{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:43:13Z","timestamp":1790710993237,"version":"4.1.0"},"reference-count":211,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T00:00:00Z","timestamp":1633478400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006014","name":"College of Medicine and Health Sciences, United Arab Emirates University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006014","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Juvenile spondyloarthritis (jSpA) is a an umbrella term for heterogeneous group of related seronegative inflammatory disorders sharing common symptoms. Although it mainly affects children and adolescents, it often remains active during adulthood. Genetic and environmental factors are involved in its occurrence, although the exact underlying immunopathophysiology remains incompletely elucidated. Accumulated evidence suggests that, in affected patients, subclinical gut inflammation caused by intestinal dysbiosis, is pivotal to the future development of synovial\u2013entheseal complex inflammation. While the predominant role of IL17\/23 axis, TNF-\u03b1, and IL-7 in the pathophysiology of SpA, including jSpA, is firmly established, the role of the cytokine macrophage migration inhibitory factor (MIF) is generally overlooked. The purpose of this review is to discuss and emphasize the role of epigenetics, neuroendocrine pathways and the hypothalamic-pituitary (HPA) axis, and to propose a novel hypothesis of the role of decreased NLRP3 gene expression and possibly MIF in the early phases of jSpA development. The decreased NLRP3 gene expression in the latter, due to hypomethylation of promotor site, is (one of) the cause for inflammasome malfunction leading to gut dysbiosis observed in patients with early jSpA. In addition, we highlight the role of MIF in the complex innate, adaptive cellular and main effector cytokine network, Finally, since treatment of advanced bone pathology in SpA remains an unmet clinical need, I suggest possible new drug targets with the aim to ultimately improve treatment efficacy and long-term outcome of jSpA patients.<\/jats:p>","DOI":"10.3389\/fmed.2021.700982","type":"journal-article","created":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T20:48:01Z","timestamp":1633553281000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Immunopathophysiology of Juvenile Spondyloarthritis (jSpA): The \u201cOut of the Box\u201d View on Epigenetics, Neuroendocrine Pathways and Role of the Macrophage Migration Inhibitory Factor (MIF)"],"prefix":"10.3389","volume":"8","author":[{"given":"Miroslav","family":"Harjacek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,6]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","DOI":"10.5772\/1304","article-title":"Challenges in Rheumatology","author":"Harjacek","year":"2011"},{"key":"B2","doi-asserted-by":"publisher","first-page":"19","DOI":"10.2147\/OARRR.S163677","article-title":"Enthesitis-related arthritis: current perspectives","volume":"11","author":"Mistry","year":"2019","journal-title":"Open Access Rheumatol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1111\/1756-185X.13922","article-title":"The conundrum of juvenile spondyloarthritis classification: Many names for a single disease? Lesson learned from an instructive clinical case","volume":"23","author":"Maniscalco","year":"2020","journal-title":"Int J Rheum Dis"},{"key":"B4","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1097\/BOR.0000000000000185","article-title":"Juvenile spondyloarthritis","volume":"27","author":"Gmuca","year":"2015","journal-title":"Curr Opin Rheumatol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/s11926-018-0751-3","article-title":"Enthesitis: Much More Than Focal Insertion Point Inflammation","volume":"20","author":"Watad","year":"2018","journal-title":"Curr Rheumatol Rep"},{"key":"B6","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1016\/j.rdc.2013.06.002","article-title":"Update on juvenile spondyloarthritis","volume":"39","author":"Ramanathan","year":"2013","journal-title":"Rheum Dis Clin North Am"},{"key":"B7","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1136\/ard.59.11.883","article-title":"Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis","volume":"59","author":"Brown","year":"2000","journal-title":"Ann Rheum Dis"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.1074\/mcp.RA117.000565","article-title":"Ranking the Contribution of Ankylosing Spondylitis-associated Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) Polymorphisms to Shaping the HLA-B*27 Peptidome","volume":"17","author":"Sanz-Bravo","year":"2018","journal-title":"Mol Cell Proteomics"},{"key":"B9","doi-asserted-by":"publisher","first-page":"R12","DOI":"10.1186\/ar3235","article-title":"Subtype specific genetic associations for juvenile idiopathic arthritis: ERAP1 with the enthesitis related arthritis subtype and IL23R with juvenile psoriatic arthritis","volume":"13","author":"Hinks","year":"2011","journal-title":"Arthritis Res Ther"},{"key":"B10","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1136\/annrheumdis-2014-206996","article-title":"Silencing or inhibition of endoplasmic reticulum aminopeptidase 1 (ERAP1) suppresses free heavy chain expression and Th17 responses in ankylosing spondylitis","volume":"75","author":"Chen","year":"2016","journal-title":"Ann Rheum Dis"},{"key":"B11","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1093\/rheumatology\/keh224","article-title":"Gene expression in juvenile arthritis and spondyloarthropathy: pro-angiogenic ELR+ chemokine genes relate to course of arthritis","volume":"43","author":"Barnes","year":"2004","journal-title":"Rheumatology (Oxford)."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1785","DOI":"10.1093\/rheumatology\/kes151","article-title":"Synovial fluid mononuclear cell gene expression profiling suggests dysregulation of innate immune genes in enthesitis-related arthritis patients","volume":"51","author":"Myles","year":"2012","journal-title":"Rheumatology (Oxford)."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e115416","DOI":"10.1371\/journal.pone.0115416","article-title":"Aberrant expression of shared master-key genes contributes to the immunopathogenesis in patients with juvenile spondyloarthritis","volume":"9","author":"Lamot","year":"2014","journal-title":"PLoS ONE."},{"key":"B14","doi-asserted-by":"publisher","first-page":"469","DOI":"10.2174\/138620710791515987","article-title":"Proteomic analysis of plasma to reveal the impact of short-term etanercept therapy in pediatric patients with enthesitis-related arthritis: a case report","volume":"13","author":"Chen","year":"2010","journal-title":"Comb Chem High Throughput Screen"},{"key":"B15","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1080\/14789450.2019.1578214","article-title":"Proteomic analysis of synovial fluid: current and potential uses to improve clinical outcomes","volume":"16","author":"Peffers","year":"2019","journal-title":"Expert Rev Proteomics"},{"key":"B16","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1111\/1756-185X.14080","article-title":"Epigenetics of ankylosing spondylitis: Recent developments","volume":"24","author":"Yang","year":"2021","journal-title":"Int J Rheum Dis"},{"key":"B17","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1097\/BOR.0000000000000471","article-title":"Epigenetics of inflammatory arthritis","volume":"30","author":"Hammaker","year":"2018","journal-title":"Curr Opin Rheumatol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1007\/s00296-018-4026-0","article-title":"The role of genetics and epigenetics in rheumatic diseases: are they really a target to be aimed at?","volume":"38","author":"Kato","year":"2018","journal-title":"Rheumatol Int"},{"key":"B19","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/978-981-15-3449-2_1","article-title":"Epigenetics in Health and Disease","volume":"1253","author":"Zhang","year":"2020","journal-title":"Adv Exp Med