":"211","author":"Kitamura","year":"2014","journal-title":"J Exp Med"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1186\/1546-0096-13-S1-O68","article-title":"Anti interferon-gamma (IFN\u03b3) monoclonal antibody treatment in a patient carrying an NLRC4 mutation and severe hemophagocytic lymphohistiocytosis","volume":"13","author":"Bracaglia","year":"2015","journal-title":"Pediatr Rheumatol Online J"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1111\/bjd.14757","article-title":"Erythematous nodes, urticarial rash and arthralgias in a large pedigree with NLRC4-related autoinflammatory disease, expansion of the phenotype","volume":"176","author":"Volker-Touw","year":"2017","journal-title":"Br J Dermatol"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1002\/art.39960","article-title":"Identification of a high-frequency somatic NLRC4 mutation as a cause of autoinflammation by pluripotent cell\u2013based phenotype dissection","volume":"69","author":"Kawasaki","year":"2017","journal-title":"Arthritis Rheumatol"},{"key":"B77","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1177\/1093526616686890","article-title":"Novel NLRC4 mutation causes a syndrome of perinatal autoinflammation with hemophagocytic lymphohistiocytosis, hepatosplenomegaly, fetal thrombotic vasculopathy, and congenital anemia and ascites","volume":"20","author":"Liang","year":"2017","journal-title":"Pediatr Dev Pathol"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1177\/2152656720928062","article-title":"Novel gene deletion in NLRC4 expanding the familial cold inflammatory syndrome phenotype","volume":"11","author":"Jeskey","year":"2020","journal-title":"Allergy Rhinol (Providence)"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1002\/art.41999.2021;0\u20133","article-title":"First description of late-onset autoinflammatory disease due to somatic NLRC4 mosaicism","volume":"74","author":"Ionescu","year":"2022","journal-title":"Arthritis Rheumatol"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.674808","article-title":"A novel mutation in the NBD domain of NLRC4 causes mild autoinflammation with recurrent urticaria","volume":"12","author":"Wang","year":"2021","journal-title":"Front Immunol"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.591713","article-title":"Distinct roles of IL-1\u03b2 and IL-18 in NLRC4-induced autoinflammation","volume":"11","author":"Sasaki","year":"2020","journal-title":"Front Immunol"},{"key":"B82","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1038\/s41577-021-00500-7","article-title":"RHO GTPases: from new partners to complex immune syndromes","volume":"21","author":"El Masri","year":"2021","journal-title":"Nat Rev Immunol"},{"key":"B83","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/nrm3153","article-title":"The \u2018invisible hand\u2019: regulation of RHO GTPases by RHOGDIs","volume":"12","author":"Garcia-Mata","year":"2011","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-020-00785-8","article-title":"The growing spectrum of human diseases caused by inherited CDC42 mutations","volume":"40","author":"Su","year":"2020","journal-title":"J Clin Immunol"},{"key":"B85","doi-asserted-by":"publisher","first-page":"e20211889","DOI":"10.1084\/jem.20211889","article-title":"Trapping of CDC42 c-terminal variants in the golgi drives pyrin inflammasome hyperactivation","volume":"219","author":"Nishitani-Isa","year":"2022","journal-title":"J Exp Med"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-020-00742-5","article-title":"Systemic inflammation and myelofibrosis in a patient with takenouchi-KosakiJ syndrome due to CDC42 Tyr64Cys mutation","volume":"40","author":"Bucciol","year":"2020","journal-title":"J Clin Immunol"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00318","article-title":"A novel CDC42 mutation in an 11-year old child manifesting as malignancy: a case report","volume":"11","author":"Szczawinska-Poplonyk","year":"2020","journal-title":"Front Immunol"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37275","article-title":"Macrothrombocytopenia and developmental delay with a de novo CDC42 mutation: Yet another locus for thrombocytopenia and developmental delay","author":"Takenouchi","year":"2015","journal-title":"Am J Med Genet A"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37526","article-title":"Further evidence of a mutation in CDC42 as a cause of a recognizable syndromic form of thrombocytopenia","author":"Takenouchi","year":"2016","journal-title":"Am J Med Genet A"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1038\/s10038-017-0396-5","article-title":"A hot-spot mutation in CDC42 (p.Tyr64Cys) and novel phenotypes in the third patient with takenouchi-kosaki