{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T18:05:57Z","timestamp":1779127557231,"version":"3.51.4"},"reference-count":135,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T00:00:00Z","timestamp":1684195200000},"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. Dent. Med"],"abstract":"<jats:p>Many autoimmune diseases show a striking female sex predilection, including primary Sj\u00f6gren's disease (pSD). Patients with pSD display exocrine gland pathology, such as salivary hypofunction and salivary and lacrimal gland inflammation. Moreover, many serious systemic disease manifestations are well-documented, including interstitial nephritis, hypergammaglobulinemia and neuropathies. Of note, women and men with pSD display distinct clinical phenotypes. While the underlying reasons for these clinical observations were poorly understood for many years, recent studies provide mechanistic insights into the specific regulatory landscapes that mediate female susceptibility to autoimmunity. We will review factors that contribute to the female sex bias, with an emphasis on those that are most relevant to pSD pathogenesis. Specifically, we will focus on sex hormones in disease, genetic alterations that likely contribute to the significant disease prevalence in females, and studies that provide evidence for the role of the gut microbiota in disease. Lastly, we will discuss therapeutics that are in clinical trials for pSD that may be particularly efficacious in targeting signaling networks that mediate inflammation in a sex-specific manner.<\/jats:p>","DOI":"10.3389\/fdmed.2023.1168645","type":"journal-article","created":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T04:57:21Z","timestamp":1684213041000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Sex-specific differences in primary Sj\u00f6gren's disease"],"prefix":"10.3389","volume":"4","author":[{"given":"Achamaporn","family":"Punnanitinont","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jill M.","family":"Kramer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1016\/j.jid.2021.06.008","article-title":"Sex bias and autoimmune diseases","volume":"142","author":"Xing","year":"2022","journal-title":"J Invest Dermatol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1146\/annurev-pathol-012513-104728","article-title":"Sj\u00f6gren's syndrome","volume":"9","author":"Mavragani","year":"2014","journal-title":"Annu Rev Pathol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"33","DOI":"10.2147\/OARRR.S167783","article-title":"Sj\u00f6gren's syndrome and systemic lupus erythematosus: links and risks","volume":"11","author":"Pasoto","year":"2019","journal-title":"Open Access Rheumatol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1983","DOI":"10.1136\/annrheumdis-2014-205375","article-title":"Epidemiology of primary Sj\u00f6gren's syndrome: a systematic review and meta-analysis","volume":"74","author":"Qin","year":"2015","journal-title":"Ann Rheum Dis"},{"key":"B5","doi-asserted-by":"publisher","first-page":"16047","DOI":"10.1038\/nrdp.2016.47","article-title":"Sj\u00f6gren syndrome","volume":"2","author":"Brito-Zeron","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1612","DOI":"10.1002\/acr.23173","article-title":"Prevalence of primary Sj\u00f6gren's syndrome in a US population-based cohort","volume":"69","author":"Maciel","year":"2017","journal-title":"Arthritis Care Res (Hoboken)"},{"key":"B7","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1136\/annrheumdis-2016-210571","article-title":"2016 American college of rheumatology\/European league against rheumatism classification criteria for primary Sj\u00f6gren's syndrome: a consensus and data-driven methodology involving three international patient cohorts","volume":"76","author":"Shiboski","year":"2017","journal-title":"Ann Rheum Dis"},{"key":"B8","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1056\/NEJMc1804598","article-title":"Primary Sj\u00f6gren's syndrome","volume":"379","author":"Mariette","year":"2018","journal-title":"N Engl J Med"},{"key":"B9","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1002\/acr.23264","article-title":"Natural history and predictors of progression to sjogren's syndrome among participants of the Sj\u00f6gren's international collaborative clinical alliance registry","volume":"70","author":"Shiboski","year":"2018","journal-title":"Arthritis Care Res (Hoboken)"},{"key":"B10","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1002\/acr.21610","article-title":"Primary sjogren's syndrome as a systemic disease: a study of participants enrolled in an international Sj\u00f6gren's