Biol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.jaut.2017.09.010","article-title":"The DNA methylation landscape of CD4+ T cells in oligoarticular juvenile idiopathic arthritis","volume":"86","author":"Chavez-Valencia","year":"2018","journal-title":"J Autoimmun"},{"key":"B21","doi-asserted-by":"publisher","first-page":"11063","DOI":"10.1038\/srep11063","article-title":"DNA methylation at IL32 in juvenile idiopathic arthritis","volume":"5","author":"Meyer","year":"2015","journal-title":"Sci Rep"},{"key":"B22","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1097\/BOR.0000000000000627","article-title":"The role of epigenetics in paediatric rheumatic disease","volume":"31","author":"Charras","year":"2019","journal-title":"Curr Opin Rheumatol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"5758","DOI":"10.3390\/ijms21165758","article-title":"Epigenetic Mechanisms of Inflammasome Regulation","volume":"21","author":"Poli","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B24","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1007\/s42399-019-00070-9","article-title":"Epigenetic alterations in juvenile spondyloarthritis patients: a preliminary study of selected genes promoter methylation and silencing","author":"Lamot","year":"2019","journal-title":"SN Compr Clin Med"},{"key":"B25","doi-asserted-by":"publisher","first-page":"190","DOI":"10.3899\/jrheum.180168","article-title":"Pediatric Rheumatology International Trials Organization (PRINTO) Toward new classification criteria for juvenile idiopathic arthritis: first steps, pediatric rheumatology international trials organization international consensus","volume":"46","author":"Martini","year":"2019","journal-title":"J Rheumatol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1186\/s13075-017-1382-1","article-title":"Genome-wide DNA methylation profile analysis identifies differentially methylated loci associated with ankylosis spondylitis","volume":"19","author":"Hao","year":"2017","journal-title":"Arthritis Res Ther"},{"key":"B27","doi-asserted-by":"publisher","first-page":"2723","DOI":"10.1007\/s10067-016-3403-x","article-title":"Evaluation of DNMT1 gene expression profile and methylation of its promoter region in patients with ankylosing spondylitis","volume":"35","author":"Aslani","year":"2016","journal-title":"Clin Rheumatol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1038\/gene.2017.17","article-title":"Promoter hypermethylation of BCL11B gene correlates with downregulation of gene transcription in ankylosing spondylitis patients","volume":"18","author":"Karami","year":"2017","journal-title":"Genes Immun"},{"key":"B29","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.jaut.2019.04.022","article-title":"Genome-wide DNA methylation analysis in ankylosing spondylitis identifies HLA-B*27 dependent and independent DNA methylation changes in whole blood","volume":"102","author":"Coit","year":"2019","journal-title":"J Autoimmun"},{"key":"B30","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1097\/BRS.0000000000001339","article-title":"Identification of Serum miR-146a and miR-155 as Novel Noninvasive Complementary Biomarkers for Ankylosing Spondylitis","volume":"41","author":"Qian","year":"2016","journal-title":"Spine (Phila Pa 1976)."},{"key":"B31","doi-asserted-by":"publisher","first-page":"20492","DOI":"10.1074\/jbc.M110.102111","article-title":"IL-10 inhibits miR-155 induction by toll-like receptors","volume":"285","author":"McCoy","year":"2010","journal-title":"J Biol Chem"},{"key":"B32","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1038\/s41580-018-0068-0","article-title":"Linking cellular stress responses to systemic homeostasis","volume":"19","author":"Galluzzi","year":"2018","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"R89","DOI":"10.1186\/ar3016","article-title":"Experimental stress in inflammatory rheumatic diseases: a review of psychophysiological stress responses","volume":"12","author":"de Brouwer","year":"2010","journal-title":"Arthritis Res Ther"},{"key":"B34","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1186\/s13075-016-1141-8","article-title":"Childhood hospitalisation with infections and later development of ankylosing spondylitis: a national case-control study","volume":"18","author":"Lindstr\u00f6m","year":"2016","journal-title":"Arthritis Res Ther"},{"key":"B35","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1136\/annrheumdis-2013-203643","article-title":"Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells","volume":"73","author":"Jacques","year":"2014","journal-title":"Ann Rheum Dis"},{"key":"B36","first-page":"841","article-title":"Testicular function in active ankylosing spondylitis. Therapeutic response to human chorionic gonadotrophin","volume":"18","author":"Tapia-Serrano","year":"1991","journal-title":"J Rheumatol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1016\/S0889-857X(05)70179-4","article-title":"Gonadal and adrenal sex steroids in ankylosing spondylitis","volume":"26","author":"Gooren","year":"2000","journal-title":"Rheum Dis Clin North Am"},{"key":"B38","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1186\/s13075-017-1407-9","article-title":"Estrogen attenuates the spondyloarthritis manifestations of the SKG arthritis model","volume":"19","author":"Jeong","year":"2017","journal-title":"Arthritis Res Ther"},{"key":"B39","doi-asserted-by":"publisher","first-page":"e44552","DOI":"10.1371\/journal.pone.0044552","article-title":"Estrogen deficiency induces the differentiation of IL-17 secreting Th17 cells: a new candidate in the pathogenesis of osteoporosis","volume":"7","author":"Tyagi","year":"2012","journal-title":"PLoS ONE"},{"key":"B40","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1111\/j.1365-2265.2005.02369.x","article-title":"Bone loss in males with ankylosing spondylitis: its relation to sex hormone levels","volume":"63","author":"Aydin","year":"2005","journal-title":"Clin Endocrinol (Oxf)."},{"key":"B41","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1002\/art.10177","article-title":"Inadequately low serum levels of steroid hormones in relation to interleukin-6 and tumor necrosis factor in untreated patients with early rheumatoid arthritis and reactive arthritis","volume":"46","author":"Straub","year":"2002","journal-title":"Arthritis Rheum"},{"key":"B42","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1007\/BF03346548","article-title":"Impaired hypothalamo-pituitary-adrenal axis in patients with ankylosing spondylitis","volume":"33","author":"Kebapcilar","year":"2010","journal-title":"J Endocrinol Invest"},{"key":"B43","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1007\/s10067-009-1326-5","article-title":"Low cortisol levels in active juvenile idiopathic arthritis","volume":"29","author":"Bilginer","year":"2010","journal-title":"Clin Rheumatol"},{"key":"B44","first-page":"S428","article-title":"Juvenile ankylosingspondylitis. Direct relationship between hyperprolactine-mia and interleukin 6","volume":"37","author":"Bravo","year":"1994","journal-title":"Abstractx. Arthritis Rheum."