syndrome","volume":"63","author":"Motokawa","year":"2018","journal-title":"J Hum Genet"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.12.015","article-title":"Functional dysregulation of CDC42 causes diverse developmental phenotypes","volume":"102","author":"Martinelli","year":"2018","journal-title":"Am J Hum Genet"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2022.01.024","article-title":"Mutations at the C-terminus of CDC42 cause distinct hematopoietic and autoinflammatory disorders","volume":"150","author":"Coppola","year":"2022","journal-title":"J Allergy Clin Immunol"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0000000000000314","article-title":"Alarming consequences \u2013 autoinflammatory disease spectrum due to mutations in proline-serine-threonine phosphatase-interacting protein 1","volume":"28","author":"Holzinger","year":"2016","journal-title":"Curr Opin Rheumatol"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.8.961","article-title":"Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder","volume":"11","author":"Wise","year":"2002","journal-title":"Hum Mol Genet"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0006147","article-title":"Pyrin modulates the intracellular distribution of PSTPIP1","volume":"4","author":"Waite","year":"2009","journal-title":"PloS One"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2135380100","article-title":"Pyrin binds the PSTPIP1\/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway","volume":"100","author":"Shoham","year":"2003","journal-title":"Proc Natl Acad Sci USA"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2007.08.029.2007;214\u201327","article-title":"Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants","volume":"28","author":"Yu","year":"2007","journal-title":"Mol Cell"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2015.04.016","article-title":"Single amino acid charge switch defines clinically distinct (PSTPIP1)\u2013associated inflammatory diseases","volume":"136","author":"Holzinger","year":"2015","journal-title":"J Allergy Clin Immunol"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M106428200","article-title":"PSTPIP is a substrate of PTP-PEST and serves as a scaffold guiding PTP-PEST toward a specific dephosphorylation of WASP","volume":"277","author":"C\u00f4t\u00e9","year":"2002","journal-title":"J Biol Chem"},{"key":"B100","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1084\/jem.20030976","article-title":"Fyn and PTP-PEST\u2013mediated regulation of wiskott-Aldrich syndrome protein (WASp) tyrosine phosphorylation is required for coupling T cell antigen receptor engagement to WASp effector function and T cell activation","volume":"199","author":"Badour","year":"2004","journal-title":"J Exp Med"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1002\/art.27521","article-title":"Impaired podosome formation and invasive migration of macrophages from patients with a PSTPIP1 mutation and PAPA syndrome","volume":"62","author":"Cortesio","year":"2010","journal-title":"Arthritis Rheumatol"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1002\/cbin.10514","article-title":"Pyrin\u2013PSTPIP1 colocalises at the leading edge during cell migration","volume":"39","author":"Akkaya-ulum","year":"2015","journal-title":"Cell Biol Int"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-07-516948","article-title":"The f-BAR protein PSTPIP1 controls extracellular matrix degradation and fi lopodia formation in macrophages","volume":"123","author":"Starnes","year":"2014","journal-title":"Blood"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kew031","article-title":"Disease activity accounts for long-term efficacy of IL-1 blockers in pyogenic sterile arthritis pyoderma gangrenosum and severe acne syndrome","volume":"55","author":"Omenetti","year":"2016","journal-title":"Rheumatol (Oxford)"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-10-055087","article-title":"Mutations in the cofilin partner Aip1\/Wdr1 cause autoinflammatory disease and macrothrombocytopenia","volume":"110","author":"Kile","year":"2007","journal-title":"Blood"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20142384","article-title":"Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1\u03b2","volume":"212","author":"Kim","year":"2015","journal-title":"J Exp Med"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kez284","article-title":"IL-18 as therapeutic target in a patient with resistant systemic juvenile idiopathic arthritis and recurrent macrophage activation syndrome","volume":"59","author":"Yasin","year":"2020","journal-title":"Rheumatol (Oxf)"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100630","article-title":"A novel anti-human IL-1R7 antibody reduces