syndrome registry","volume":"64","author":"Malladi","year":"2012","journal-title":"Arthritis Care Res (Hoboken)"},{"key":"B11","doi-asserted-by":"publisher","first-page":"4029","DOI":"10.1093\/rheumatology\/keab364","article-title":"Mortality in patients with primary Sj\u00f6gren's syndrome: a systematic review and meta-analysis","volume":"60","author":"Huang","year":"2021","journal-title":"Rheumatology (Oxford)"},{"key":"B12","doi-asserted-by":"publisher","first-page":"958670","DOI":"10.3389\/fmed.2022.958670","article-title":"Sex differences in comorbidities associated with Sj\u00f6gren's disease","volume":"9","author":"Bruno","year":"2022","journal-title":"Front Med (Lausanne)"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1388","DOI":"10.1111\/1756-185X.13940","article-title":"Male patients with primary Sj\u00f6gren's syndrome: a distinct clinical subgroup?","volume":"23","author":"Park","year":"2020","journal-title":"Int J Rheum Dis"},{"key":"B14","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s13293-017-0146-6","article-title":"Long-term follow-up in primary Sj\u00f6gren's syndrome reveals differences in clinical presentation between female and male patients","volume":"8","author":"Ramirez Sepulveda","year":"2017","journal-title":"Biol Sex Differ"},{"key":"B15","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1006\/jaut.1994.1027","article-title":"Comparisons of double immunodiffusion, ELISA, western blot and CAPE blot for the detection of anti-SSA antibody: study of anti-SSA prevalence in systemic lupus erythematosus","volume":"7","author":"Chretien","year":"1994","journal-title":"J Autoimmun"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.1016\/S0002-9440(10)63505-5","article-title":"Development of autoimmune exocrinopathy resembling Sj\u00f6gren's syndrome in estrogen-deficient mice of healthy background","volume":"163","author":"Ishimaru","year":"2003","journal-title":"Am J Pathol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"2924","DOI":"10.1128\/MCB.26.8.2924-2935.2006","article-title":"Novel role for RbAp48 in tissue-specific, estrogen deficiency-dependent apoptosis in the exocrine glands","volume":"26","author":"Ishimaru","year":"2006","journal-title":"Mol Cell Biol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"2915","DOI":"10.1084\/jem.20080174","article-title":"Expression of the retinoblastoma protein RbAp48 in exocrine glands leads to Sj\u00f6gren's syndrome-like autoimmune exocrinopathy","volume":"205","author":"Ishimaru","year":"2008","journal-title":"J Exp Med"},{"key":"B19","doi-asserted-by":"publisher","first-page":"2249","DOI":"10.1093\/nar\/20.9.2249","article-title":"Tissue-specific expression in the salivary glands of transgenic mice","volume":"20","author":"Mikkelsen","year":"1992","journal-title":"Nucleic Acids Res"},{"key":"B20","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1111\/j.1600-0722.2009.00659.x","article-title":"Functional estrogen receptors alpha and beta are expressed in normal human salivary gland epithelium and apparently mediate immunomodulatory effects","volume":"117","author":"Tsinti","year":"2009","journal-title":"Eur J Oral Sci"},{"key":"B21","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.ajpath.2014.09.006","article-title":"Aromatase controls Sj\u00f6gren syndrome-like lesions through monocyte chemotactic protein-1 in target organ and adipose tissue-associated macrophages","volume":"185","author":"Iwasa","year":"2015","journal-title":"Am J Pathol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"12628","DOI":"10.1073\/pnas.0405099101","article-title":"Aromatase-deficient mice spontaneously develop a lymphoproliferative autoimmune disease resembling Sj\u00f6gren's syndrome","volume":"101","author":"Shim","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1002\/acr.24014","article-title":"Sj\u00f6gren's syndrome is associated with reduced lifetime sex hormone exposure: a case-control study","volume":"72","author":"McCoy","year":"2020","journal-title":"Arthritis Care Res (Hoboken)"},{"key":"B24","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1038\/nri2815","article-title":"The X chromosome in immune functions: when a chromosome makes the difference","volume":"10","author":"Libert","year":"2010","journal-title":"Nat Rev Immunol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.clim.2016.04.002","article-title":"Klinefelter's syndrome (47,XXY) is in excess among men with Sj\u00f6gren's syndrome","volume":"168","author":"Harris","year":"2016","journal-title":"Clin Immunol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1177\/0961203315580873","article-title":"Development