},{"key":"B45","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1016\/j.semarthrit.2013.04.008","article-title":"Role of neuroendocrine and neuroimmune mechanisms in chronic inflammatory rheumatic diseases\u2013the 10-year update","volume":"43","author":"Straub","year":"2013","journal-title":"Semin Arthritis Rheum"},{"key":"B46","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1007\/s00393-020-00951-8","article-title":"Interaction of pain and chronic inflammation","volume":"80","author":"Seifert","year":"2020","journal-title":"Z Rheumatol"},{"key":"B47","doi-asserted-by":"publisher","first-page":"986","DOI":"10.3390\/ijms19040986","article-title":"Role of the Hypothalamic-Pituitary-Adrenal Axis in Health and Disease","volume":"19","author":"DeMorrow","year":"2018","journal-title":"Int J Mol Sci"},{"key":"B48","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1530\/EC-17-0361","article-title":"Role of 11\u03b2-HSD type 1 in abnormal HPA axis activity during immune-mediated arthritis","volume":"7","author":"Sattler","year":"2018","journal-title":"Endocr Connect"},{"key":"B49","doi-asserted-by":"publisher","first-page":"S3","DOI":"10.1186\/ar4687","article-title":"Circadian rhythms in rheumatology-a glucocorticoid perspective","volume":"16","author":"Spies","year":"2014","journal-title":"Arthritis Res Ther"},{"key":"B50","doi-asserted-by":"publisher","first-page":"794","DOI":"10.3389\/fimmu.2018.00794","article-title":"Androgen-Induced Immunosuppression","volume":"9","author":"Gubbels Bupp","year":"2018","journal-title":"Front Immunol"},{"key":"B51","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1080\/10253890.2017.1369523","article-title":"Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: sex differences in regulation of stress responsivity","volume":"20","author":"Oyola","year":"2017","journal-title":"Stress"},{"key":"B52","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1615\/CritRevImmunol.v37.i2-6.90","article-title":"Macrophage Migration Inhibitory Factor (MIF): A Glucocorticoid Counter-Regulator within the Immune System","volume":"37","author":"Calandra","year":"2017","journal-title":"Crit Rev Immunol"},{"key":"B53","doi-asserted-by":"publisher","first-page":"2366","DOI":"10.2353\/ajpath.2010.091204","article-title":"Identification of NURR1 as a mediator of MIF signaling during chronic arthritis: effects on glucocorticoid-induced MKP1","volume":"177","author":"Ralph","year":"2010","journal-title":"Am J Pathol"},{"key":"B54","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1111\/joim.12626","article-title":"Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis","volume":"282","author":"Koopman","year":"2017","journal-title":"J Intern Med"},{"key":"B55","first-page":"1003","article-title":"Neuromodulation in Psoriasis and Psoriatic Arthritis","volume":"2","author":"Yang","year":"2018","journal-title":"Ann Chron Dise"},{"key":"B56","doi-asserted-by":"publisher","first-page":"2287","DOI":"10.1152\/physrev.00035.2017","article-title":"Neuroimmune Communication in Health and Disease","volume":"98","author":"Reardon","year":"2018","journal-title":"Physiol Rev"},{"key":"B57","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s10286-021-00787-5","article-title":"Peripheral neuroimmune interactions: selected review and some clinical implications","author":"Shouman","year":"2021","journal-title":"Clin Auton Res"},{"key":"B58","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1006\/brbi.1996.0034","article-title":"The autonomic nervous system and the immune system in juvenile rheumatoid arthritis","volume":"10","author":"Kuis","year":"1996","journal-title":"Brain Behav Immun"},{"key":"B59","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/S0165-5728(96)00125-7","article-title":"Functional alpha 1-adrenergic receptors on leukocytes of patients with polyarticular juvenile rheumatoid arthritis","volume":"71","author":"Heijnen","year":"1996","journal-title":"J Neuroimmunol"},{"key":"B60","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.rdc.2004.09.003","article-title":"Sympathetic neurotransmitters in joint inflammation","volume":"31","author":"Straub","year":"2005","journal-title":"Rheum Dis Clin North Am"},{"key":"B61","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1111\/j.1365-3083.2009.02266.x","article-title":"Cell specific synovial expression of nicotinic alpha 7 acetylcholine receptor in rheumatoid arthritis and psoriatic arthritis","volume":"70","author":"Westman","year":"2009","journal-title":"Scand J Immunol"},{"key":"B62","doi-asserted-by":"publisher","first-page":"667","DOI":"10.3109\/08820139.2014.914532","article-title":"Activation of \u03b17nAChR by Nicotine Reduced the Th17 Response in CD4+T Lymphocytes","volume":"7","author":"Zhigang","year":"2014","journal-title":"Immunological Investigations"},{"key":"B63","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/1476-511X-10-19","article-title":"Can vagus nerve stimulation halt or ameliorate rheumatoid arthritis and lupus?","volume":"10","author":"Das","year":"2011","journal-title":"Lipids Health Dis"},{"key":"B64","doi-asserted-by":"publisher","first-page":"107391","DOI":"10.1016\/j.intimp.2021.107391","article-title":"Cholinergic modulation of the immune system - A novel therapeutic target for myocardial inflammation","volume":"93","author":"Lu","year":"2021","journal-title":"Int Immunopharmacol"},{"key":"B65","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1136\/annrheumdis-2018-eular.4731","article-title":"SAT0298 Transcutaneous vagus nerve stimulation in patients with psoriatic arthritis or ankylosing spondylitis","volume":"77","author":"Rasmussen","year":"2018","journal-title":"Annals of the Rheum Dis."},{"key":"B66","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1136\/gutjnl-2018-317855","article-title":"Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice","volume":"69","author":"Torres","year":"2020","journal-title":"Gut"},{"key":"B67","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1038\/nature11053","article-title":"Human gut microbiome viewed across age and geography","volume":"486","author":"Yatsunenko","year":"2012","journal-title":"Nature"},{"key":"B68","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1097\/BOR.0000000000000187","article-title":"The intestinal microbiome in spondyloarthritis","volume":"27","author":"Gill","year":"2015","journal-title":"Curr Opin Rheumatol"},{"key":"B69","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.clim.2015.05.001","article-title":"Gut microbes, immunity, and spondyloarthritis","volume":"159","author":"Stoll","year":"2015","journal-title":"Clin Immunol"},{"key":"B70","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1038\/s41584-020-0454-9","article-title":"Revisiting the gut\u2013joint axis: links between gut inflammation and spondyloarthritis","volume":"16","author":"Gracey","year":"2020","journal-title":"Nat Rev Rheumatol"},{"key":"B71","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1111\/imr.12826","article-title":"Microbial orchestra in juvenile idiopathic arthritis: Sounds of disarray?","volume":"294","author":"Arvonen","year":"2020","journal-title":"Immunol Rev"},{"key":"B72","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jaut.2019.01.001","article-title":"Gut microbiota in children and altered profiles in juvenile idiopathic arthritis","volume":"98","author":"De Filippo","year":"2019","journal-title":"J Autoimmun"},{"key":"B73","doi-asserted-by":"publisher","first-page":"108415","DOI":"10.1016\/j.clim.2020.108415","article-title":"Gut microbiota in chronic inflammatory disorders: A focus on pediatric inflammatory bowel diseases and juvenile idiopathic arthritis","volume":"215","author":"Ricciuto","year":"2020","journal-title":"Clin Immunol"},{"key":"B74","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1007\/s12519-020-00371-3","article-title":"Intestinal microbiota and juvenile idiopathic arthritis: current understanding and future prospective","volume":"17","author":"Xin","year":"2021","journal-title":"World J Pediatr"},{"key":"B75","doi-asserted-by":"publisher","first-page":"1703","DOI":"10.3389\/fmicb.2016.01703","article-title":"Alteration of Fecal Microbiota Profiles in Juvenile Idiopathic Arthritis. Associations with HLA-B27 Allele and Disease Status","volume":"7","author":"Di Paola","year":"2016","journal-title":"Front Microbiol."