IL-18-mediated inflammatory signaling","volume":"296","author":"Li","year":"2021","journal-title":"J Biol Chem"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2017.07.021","article-title":"Neutralization of IFN-\u03b3 reverts clinical and laboratory features in a mouse model of macrophage activation syndrome","volume":"141","author":"Prencipe","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032414-112227","article-title":"Molecular mechanisms in genetically defined autoinflammatory diseases: disorders of amplified danger signaling","volume":"33","author":"de Jesus","year":"2015","journal-title":"Annu Rev Immunol"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3777","article-title":"The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation","volume":"18","author":"Manthiram","year":"2017","journal-title":"Nat Immunol"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.08.017","article-title":"Monogenic autoinflammatory disorders: Conceptual overview, phenotype, and clinical approach","volume":"146","author":"Nigrovic","year":"2020","journal-title":"J Allergy Clin Immunol"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.604206","article-title":"Actin remodeling defects leading to autoinflammation and immune dysregulation","volume":"11","author":"Papa","year":"2021","journal-title":"Front Immunol"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01745","article-title":"The pyrin inflammasome in health and disease","volume":"10","author":"Schnappauf","year":"2019","journal-title":"Front Immunol"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.00237","article-title":"Identification of the PANoptosome: A molecular platform triggering pyroptosis, apoptosis, and necroptosis (PANoptosis)","volume":"10","author":"Christgen","year":"2020","journal-title":"Front Cell Infect Microbiol"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03875-8","article-title":"AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence","volume":"597","author":"Lee","year":"2021","journal-title":"Nature."},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-05-1980","article-title":"Severe imbalance of IL-18\/IL-18BP in patients with secondary hemophagocytic syndrome","volume":"106","author":"Mazodier","year":"2005","journal-title":"Blood."},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2021.155781","article-title":"Balance between interleukin-18 and interleukin-18 binding protein in auto-inflammatory diseases","volume":"150","author":"Harel","year":"2022","journal-title":"Cytokine."},{"key":"B119","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20190669","article-title":"Inherited IL-18BP deficiency in human fulminant viral hepatitis","volume":"216","author":"Belkaya","year":"2019","journal-title":"J Exp Med"},{"key":"B120","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1900510","article-title":"Regulatory role for NK cells in a mouse model of systemic juvenile idiopathic arthritis","volume":"203","author":"Vandenhaute","year":"2019","journal-title":"J Immunol"},{"key":"B121","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019003664","article-title":"Functional and genetic testing in adults with HLH reveals an inflammatory profile rather than a cytotoxicity defect","volume":"136","author":"Carvelli","year":"2020","journal-title":"Blood"},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00827","article-title":"Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19)","volume":"11","author":"Diao","year":"2020","journal-title":"Front Immunol"},{"key":"B123","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019003846","article-title":"Interleukin-18 and cytotoxic impairment are independent and synergistic causes of murine virus-induced hyperinflammation","volume":"136","author":"Tsoukas","year":"2020","journal-title":"Blood"},{"key":"B124","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.29606","article-title":"An efficient diagnosis: A patient with X-linked inhibitor of apoptosis protein (XIAP) deficiency in the setting of infantile hemophagocytic lymphohistiocytosis was diagnosed using high serum interleukin-18 combined with common laboratory parameters","volume":"69","author":"Higuchi","year":"2022","journal-title":"Pediatr Blood Cancer"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.930141\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T13:00:25Z","timestamp":1658754025000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.930141\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,25]]},"references-count":124,"alternative-id":["10.3389\/fimmu.2022.930141"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.930141","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,25]]},"article-number":"930141"}}