of mixed connective tissue disease and Sj\u00f6gren's syndrome in a patient with trisomy X","volume":"24","author":"Fujimoto","year":"2015","journal-title":"Lupus"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1002\/art.39560","article-title":"X chromosome dose and sex bias in autoimmune diseases: increased prevalence of 47,XXX in systemic lupus erythematosus and Sj\u00f6gren's syndrome","volume":"68","author":"Liu","year":"2016","journal-title":"Arthritis Rheumatol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2024624118","article-title":"The dynamic epigenetic regulation of the inactive X chromosome in healthy human B cells is dysregulated in lupus patients","volume":"118","author":"Pyfrom","year":"2021","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B29","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1083\/jcb.153.4.773","article-title":"Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation","volume":"153","author":"Csankovszki","year":"2001","journal-title":"J Cell Biol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1007\/s00281-018-0712-y","article-title":"Female predisposition to TLR7-driven autoimmunity: gene dosage and the escape from X chromosome inactivation","volume":"41","author":"Souyris","year":"2019","journal-title":"Semin Immunopathol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1790","DOI":"10.1016\/j.cell.2021.02.015","article-title":"B cell-specific XIST complex enforces X-inactivation and restrains atypical B cells","volume":"184","author":"Yu","year":"2021","journal-title":"Cell"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.126751","article-title":"Altered X-chromosome inactivation in T cells may promote sex-biased autoimmune diseases","volume":"4","author":"Syrett","year":"2019","journal-title":"JCI Insight"},{"key":"B33","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1111\/odi.12825","article-title":"Sj\u00f6gren's syndrome X-chromosome dose effect: an epigenetic perspective","volume":"25","author":"Mougeot","year":"2019","journal-title":"Oral Dis"},{"key":"B34","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1007\/s11926-021-01047-1","article-title":"TLR7 Signaling in lupus B cells: new insights into synergizing factors and downstream signals","volume":"23","author":"Satterthwaite","year":"2021","journal-title":"Curr Rheumatol Rep"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1669","DOI":"10.1126\/science.1124978","article-title":"Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication","volume":"312","author":"Pisitkun","year":"2006","journal-title":"Science"},{"key":"B36","doi-asserted-by":"publisher","first-page":"6573","DOI":"10.4049\/jimmunol.177.10.6573","article-title":"Nucleic acid-sensing TLRs as modifiers of autoimmunity","volume":"177","author":"Deane","year":"2006","journal-title":"J Immunol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1016\/j.tripleo.2010.01.006","article-title":"Expression of toll-like receptors 7, 8, and 9 in primary Sj\u00f6gren's syndrome","volume":"109","author":"Zheng","year":"2010","journal-title":"Oral Surg Oral Med Oral Pathol Oral Radiol Endod"},{"key":"B38","doi-asserted-by":"publisher","first-page":"2770","DOI":"10.1073\/pnas.0510837103","article-title":"Activation of IFN pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sj\u00f6gren's syndrome","volume":"103","author":"Gottenberg","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B39","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1111\/sji.12520","article-title":"Expression of toll-like receptors in peripheral blood mononuclear cells of patients with primary Sj\u00f6gren's syndrome","volume":"85","author":"Karlsen","year":"2017","journal-title":"Scand J Immunol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1136\/annrheumdis-2016-209589","article-title":"Contrasting expression pattern of RNA-sensing receptors TLR7, RIG-I and MDA5 in interferon-positive and interferon-negative patients with primary Sj\u00f6gren's syndrome","volume":"76","author":"Maria","year":"2017","journal-title":"Ann Rheum Dis"},{"key":"B41","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1111\/cei.13242","article-title":"Activation of toll-like receptor 7 signaling in labial salivary glands of primary Sj\u00f6gren's syndrome patients","volume":"196","author":"Shimizu","year":"2019","journal-title":"Clin Exp Immunol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1111\/sji.12368","article-title":"TLR-7 and -9 stimulation of peripheral blood B cells indicate altered TLR signalling in primary Sj\u00f6gren's syndrome patients by increased