},{"key":"B76","doi-asserted-by":"publisher","first-page":"2162","DOI":"10.3748\/wjg.v25.i18.2162","article-title":"Inflammatory bowel diseases and spondyloarthropathies: From pathogenesis to treatment","volume":"25","author":"Fragoulis","year":"2019","journal-title":"World J Gastroenterol"},{"key":"B77","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1002\/art.40405","article-title":"Effects of HLA-B27 on Gut Microbiota in Experimental Spondyloarthritis Implicate an Ecological Model of Dysbiosis","volume":"70","author":"Gill","year":"2018","journal-title":"Arthritis Rheumatol"},{"key":"B78","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1007\/s11306-014-0677-3","article-title":"Metabonomics of human fecal extracts characterize ulcerative colitis, Crohn's disease and healthy individuals","volume":"11","author":"Bjerrum","year":"2015","journal-title":"Metabolomics"},{"key":"B79","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1038\/gene.2016.38","article-title":"Fecal metabolomics in pediatric spondyloarthritis implicate decreased metabolic diversity and altered tryptophan metabolism as pathogenic factors","volume":"17","author":"Stoll","year":"2016","journal-title":"Genes Immun"},{"key":"B80","doi-asserted-by":"publisher","first-page":"2668","DOI":"10.3389\/fimmu.2018.02668","article-title":"The Early Phases of Ankylosing Spondylitis: Emerging Insights From Clinical and Basic Science","volume":"9","author":"Watad","year":"2018","journal-title":"Front Immunol"},{"key":"B81","doi-asserted-by":"publisher","first-page":"P86","DOI":"10.1186\/1546-0096-11-S2-P86","article-title":"PReS-FINAL-2074: The role of the probiotic VSL-3 as adjuvant therapy in patients with undifferentiated spondyloarthritis (ERA)","volume":"11","author":"Vidovic","year":"2013","journal-title":"Pediatr Rheumatol."},{"key":"B82","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1111\/cei.12818","article-title":"Effect of probiotics on clinical and immune parameters in enthesitis-related arthritis category of juvenile idiopathic arthritis","volume":"185","author":"Shukla","year":"2016","journal-title":"Clin Exp Immunol"},{"key":"B83","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1007\/s12016-020-08823-4","article-title":"IL-23\/IL-17 Axis in inflammatory rheumatic diseases","volume":"60","author":"Li","year":"2021","journal-title":"Clin Rev Allergy Immunol"},{"key":"B84","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/ijms21176401","article-title":"The role of the IL-23\/IL-17 pathway in the pathogenesis of spondyloarthritis","volume":"21","author":"Tsukazaki","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B85","doi-asserted-by":"publisher","first-page":"450","DOI":"10.3389\/fimmu.2019.00450","article-title":"Th17 and Th1 lymphocytes in oligoarticular juvenile idiopathic arthritis","volume":"10","author":"Maggi","year":"2019","journal-title":"Front Immunol"},{"key":"B86","doi-asserted-by":"publisher","first-page":"1730","DOI":"10.3899\/jrheum.081179","article-title":"Th1 and Th17 predominance in the enthesitis-related arthritis form of juvenile idiopathic arthritis","volume":"36","author":"Mahendra","year":"2009","journal-title":"J Rheumatol"},{"key":"B87","doi-asserted-by":"publisher","first-page":"7453236","DOI":"10.1155\/2019\/7453236","article-title":"IL-7 is a Key Driver Cytokine in Spondyloarthritis?","volume":"2019","author":"Gon\u00e7alves","year":"2019","journal-title":"J Immunol Res"},{"key":"B88","doi-asserted-by":"publisher","first-page":"382","DOI":"10.3389\/fimmu.2019.00382","article-title":"Anti-TNF therapy in spondyloarthritis and related diseases, impact on the immune system and prediction of treatment responses","volume":"10","author":"Menegatti","year":"2019","journal-title":"Front Immunol"},{"key":"B89","doi-asserted-by":"publisher","first-page":"2161","DOI":"10.1080\/14656566.2020.1796970","article-title":"Pharmacotherapy for juvenile spondyloarthritis: an overview of the available therapies","volume":"21","author":"Marino","year":"2020","journal-title":"Expert Opin Pharmacother"},{"key":"B90","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1046\/j.0818-9641.2002.01148.x","article-title":"Macrophage migration inhibitory factor exhibits a pronounced circadian rhythm relevant to its role as a glucocorticoid counter-regulator","volume":"81","author":"Petrovsky","year":"2003","journal-title":"Immunol Cel Biol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.3389\/fimmu.2020.01273","article-title":"Role of MIF Cytokine\/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair","volume":"11","author":"Farr","year":"2020","journal-title":"Front Immunol"},{"key":"B92","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1016\/j.it.2019.03.002","article-title":"Rediscovering MIF: new tricks for an old cytokine","volume":"40","author":"Harris","year":"2019","journal-title":"Trends Immunol"},{"key":"B93","doi-asserted-by":"publisher","first-page":"e21418","DOI":"10.1096\/fj.202001605R","article-title":"Macrophage migration inhibitory factor promotes the migration of dendritic cells through CD74 and the activation of the Src\/PI3K\/myosin II pathway","volume":"35","author":"Ives","year":"2021","journal-title":"FASEB J"},{"key":"B94","doi-asserted-by":"publisher","first-page":"2619","DOI":"10.3892\/mmr.2016.4847","article-title":"Macrophage migration inhibitory factor induces autophagy to resist hypoxia\/serum deprivation-induced apoptosis via the AMP-activated protein kinase\/mammalian target of rapamycin signaling pathway","volume":"13","author":"Xia","year":"2016","journal-title":"Mol Med Rep"},{"key":"B95","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/JLB.3A0420-242RRR.","article-title":"Macrophage migration inhibitory factor inhibits neutrophil apoptosis by inducing cytokine release from mononuclear cells","author":"Schindler","year":"2021","journal-title":"J Leukoc Biol"},{"key":"B96","doi-asserted-by":"publisher","first-page":"e37613","DOI":"10.1371\/journal.pone.0037613","article-title":"Macrophage migration inhibitory factor induces autophagy via reactive oxygen species generation","volume":"7","author":"Chuang","year":"2012","journal-title":"PLoS ONE"},{"key":"B97","doi-asserted-by":"publisher","first-page":"7825072","DOI":"10.1155\/2020\/7825072","article-title":"The Role of MIF-173G\/C Gene Polymorphism in the Susceptibility of Autoimmune Diseases","volume":"2020","author":"Du","year":"2020","journal-title":"Mediators Inflamm"},{"key":"B98","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1016\/j.jdermsci.2008.11.002","article-title":"Association of MIF promoter polymorphisms with psoriasis in a Han population in northeastern China","volume":"53","author":"Wu","year":"2009","journal-title":"J Dermatol Sci"},{"key":"B99","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.gene.2013.05.012","article-title":"Association of the macrophage migration inhibitory factor gene\u2212173G\/C polymorphism with inflammatory bowel disease: a meta-analysis of 4296 subjects","volume":"526","author":"Zhang","year":"2013","journal-title":"Gene"},{"key":"B100","doi-asserted-by":"publisher","first-page":"1398","DOI":"10.1002\/art.10882","article-title":"Functional and prognostic relevance of the\u2212173 polymorphism of the macrophage migration inhibitory factor gene in systemic-onset juvenile idiopathic arthritis","volume":"48","author":"De Benedetti","year":"2003","journal-title":"Arthritis Rheum"},{"key":"B101","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.cellsig.2010.08.013","article-title":"Activation of the JNK signalling pathway by macrophage migration inhibitory factor (MIF) and dependence on CXCR4 and CD74","volume":"23","author":"Lue","year":"2011","journal-title":"Cell Signal"},{"key":"B102","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1073\/pnas.012511599","article-title":"Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: regulatory role in the innate immune response","volume":"99","author":"Mitchell","year":"2002","journal-title":"Proc Natl Acad Sci USA."},{"key":"B103","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.jcmgh.2020.01.009","article-title":"CD74 Signaling Links Inflammation to Intestinal Epithelial Cell Regeneration and Promotes Mucosal Healing","volume":"10","author":"Farr","year":"2020","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"B104","doi-asserted-by":"crossref","first-page":"195","DOI":"10.55563\/clinexprheumatol\/lezc69","article-title":"CD74 is a T cell antigen in spondyloarthritis","volume":"38","author":"Sogkas","year":"2020","journal-title":"Clin Exp Rheumatol"},{"key":"B105","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1111\/j.1365-2567.2008.02825.x","article-title":"Differential and cell-type specific regulation of responses to Toll-like receptor agonists by ISO-1","volume":"125","author":"West","year":"2008","journal-title":"Immunology"},{"key":"B106","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1179\/096805103125001513","article-title":"Macrophage migration inhibitory factor (MIF) regulates host responses to endotoxin through modulation of Toll-like receptor 4 (TLR4)","volume":"9","author":"Roger","year":"2003","journal-title":"J Endotoxin Res"},{"key":"B107","doi-asserted-by":"publisher","first-page":"2079","DOI":"10.1007\/s10067-015-2952-8","article-title":"Single nucleotide polymorphism of toll-like receptor 4 (TLR4) is associated with juvenile spondyloarthritis in Croatian population","volume":"34","author":"Perica","year":"2015","journal-title":"Clin Rheumatol"},{"key":"B108","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1007\/s00296-012-2396-2","article-title":"Lack of association of single nucleotide polymorphisms in toll-like receptors 2 and 4 with enthesitis-related arthritis category of juvenile idiopathic arthritis in Indian population","volume":"33","author":"Myles","year":"2013","journal-title":"Rheumatol Int"},{"key":"B109","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1038\/35041591","article-title":"Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1","volume":"408","author":"Kleemann","year":"2000","journal-title":"Nature"},{"key":"B110","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1677\/joe.0.1790015","article-title":"Macrophage migration inhibitory factor: a neuroendocrine modulator of chronic inflammation","volume":"179","author":"Baugh","year":"2003","journal-title":"J Endocrinol"},{"key":"B111","doi-asserted-by":"publisher","first-page":"2223","DOI":"10.1038\/s41467-018-04581-2","article-title":"Macrophage migration inhibitory factor is required for NLRP3 inflammasome activation","volume":"9","author":"Lang","year":"2018","journal-title":"Nat Commun"},{"key":"B112","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.3346\/jkms.2013.28.9.1289","article-title":"Caspase-1 level in synovial fluid is high in patients with spondyloarthropathy but not in patients with gout","volume":"28","author":"Son","year":"2013","journal-title":"J Korean Med Sci"},{"key":"B113","doi-asserted-by":"publisher","first-page":"1748","DOI":"10.1053\/j.gastro.2011.01.056","article-title":"Hypoxia and metabolic factors that influence inflammatory bowel disease pathogenesis","volume":"140","author":"Glover","year":"2011","journal-title":"Gastroenterology"},{"key":"B114","doi-asserted-by":"publisher","first-page":"10493","DOI":"10.1074\/jbc.REV120.011188","article-title":"Oxygen battle in the gut: Hypoxia and hypoxia-inducible factors in metabolic and inflammatory responses in the intestine","volume":"295","author":"Singhal","year":"2020","journal-title":"J Biol Chem"},{"key":"B115","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/19490976.2021.1880241","article-title":"Intestinal Inflammation as a Dysbiosis of Energy Procurement: New Insights into an Old Topic","volume":"13","author":"Lee","year":"2021","journal-title":"Gut Microbes"},{"key":"B116","doi-asserted-by":"publisher","first-page":"609689","DOI":"10.3389\/fimmu.2020.609689","article-title":"Local Stabilization of hypoxia-inducible factor-1\u03b1 controls intestinal inflammation via enhanced gut barrier function and immune regulation","volume":"11","author":"Kim","year":"2021","journal-title":"Front Immunol"},{"key":"B117","doi-asserted-by":"publisher","first-page":"806","DOI":"10.3389\/fimmu.2019.00806","article-title":"Intestinal epithelial cells-derived hypoxia-inducible factor-1\u03b1 is essential for the homeostasis of intestinal intraepithelial lymphocytes","volume":"10","author":"Sun","year":"2019","journal-title":"Front Immunol"},{"key":"B118","doi-asserted-by":"publisher","first-page":"2036","DOI":"10.1053\/j.gastro.2008.03.009","article-title":"Hypoxia-inducible factor augments experimental colitis through an MIF-dependent inflammatory signaling cascade","volume":"134","author":"Shah","year":"2008","journal-title":"Gastroenterology"},{"key":"B119","doi-asserted-by":"publisher","first-page":"764","DOI":"10.4049\/jimmunol.0903421","article-title":"Macrophage migration inhibitory factor counterregulates dexamethasone-mediated suppression of hypoxia-inducible factor-1 alpha function and differentially influences human CD4+ T cell proliferation under hypoxia","volume":"186","author":"Gaber","year":"2011","journal-title":"J Immunol"},{"key":"B120","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1158\/0008-5472.CAN-06-3292","article-title":"Amplification of tumor hypoxic responses by macrophage migration inhibitory factor-dependent hypoxia-inducible factor stabilization","volume":"67","author":"Winner","year":"2007","journal-title":"Cancer Res"},{"key":"B121","first-page":"927","article-title":"Macrophage migration inhibitory factor upregulates angiogenic factors and correlates with clinical measures in rheumatoid arthritis","volume":"34","author":"Kim","year":"2007","journal-title":"J Rheumatol"},{"key":"B122","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1111\/j.1365-2567.2009.03203.x","article-title":"Hypoxic stress up-regulates the expression of Toll-like receptor 4 in macrophages via hypoxia-inducible factor","volume":"129","author":"Kim","year":"2010","journal-title":"Immunology"},{"key":"B123","doi-asserted-by":"publisher","first-page":"184","DOI":"10.3389\/fphar.2016.00184","article-title":"Hypoxia-Inducible Factor (HIF) as a target for novel therapies in rheumatoid arthritis","volume":"7","author":"Hua","year":"2016","journal-title":"Front Pharmacol"},{"key":"B124","doi-asserted-by":"publisher","first-page":"346","DOI":"10.3389\/fmicb.2018.00346","article-title":"Searching for the bacterial effector: the example of the multi-skilled commensal bacterium Faecalibacterium prausnitzii","volume":"9","author":"Mart\u00edn","year":"2018","journal-title":"Front Microbiol"},{"key":"B125","doi-asserted-by":"publisher","first-page":"4796","DOI":"10.3748\/wjg.v25.i33.4796","article-title":"Role of NLRP3 inflammasome in inflammatory bowel diseases","volume":"25","author":"Tourkochristou","year":"2019","journal-title":"World J Gastroenterol"},{"key":"B126","doi-asserted-by":"publisher","first-page":"1896","DOI":"10.1038\/s41467-017-01917-2","article-title":"Remodelling of the gut microbiota by hyperactive NLRP3 induces regulatory T cells to maintain homeostasis","volume":"8","author":"Yao","year":"2017","journal-title":"Nat Commun"},{"key":"B127","doi-asserted-by":"publisher","first-page":"276","DOI":"10.3389\/fimmu.2019.00276","article-title":"NLRP3 inflammasome and inflammatory bowel disease","volume":"10","author":"Zhen","year":"2019","journal-title":"Front Immunol"},{"key":"B128","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1186\/s12881-020-01140-9","article-title":"Influence of MIF polymorphisms on CpG island hyper-methylation of CDKN2A in the patients with ulcerative colitis","volume":"21","author":"Sakurai","year":"2020","journal-title":"BMC Med Genet"},{"key":"B129","doi-asserted-by":"publisher","first-page":"614","DOI":"10.5152\/balkanmedj.2016.141103","article-title":"Evaluation of MIF\u2212173 G\/C polymorphism in turkish patients with ankylosing spondylitis","volume":"33","author":"G\u00fcrel","year":"2016","journal-title":"Balkan Med J"},{"key":"B130","doi-asserted-by":"publisher","first-page":"34","DOI":"10.3109\/s10165-009-0230-9","article-title":"Evaluation of inflammation and oxidative stress in ankylosing spondylitis: a role for macrophage migration inhibitory factor","volume":"20","author":"Kozaci","year":"2010","journal-title":"Mod Rheumatol"},{"key":"B131","doi-asserted-by":"publisher","first-page":"1796","DOI":"10.1002\/art.40175","article-title":"Macrophage migration inhibitory factor induces inflammation and predicts spinal progression in ankylosing