secretion of cytokines","volume":"82","author":"Karlsen","year":"2015","journal-title":"Scand J Immunol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1111\/j.1365-3083.2006.01811.x","article-title":"Role of dendritic cells in Sj\u00f6gren's syndrome","volume":"64","author":"Vogelsang","year":"2006","journal-title":"Scand J Immunol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1755","DOI":"10.1136\/annrheumdis-2016-210509","article-title":"H1n1 vaccination in Sj\u00f6gren's syndrome triggers polyclonal B cell activation and promotes autoantibody production","volume":"76","author":"Brauner","year":"2017","journal-title":"Ann Rheum Dis"},{"key":"B45","doi-asserted-by":"publisher","first-page":"281","DOI":"10.3389\/fimmu.2019.00281","article-title":"Single cell based phosphorylation profiling identifies alterations in toll-like receptor 7 and 9 signaling in patients with primary Sj\u00f6gren's syndrome","volume":"10","author":"Davies","year":"2019","journal-title":"Front Immunol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"676010","DOI":"10.3389\/fimmu.2021.676010","article-title":"TLR7 Signaling drives the development of Sj\u00f6gren's syndrome","volume":"12","author":"Wang","year":"2021","journal-title":"Front Immunol"},{"key":"B47","doi-asserted-by":"publisher","first-page":"9478","DOI":"10.3390\/ijms21249478","article-title":"Toll-Like receptor 7 is required for lacrimal gland autoimmunity and type 1 diabetes development in male nonobese diabetic mice","volume":"21","author":"Debreceni","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B48","doi-asserted-by":"publisher","first-page":"8593","DOI":"10.1038\/s41598-022-12608-4","article-title":"Bone marrow-derived macrophages from a murine model of Sj\u00f6gren's syndrome demonstrate an aberrant, inflammatory response to apoptotic cells","volume":"12","author":"Witas","year":"2022","journal-title":"Sci Rep"},{"key":"B49","doi-asserted-by":"publisher","first-page":"3651","DOI":"10.1172\/JCI42081","article-title":"TLR8 Deficiency leads to autoimmunity in mice","volume":"120","author":"Demaria","year":"2010","journal-title":"J Clin Invest"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1034336","DOI":"10.3389\/fimmu.2022.1034336","article-title":"TLR7 Agonism accelerates disease in a mouse model of primary Sj\u00f6gren's syndrome and drives expansion of T-bet(+) B cells","volume":"13","author":"Punnanitinont","year":"2022","journal-title":"Front Immunol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aap8855","article-title":"TLR7 Escapes X chromosome inactivation in immune cells","volume":"3","author":"Souyris","year":"2018","journal-title":"Sci Immunol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"e12662","DOI":"10.1111\/sji.12662","article-title":"Transcription profiling of peripheral B cells in antibody-positive primary Sj\u00f6gren's syndrome reveals upregulated expression of CX3CR1 and a type I and type II interferon signature","volume":"87","author":"Imgenberg-Kreuz","year":"2018","journal-title":"Scand J Immunol"},{"key":"B53","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1002\/art.37828","article-title":"Expansion of autoreactive unresponsive CD21-\/low B cells in Sj\u00f6gren's syndrome-associated lymphoproliferation","volume":"65","author":"Saadoun","year":"2013","journal-title":"Arthritis Rheum"},{"key":"B54","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1002\/art.40352","article-title":"Accumulation of antigen-driven lymphoproliferations in complement receptor 2\/CD21(-\/low) B cells from patients with Sj\u00f6gren's syndrome","volume":"70","author":"Glauzy","year":"2018","journal-title":"Arthritis Rheumatol"},{"key":"B55","doi-asserted-by":"publisher","first-page":"R166","DOI":"10.1186\/ar4682","article-title":"Altered phenotype and Stat1 expression in toll-like receptor 7\/8 stimulated monocyte-derived dendritic cells from patients with primary Sj\u00f6gren's syndrome","volume":"16","author":"Vogelsang","year":"2014","journal-title":"Arthritis Res Ther"},{"key":"B56","doi-asserted-by":"publisher","first-page":"578","DOI":"10.3389\/fimmu.2019.00578","article-title":"Lysosomal pH is regulated in a sex dependent manner in immune cells expressing CXorf21","volume":"10","author":"Harris","year":"2019","journal-title":"Front Immunol"},{"key":"B57","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1038\/s41586-020-2282-0","article-title":"TASL Is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9","volume":"581","author":"Heinz","year":"2020","journal-title":"Nature"},{"key":"B58","doi-asserted-by":"publisher","first-page":"2160","DOI":"10.3389\/fimmu.2019.02160","article-title":"Characterization