spondylitis","volume":"69","author":"Ranganathan","year":"2017","journal-title":"Arthritis Rheumatol"},{"key":"B132","doi-asserted-by":"crossref","first-page":"275","DOI":"10.55563\/clinexprheumatol\/2l5emt","article-title":"MiR-451 suppresses inflammatory responses in ankylosing spondylitis by targeting macrophage migration inhibitory factor","volume":"38","author":"Park","year":"2020","journal-title":"Clin Exp Rheumatol"},{"key":"B133","first-page":"14562","article-title":"MiR-451 inhibits synovial fibroblasts proliferation and inflammatory cytokines secretion in rheumatoid arthritis through mediating p38MAPK signaling pathway","volume":"8","author":"Wang","year":"2015","journal-title":"Int J Clin Exp Pathol"},{"key":"B134","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1002\/art.38269","article-title":"MicroRNA-451 down-regulates neutrophil chemotaxis via p38 MAPK","volume":"66","author":"Murata","year":"2014","journal-title":"Arthritis Rheumatol"},{"key":"B135","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1080\/15548627.2016.1164358","article-title":"Loss of autophagy enhances MIF\/macrophage migration inhibitory factor release by macrophages","volume":"12","author":"Lee","year":"2016","journal-title":"Autophagy"},{"key":"B136","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1007\/s10067-016-3262-5","article-title":"Autophagy in the pathogenesis of ankylosing spondylitis","volume":"35","author":"Ciccia","year":"2016","journal-title":"Clin Rheumatol"},{"key":"B137","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1359\/jbmr.060310","article-title":"Transgenic mice overexpressing macrophage migration inhibitory factor (MIF) exhibit high-turnover osteoporosis","volume":"21","author":"Onodera","year":"2006","journal-title":"J Bone Miner Res"},{"key":"B138","doi-asserted-by":"publisher","first-page":"1688","DOI":"10.1002\/jbmr.2854","article-title":"Macrophage Migration Inhibitory Factor (MIF) supports homing of osteoclast precursors to peripheral osteolytic lesions","volume":"31","author":"Movila","year":"2016","journal-title":"J Bone Miner Res"},{"key":"B139","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.cyto.2014.11.015","article-title":"Macrophage migration inhibitory factor is essential for osteoclastogenic mechanisms in vitro and in vivo mouse model of arthritis","volume":"72","author":"Gu","year":"2015","journal-title":"Cytokine"},{"key":"B140","doi-asserted-by":"publisher","first-page":"1759720X20969260","DOI":"10.1177\/1759720X20969260","article-title":"Loss and gain of bone in spondyloarthritis: what drives these opposing clinical features?","volume":"12","author":"Clunie","year":"2020","journal-title":"Ther Adv Musculoskelet Dis"},{"key":"B141","doi-asserted-by":"publisher","first-page":"1056","DOI":"10.1002\/art.40468","article-title":"Inflammation intensity-dependent expression of osteoinductive wnt proteins is critical for ectopic new bone formation in ankylosing spondylitis","volume":"70","author":"Li","year":"2018","journal-title":"Arthritis Rheumatol"},{"key":"B142","doi-asserted-by":"publisher","first-page":"e12109","DOI":"10.15252\/emmm.202012109","article-title":"Aberrant upregulation of CaSR promotes pathological new bone formation in ankylosing spondylitis","volume":"12","author":"Li","year":"2020","journal-title":"EMBO Mol Med"},{"key":"B143","first-page":"322","article-title":"Interactions of the innate and adaptive arms of the immune system in the pathogenesis of spondyloarthritis","volume":"29","author":"Stoll","year":"2011","journal-title":"Clin Exp Rheumatol"},{"key":"B144","doi-asserted-by":"publisher","first-page":"885","DOI":"10.3389\/fimmu.2018.00885","article-title":"Whodunit? The contribution of interleukin (IL)-17\/IL-22-producing \u03b3\u03b4 T cells, \u03b1\u03b2 T cells, and innate lymphoid cells to the pathogenesis of spondyloarthritis","volume":"9","author":"Reinhardt","year":"2018","journal-title":"Front Immunol"},{"key":"B145","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1007\/s11926-019-0834-9","article-title":"ILC3 in axial spondyloarthritis: the gut angle","volume":"21","author":"Mauro","year":"2019","journal-title":"Curr Rheumatol Rep"},{"key":"B146","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jaut.2020.102435","article-title":"Selective targeting of PI3K\u03b4 suppresses human IL-17-producing T cells and innate-like lymphocytes and may be therapeutic for IL-17-mediated diseases","volume":"111","author":"Chen","year":"2020","journal-title":"Journal of Autoimmunity"},{"key":"B147","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1136\/annrheumdis-2020-217309","article-title":"Normal human enthesis harbors conventional CD4+and CD8+ T cells with regulatory features and inducible IL-17A and TNF expression","volume":"79","author":"Watad","year":"2020","journal-title":"Ann Rheum Dis"},{"key":"B148","doi-asserted-by":"publisher","first-page":"1566","DOI":"10.1136\/annrheumdis-2019-215349","article-title":"Integrin and transcriptomic profiles identify a distinctive synovial CD8+ T cell subpopulation in spondyloarthritis","volume":"78","author":"Qaiyum","year":"2019","journal-title":"Ann Rheum Dis"},{"key":"B149","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1097\/BOR.0000000000000716","article-title":"Barrier lymphocytes in spondyloarthritis","volume":"32","author":"Adam Berlinberg","year":"2020","journal-title":"Curr Opin Rheumatol"},{"key":"B150","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1016\/j.berh.2018.07.010","article-title":"Th17 cell responses in spondyloarthritis","volume":"31","author":"Gaston","year":"2017","journal-title":"Best Pract Res Clin Rheumatol"},{"key":"B151","doi-asserted-by":"publisher","first-page":"e000821","DOI":"10.1136\/rmdopen-2018-000821","article-title":"MAIT cells: potent major cellular players in the IL-17 pathway of spondyloarthritis?","volume":"4","author":"Toussirot","year":"2018","journal-title":"RMD Open."},{"key":"B152","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/s41467-018-07911-6","article-title":"ROR\u03b3t inhibition selectively targets IL-17 producing iNKT and \u03b3\u03b4-T cells enriched in Spondyloarthritis patients","volume":"10","author":"Venken","year":"2019","journal-title":"Nat Commun."},{"key":"B153","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1038\/nm.2817","article-title":"IL-23 induces spondyloarthropathy by acting on ROR-\u03b3t+CD3+CD4\u2013CD8\u2013 entheseal resident T cells","volume":"18","author":"Sherlock","year":"2012","journal-title":"Nat med"},{"key":"B154","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1136\/annrheumdis-2019-215356corr1","article-title":"The role of IL-17A in axial spondyloarthritis and psoriatic arthritis: Recent advances and controversies","volume":"215356","author":"McGonagle","year":"2019","journal-title":"Ann Rheum Dis"},{"key":"B155","doi-asserted-by":"publisher","first-page":"2003","DOI":"10.1002\/art.40582","article-title":"Proinflammatory CX3CR1+CD59+tumor necrosis factor-like molecule 1A+interleukin-23+ monocytes are expanded in patients with ankylosing spondylitis and modulate innate lymphoid cell 3 immune functions","volume":"12","author":"Ciccia","year":"2018","journal-title":"Arthritis Rheum."},{"key":"B156","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13075-019-1885-z","article-title":"Targeting inflammatory pathways in axial spondyloarthritis","volume":"21","author":"Furst","year":"2019","journal-title":"Arthritis Res Ther"},{"key":"B157","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1007\/s00109-017-1528-2","article-title":"Synovial cell production of IL-26 induces bone mineralization in spondyloarthritis","volume":"95","author":"Heftdal","year":"2017","journal-title":"J Mol Med"},{"key":"B158","doi-asserted-by":"publisher","first-page":"1272","DOI":"10.3390\/ijms18061272","article-title":"Osteoblast role in rheumatic diseases","volume":"18","author":"Corrado","year":"2017","journal-title":"Int J Mol Sci"},{"key":"B159","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/1745-6150-3-6","article-title":"The control of CD4+CD25+Foxp3+ regulatory T cell survival","volume":"3","author":"Pandiyan","year":"2008","journal-title":"Biology Direct."