of cxorf21 provides molecular insight into female-bias immune response in SLE pathogenesis","volume":"10","author":"Harris","year":"2019","journal-title":"Front Immunol"},{"key":"B59","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.3389\/fimmu.2017.01075","article-title":"The toll for trafficking: toll-like receptor 7 delivery to the endosome","volume":"8","author":"Petes","year":"2017","journal-title":"Front Immunol"},{"key":"B60","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/s0952-7915(97)80075-1","article-title":"Molecular mechanisms in B cell antigen receptor signaling","volume":"9","author":"Kurosaki","year":"1997","journal-title":"Curr Opin Immunol"},{"key":"B61","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1002\/art.40059","article-title":"Enhanced bruton's tyrosine kinase activity in peripheral blood B lymphocytes from patients with autoimmune disease","volume":"69","author":"Corneth","year":"2017","journal-title":"Arthritis Rheumatol"},{"key":"B62","doi-asserted-by":"publisher","first-page":"3744","DOI":"10.1182\/blood-2011-12-397919","article-title":"Btk levels set the threshold for B-cell activation and negative selection of autoreactive B cells in mice","volume":"119","author":"Kil","year":"2012","journal-title":"Blood"},{"key":"B63","doi-asserted-by":"publisher","first-page":"58","DOI":"10.4049\/jimmunol.1600208","article-title":"Enhanced expression of bruton's tyrosine kinase in B cells drives systemic autoimmunity by disrupting T cell homeostasis","volume":"197","author":"Corneth","year":"2016","journal-title":"J Immunol"},{"key":"B64","doi-asserted-by":"publisher","first-page":"109171","DOI":"10.1016\/j.clim.2022.109171","article-title":"De novo molecular subtyping of salivary gland tissue in the context of Sj\u00f6gren's syndrome heterogeneity","volume":"245","author":"Jung","year":"2022","journal-title":"Clin Immunol"},{"key":"B65","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1038\/icb.2010.158","article-title":"CXCR3 Ligands: redundant, collaborative and antagonistic functions","volume":"89","author":"Groom","year":"2011","journal-title":"Immunol Cell Biol"},{"key":"B66","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.jaut.2012.12.006","article-title":"Overexpression of X-linked genes in T cells from women with lupus","volume":"41","author":"Hewagama","year":"2013","journal-title":"J Autoimmun"},{"key":"B67","doi-asserted-by":"publisher","first-page":"2730","DOI":"10.1002\/art.10577","article-title":"Involvement of the interferon-gamma-induced T cell-attracting chemokines, interferon-gamma-inducible 10-kd protein (CXCL10) and monokine induced by interferon-gamma (CXCL9), in the salivary gland lesions of patients with Sj\u00f6gren's syndrome","volume":"46","author":"Ogawa","year":"2002","journal-title":"Arthritis Rheum"},{"key":"B68","doi-asserted-by":"publisher","first-page":"2581","DOI":"10.4049\/jimmunol.176.4.2581","article-title":"Epithelial CXCR3-B regulates chemokines bioavailability in normal, but not in Sj\u00f6gren's syndrome, salivary glands","volume":"176","author":"Sfriso","year":"2006","journal-title":"J Immunol"},{"key":"B69","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1167\/iovs.09-3425","article-title":"Expression of CXCL9, -10, -11, and CXCR3 in the tear film and ocular surface of patients with dry eye syndrome","volume":"51","author":"Yoon","year":"2010","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B70","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1038\/nri3804","article-title":"Dynamics of B cells in germinal centres","volume":"15","author":"De Silva","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"B71","doi-asserted-by":"publisher","first-page":"681941","DOI":"10.3389\/fimmu.2021.681941","article-title":"The transcriptome of paired Major and Minor salivary gland tissue in patients with primary Sj\u00f6gren's syndrome","volume":"12","author":"Verstappen","year":"2021","journal-title":"Front Immunol"},{"key":"B72","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1111\/sji.12121","article-title":"Upregulation of membrane-bound CD40L on CD4+ T cells in women with primary Sj\u00f6gren's syndrome","volume":"79","author":"Belkhir","year":"2014","journal-title":"Scand J Immunol"},{"key":"B73","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.jaut.2006.02.002","article-title":"Elevated levels of soluble CD40 ligand (sCD40L) in serum of patients with systemic autoimmune diseases","volume":"26","author":"Goules","year":"2006","journal-title":"J