},{"key":"B160","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1097\/BOR.0b013e32836202dc","article-title":"Dendritic and regulatory T cells in spondyloarthritis","volume":"25","author":"Wright","year":"2013"},{"key":"B161","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1002\/path.1044","article-title":"Macrophages expressing the scavenger receptor CD163: a link between immune alterations of the gut and synovial inflammation in spondyloarthropathy","volume":"196","author":"Baeten","year":"2002","journal-title":"J Pathol"},{"key":"B162","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1093\/rheumatology\/kev245","article-title":"Ankylosing spondylitis patients display altered dendritic cell and T cell populations that implicate pathogenic roles for the IL-23 cytokine axis and intestinal inflammation","volume":"55","author":"Wright","year":"2016","journal-title":"Rheumatology (Oxford)."},{"key":"B163","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1002\/kjm2.12184","article-title":"Aberrant distribution and function of plasmacytoid dendritic cells in patients with ankylosing spondylitis are associated with unfolded protein response","volume":"36","author":"Liu","year":"2020","journal-title":"Kaohsiung J Med Sci"},{"key":"B164","first-page":"515","article-title":"Interleukin 17 levels are increased in juvenile idiopathic arthritis synovial fluid and induce synovial fibroblasts to produce proinflammatory cytokines and matrix metalloproteinases","volume":"35","author":"Agarwal","year":"2008","journal-title":"J Rheumatol"},{"key":"B165","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.clim.2015.07.012","article-title":"Natural killer cell and gamma delta T cell alterations in enthesitis related arthritis category of juvenile idiopathic arthritis","volume":"161","author":"Gaur","year":"2015"},{"key":"B166","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.cellsig.2019.01.006","article-title":"Evolving complexity of MIF signaling","volume":"57","author":"Jankauskas","year":"2019","journal-title":"Cell Signal"},{"key":"B167","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1136\/annrheumdis-2014-206323","article-title":"Type 3 innate lymphoid cells producing IL-17 and IL-22 are expanded in the gut, in the peripheral blood, synovial fluid and bone marrow of patients with ankylosing spondylitis","volume":"74","author":"Ciccia","year":"2015","journal-title":"Ann Rheum Dis"},{"key":"B168","doi-asserted-by":"publisher","first-page":"3430","DOI":"10.1002\/art.23998","article-title":"Identification of interleukin-7 as a candidate disease mediator in spondylarthritis","volume":"58","author":"Rihl","year":"2008","journal-title":"Arthritis & Rheumatism"},{"key":"B169","doi-asserted-by":"publisher","first-page":"1910","DOI":"10.1172\/JCI121668","article-title":"IL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease","volume":"12","author":"Belarif","year":"2019","journal-title":"J Clin Invest"},{"key":"B170","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1002\/art.39515","article-title":"Activation-induced killer cell immunoglobulin-like receptor 3DL2 binding to HLA-B27 licenses pathogenic T cell differentiation in spondyloarthritis","volume":"68","author":"Ridley","year":"2016","journal-title":"Arthritis Rheumatol"},{"key":"B171","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1002\/eji.201747195","article-title":"CXCL4 is a novel inducer of human Th17 cells and correlates with IL-17 and IL-22 in psoriatic arthritis","volume":"48","author":"Affandi","year":"2018","journal-title":"Eur J Immunol"},{"key":"B172","doi-asserted-by":"publisher","first-page":"4551","DOI":"10.3892\/mmr.2020.11576","article-title":"Ankylosis progressive homolog upregulation inhibits cell viability and mineralization during fibroblast ossification by regulating the Wnt\/\u03b2-catenin signaling pathway","volume":"22","author":"He","year":"2020","journal-title":"Mol Med Rep"},{"key":"B173","doi-asserted-by":"publisher","first-page":"200","DOI":"10.3109\/03008207.2015.1127916","article-title":"Downregulation of dickkopf-1 enhances the proliferation and osteogenic potential of fibroblasts isolated from ankylosing spondylitis patients via the Wnt\/\u03b2-catenin signaling pathway in vitro","volume":"57","author":"Zou","year":"2016","journal-title":"Connect Tissue Res"},{"key":"B174","doi-asserted-by":"publisher","first-page":"E1349","DOI":"10.1097\/BRS.0000000000003169","article-title":"Treg-promoted new bone formation through suppressing TH17 by secreting interleukin-10 in ankylosing spondylitis","volume":"44","author":"Xu","year":"2019","journal-title":"Spine (Phila Pa 1976)."},{"key":"B175","doi-asserted-by":"publisher","first-page":"iv67","DOI":"10.1093\/rheumatology\/keaa408","article-title":"Intestinal and enthesis innate immunity in early axial spondyloarthropathy","volume":"59","author":"Sharif","year":"2020","journal-title":"Rheumatology (Oxford)."},{"key":"B176","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1080\/09273948.2016.1175641","article-title":"Autoinflammation and HLA-B27: Beyond Antigen Presentation","volume":"24","author":"Sibley","year":"2016","journal-title":"Ocul Immunol Inflamm"},{"key":"B177","doi-asserted-by":"publisher","first-page":"P299","DOI":"10.1186\/1546-0096-9-S1-P299","article-title":"Clavicular cortical hyperostosis: new autoinflammatory entity or part of the juvenile spondyloarthropathies clinical picture?","volume":"9","author":"Lamot","year":"2011","journal-title":"Pediatr Rheumatol."},{"key":"B178","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1002\/acr.23323","article-title":"Prevalence of sacroiliitis in inflammatory bowel disease using a standardized computed tomography scoring system","volume":"70","author":"Chan","year":"2018","journal-title":"Arthritis Care Res."},{"key":"B179","doi-asserted-by":"publisher","first-page":"650619","DOI":"10.3389\/fmed.2021.650619","article-title":"The increased levels of fecal calprotectin in children with active enthesitis related arthritis and MRI signs of sacroiliitis: the results of a single center cross-sectional exploratory study in juvenile idiopathic arthritis patients","volume":"8","author":"Lamot","year":"2021","journal-title":"Front Med (Lausanne)"},{"key":"B180","first-page":"335","article-title":"Destructive hip lesions in seronegative spondyloarthropathies: relation to gut inflammation","volume":"17","author":"Mielants","year":"1990","journal-title":"J Rheumatol"},{"key":"B181","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/0016-5085(89)91557-6","article-title":"Ileocolonoscopy in seronegative spondylarthropathy","volume":"96","author":"De Vos","year":"1989","journal-title":"Gastroenterology"},{"key":"B182","doi-asserted-by":"publisher","first-page":"2009","DOI":"10.1007\/s10067-016-3287-9","article-title":"Associations between ERAP1 polymorphisms and susceptibility to ankylosing spondylitis: a meta-analysis","volume":"35","author":"Lee","year":"2016","journal-title":"Clin Rheumatol"},{"key":"B183","first-page":"498","article-title":"HLA-B*27\/HLA-B*07 in combination with D6S273-134 allele is associated with increased susceptibility to juvenile spondyloarthropathies","volume":"26","author":"Harjacek","year":"2008","journal-title":"Clin Exp Rheumatol"},{"key":"B184","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.3389\/fimmu.2018.01208","article-title":"The importance of sex stratification in autoimmune disease biomarker research: a systematic review","volume":"9","author":"Purnamawati","year":"2018","journal-title":"Front Immunol"},{"key":"B185","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1016\/j.jbspin.2016.09.005","article-title":"Defective autophagy activity and its association with spinal damage in patients with ankylosing spondylitis","volume":"84","author":"Park","year":"2017","journal-title":"Joint Bone Spine"},{"key":"B186","doi-asserted-by":"publisher","first-page":"1461","DOI":"10.3390\/biom10101461","article-title":"Understanding the pathogenesis of spondyloarthritis","volume":"10","author":"Sharip","year":"2020","journal-title":"Biomolecules"},{"key":"B187","doi-asserted-by":"publisher","first-page":"2240","DOI":"10.1093\/rheumatology\/kez204","article-title":"Apremilast increases IL-10-producing regulatory B cells and decreases proinflammatory T cells and innate cells in psoriatic arthritis and psoriasis","volume":"58","author":"Mavropoulos","year":"2019","journal-title":"Rheumatology (Oxford)."