Autoimmun"},{"key":"B74","doi-asserted-by":"publisher","first-page":"6352","DOI":"10.4049\/jimmunol.179.9.6352","article-title":"Demethylation of CD40LG on the inactive X in T cells from women with lupus","volume":"179","author":"Lu","year":"2007","journal-title":"J Immunol"},{"key":"B75","doi-asserted-by":"publisher","first-page":"e21996","DOI":"10.1096\/fj.202100679RR","article-title":"VGLL3 Activates inflammatory responses by inducing interleukin-1alpha secretion","volume":"35","author":"Takakura","year":"2021","journal-title":"FASEB J"},{"key":"B76","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1038\/ni.3643","article-title":"A gene network regulated by the transcription factor VGLL3 as a promoter of sex-biased autoimmune diseases","volume":"18","author":"Liang","year":"2017","journal-title":"Nat Immunol"},{"key":"B77","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1038\/s41586-020-2277-x","article-title":"Complement genes contribute sex-biased vulnerability in diverse disorders","volume":"582","author":"Kamitaki","year":"2020","journal-title":"Nature"},{"key":"B78","doi-asserted-by":"publisher","first-page":"38717","DOI":"10.1038\/srep38717","article-title":"Sexual dimorphic function of IL-17 in salivary gland dysfunction of the C57BL\/6.NOD-Aec1Aec2 model of Sj\u00f6gren's syndrome","volume":"6","author":"Voigt","year":"2016","journal-title":"Sci Rep"},{"key":"B79","doi-asserted-by":"publisher","first-page":"693911","DOI":"10.3389\/fimmu.2021.693911","article-title":"Deregulation of the kallikrein protease family in the salivary glands of the Sj\u00f6gren's syndrome ERdj5 knockout mouse model","volume":"12","author":"Moustardas","year":"2021","journal-title":"Front Immunol"},{"key":"B80","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s13293-017-0153-7","article-title":"Sex influences eQTL effects of SLE and Sj\u00f6gren's syndrome-associated genetic polymorphisms","volume":"8","author":"Linden","year":"2017","journal-title":"Biol Sex Differ"},{"key":"B81","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1111\/cei.13118","article-title":"Diminished CXCR5 expression in peripheral blood of patients with Sj\u00f6gren's syndrome may relate to both genotype and salivary gland homing","volume":"192","author":"Aqrawi","year":"2018","journal-title":"Clin Exp Immunol"},{"key":"B82","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1093\/jmcb\/mjq023","article-title":"Gender-dependent expression of murine Irf5 gene: implications for sex bias in autoimmunity","volume":"2","author":"Shen","year":"2010","journal-title":"J Mol Cell Biol"},{"key":"B83","doi-asserted-by":"publisher","first-page":"1284","DOI":"10.1038\/ng.2792","article-title":"Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sj\u00f6gren's syndrome","volume":"45","author":"Lessard","year":"2013","journal-title":"Nat Genet"},{"key":"B84","doi-asserted-by":"publisher","first-page":"1294","DOI":"10.1002\/art.40040","article-title":"Genome-Wide association analysis reveals genetic heterogeneity of Sj\u00f6gren's syndrome according to ancestry","volume":"69","author":"Taylor","year":"2017","journal-title":"Arthritis Rheumatol"},{"key":"B85","doi-asserted-by":"publisher","first-page":"17005","DOI":"10.1074\/jbc.M412584200","article-title":"The interferon regulatory factor, IRF5, is a central mediator of toll-like receptor 7 signaling","volume":"280","author":"Schoenemeyer","year":"2005","journal-title":"J Biol Chem"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1111\/odi.14506","article-title":"Association of G protein-coupled receptor 78 with salivary dysfunction in male Sj\u00f6gren's patients","author":"Tanaka","year":"2023","journal-title":"Oral Dis"},{"key":"B87","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1182\/blood-2011-08-371831","article-title":"The TLR-mediated response of plasmacytoid dendritic cells is positively regulated by estradiol in vivo through cell-intrinsic estrogen receptor alpha signaling","volume":"119","author":"Seillet","year":"2012","journal-title":"Blood"},{"key":"B88","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1177\/0961203311425522","article-title":"TLR7\/8\/9 Polymorphisms and their associations in systemic lupus erythematosus patients from southern Brazil","volume":"21","author":"dos Santos","year":"2012","journal-title":"Lupus"},{"key":"B89","doi-asserted-by":"publisher","first-page":"15838","DOI":"10.1073\/pnas.1001337107","article-title":"Sex-specific association of X-linked toll-like receptor 7 (TLR7) with male systemic lupus erythematosus","volume":"107","author":"Shen","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B90","doi-asserted-by":"publisher","first-page":"3792","DOI":"10.1038\/srep03792","article-title":"Genetic