},{"key":"B188","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1007\/s11427-017-9169-6","article-title":"The regulation effect of AMPK in immune related diseases","volume":"61","author":"Wang","year":"2018","journal-title":"Sci China Life Sci"},{"key":"B189","doi-asserted-by":"publisher","first-page":"920","DOI":"10.3389\/fimmu.2017.00920","article-title":"Innate immune activation can trigger experimental spondyloarthritis in HLA-B27\/Hu\u03b22m transgenic rats","volume":"8","author":"van Tok","year":"2017","journal-title":"Front Immunol"},{"key":"B190","doi-asserted-by":"publisher","first-page":"1829","DOI":"10.1002\/jbmr.3172","article-title":"mTORC1 inhibits NF-\u03baB\/NFATc1 signaling and prevents osteoclast precursor differentiation, in vitro and in mice","volume":"32","author":"Zhang","year":"2017","journal-title":"J Bone Miner Res"},{"key":"B191","doi-asserted-by":"publisher","first-page":"2344","DOI":"10.3389\/fimmu.2019.02344","article-title":"mTOR blockade by rapamycin in spondyloarthritis: impact on inflammation and new bone formation in vitro and in vivo","volume":"10","author":"Chen","year":"2020","journal-title":"Front Immunol"},{"key":"B192","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.1002\/jcb.26275","article-title":"Effect of metformin on ossification and inflammation of fibroblasts in ankylosing spondylitis: An in vitro study","volume":"119","author":"Qin","year":"2018","journal-title":"J Cell Biochem"},{"key":"B193","doi-asserted-by":"publisher","first-page":"746","DOI":"10.1002\/art.40414","article-title":"The role of autophagy in the degradation of misfolded HLA-B27 heavy chains","volume":"70","author":"Navid","year":"2018","journal-title":"Arthritis Rheumatol"},{"key":"B194","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/j.pcl.2018.03.006","article-title":"Juvenile spondyloarthritis: a distinct form of juvenile arthritis","volume":"65","author":"Weiss","year":"2018","journal-title":"Pediatr Clin North Am"},{"key":"B195","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1038\/nm1538","article-title":"Dickkopf-1 is a master regulator of joint remodeling","volume":"13","author":"Diarra","year":"2007","journal-title":"Nat Med"},{"key":"B196","doi-asserted-by":"publisher","first-page":"1107","DOI":"10.1016\/S0140-6736(08)61452-X","article-title":"Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease","volume":"372","author":"Anderson","year":"2008","journal-title":"Lancet"},{"key":"B197","doi-asserted-by":"publisher","first-page":"2481","DOI":"10.1159\/000480211","article-title":"Cui L: MicroRNA-199a-5p induced autophagy and inhibits the pathogenesis of ankylosing spondylitis by modulating the mTOR directly targeting ras homolog enriched in brain (Rheb)","volume":"42","author":"Wang","year":"2017","journal-title":"Cell Physiol Biochem."},{"key":"B198","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1136\/ard.61.10.941","article-title":"A 26 week randomised, double blind, placebo controlled exploratory study of sulfasalazine in juvenile onset spondyloarthropathies","volume":"61","author":"Burgos-Vargas","year":"2002","journal-title":"Ann Rheum Dis"},{"key":"B199","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/s12969-018-0255-8","article-title":"Methotrexate in juvenile idiopathic arthritis: advice and recommendations from the MARAJIA expert consensus meeting","volume":"16","author":"Ferrara","year":"2018","journal-title":"Pediatr Rheumatol Online J"},{"key":"B200","doi-asserted-by":"publisher","first-page":"622770","DOI":"10.3389\/fimmu.2021.622770","article-title":"Clinical trials supporting the role of the IL-17\/IL-23 axis in axial spondyloarthritis","volume":"12","author":"Ceribelli","year":"2021","journal-title":"Front Immunol"},{"key":"B201","doi-asserted-by":"publisher","first-page":"1340","DOI":"10.1136\/annrheumdis-2016-210322","article-title":"Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study","volume":"76","author":"van der Heijde","year":"2017","journal-title":"Ann Rheum Dis"},{"key":"B202","doi-asserted-by":"publisher","first-page":"e001609","DOI":"10.1136\/rmdopen-2021-001609","article-title":"Median time to pain improvement and the impact of baseline pain severity on pain response in patients with psoriatic arthritis treated with tofacitinib","volume":"7","author":"de Vlam","year":"2021","journal-title":"RMD Open"},{"key":"B203","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1021\/acs.jmedchem.9b00293","article-title":"Discovery of selective inhibitors of endoplasmic reticulum aminopeptidase 1","volume":"63","author":"Maben","year":"2020","journal-title":"J Med Chem"},{"key":"B204","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1007\/s10067-020-05207-z","article-title":"Molecular mechanisms and clinical studies of iguratimod for the treatment of ankylosing spondylitis","volume":"40","author":"Liu","year":"2021","journal-title":"Clin Rheumatol"},{"key":"B205","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1080\/14728222.2019.1656718","article-title":"Macrophage migration inhibitory factor (MIF) as a therapeutic target for rheumatoid arthritis and systemic lupus erythematosus","volume":"23","author":"Bilsborrow","year":"2019","journal-title":"Expert Opin Ther Targets"},{"key":"B206","doi-asserted-by":"publisher","first-page":"1728","DOI":"10.1016\/j.drudis.2021.03.012","article-title":"Epigenetic regulation in macrophage migration inhibitory factor (MIF)-mediated signaling in cancer and inflammation","volume":"26","author":"Osipyan","year":"2021","journal-title":"Drug Discov Today"},{"key":"B207","doi-asserted-by":"publisher","first-page":"397","DOI":"10.2119\/molmed.2011.00030","article-title":"HDAC inhibition in rheumatoid arthritis and juvenile idiopathic arthritis","volume":"17","author":"Vojinovic","year":"2011"},{"key":"B208","doi-asserted-by":"publisher","first-page":"599","DOI":"10.3899\/jrheum.120924","article-title":"Safety of rituximab in combination with other biologic disease-modifying antirheumatic drugs in rheumatoid arthritis: an open-label study","volume":"40","author":"Rigby","year":"2013","journal-title":"J Rheumatol"},{"key":"B209","doi-asserted-by":"publisher","first-page":"640070","DOI":"10.3389\/fimmu.2021.640070","article-title":"Novel bispecific antibody for synovial-specific target delivery of anti-TNF therapy in rheumatoid arthritis","volume":"12","author":"Ferrari","year":"2021","journal-title":"Front Immunol"},{"key":"B210","doi-asserted-by":"publisher","first-page":"2301","DOI":"10.3390\/cells9102301","article-title":"The Multi-omics architecture of juvenile idiopathic arthritis","volume":"9","author":"Hou","year":"2020","journal-title":"Cells"},{"key":"B211","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1038\/s41584-021-00590-6","article-title":"Biological classification of childhood arthritis: roadmap to a molecular nomenclature","volume":"17","author":"Nigrovic","year":"2021","journal-title":"Nat Rev Rheumatol"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.700982\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T06:11:16Z","timestamp":1673417476000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.700982\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,6]]},"references-count":211,"alternative-id":["10.3389\/fmed.2021.700982"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2021.700982","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,6]]},"article-number":"700982"}}