variations in toll-like receptors (TLRs 3\/7\/8) are associated with systemic lupus erythematosus in a Taiwanese population","volume":"4","author":"Wang","year":"2014","journal-title":"Sci Rep"},{"key":"B91","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1016\/j.jbspin.2020.05.004","article-title":"Bruton's tyrosine kinase in systemic lupus erythematosus","volume":"87","author":"Liao","year":"2020","journal-title":"Joint Bone Spine"},{"key":"B92","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1007\/s10067-017-3717-3","article-title":"Increased expression of bruton's tyrosine kinase in peripheral blood is associated with lupus nephritis","volume":"37","author":"Kong","year":"2018","journal-title":"Clin Rheumatol"},{"key":"B93","doi-asserted-by":"publisher","first-page":"1842","DOI":"10.1002\/art.42270","article-title":"Strong association of combined genetic deficiencies in the classical complement pathway with risk of systemic lupus erythematosus and primary Sj\u00f6gren's syndrome","volume":"74","author":"Lundtoft","year":"2022","journal-title":"Arthritis Rheumatol"},{"key":"B94","doi-asserted-by":"publisher","first-page":"108406","DOI":"10.1016\/j.clim.2020.108406","article-title":"Overexpression of CXCR5 in CD4(+) T cells of SLE patients caused by excessive SETD3","volume":"214","author":"Liao","year":"2020","journal-title":"Clin Immunol"},{"key":"B95","doi-asserted-by":"publisher","first-page":"4287","DOI":"10.1038\/s41467-022-30773-y","article-title":"Genome-wide association study identifies Sj\u00f6gren's risk loci with functional implications in immune and glandular cells","volume":"13","author":"Khatri","year":"2022","journal-title":"Nat Commun"},{"key":"B96","doi-asserted-by":"publisher","first-page":"6758","DOI":"10.1073\/pnas.0701266104","article-title":"Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus","volume":"104","author":"Graham","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B97","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.immuni.2011.05.010","article-title":"Unc93B1 restricts systemic lethal inflammation by orchestrating toll-like receptor 7 and 9 trafficking","volume":"35","author":"Fukui","year":"2011","journal-title":"Immunity"},{"key":"B98","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1093\/intimm\/dxt015","article-title":"Expression of murine Unc93b1 is up-regulated by interferon and estrogen signaling: implications for sex bias in the development of autoimmunity","volume":"25","author":"Panchanathan","year":"2013","journal-title":"Int Immunol"},{"key":"B99","doi-asserted-by":"publisher","first-page":"5327","DOI":"10.4049\/jimmunol.1501684","article-title":"Sex differences in plasmacytoid dendritic cell levels of IRF5 drive higher IFN-alpha production in women","volume":"195","author":"Griesbeck","year":"2015","journal-title":"J Immunol"},{"key":"B100","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/j.resmic.2019.03.003","article-title":"Serum level of sex steroid hormone is associated with diversity and profiles of human gut microbiome","volume":"170","author":"Shin","year":"2019","journal-title":"Res Microbiol"},{"key":"B101","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1016\/j.tim.2020.11.001","article-title":"The interplay of sex steroids, the immune response, and the intestinal Microbiota","volume":"29","author":"Pace","year":"2021","journal-title":"Trends Microbiol"},{"key":"B102","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.1126\/science.1233521","article-title":"Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity","volume":"339","author":"Markle","year":"2013","journal-title":"Science"},{"key":"B103","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/j.immuni.2013.08.013","article-title":"Gender bias in autoimmunity is influenced by microbiota","volume":"39","author":"Yurkovetskiy","year":"2013","journal-title":"Immunity"},{"key":"B104","doi-asserted-by":"publisher","first-page":"897971","DOI":"10.3389\/fimmu.2022.897971","article-title":"Sex-dependent lupus Blautia (Ruminococcus) gnavus strain induction of zonulin-mediated intestinal permeability and autoimmunity","volume":"13","author":"Silverman","year":"2022","journal-title":"Front Immunol"},{"key":"B105","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1186\/s40168-017-0300-8","article-title":"Control of lupus nephritis by changes of gut microbiota","volume":"5","author":"Mu","year":"2017","journal-title":"Microbiome"},{"key":"B106","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.chom.2018.11.009","article-title":"A diet-sensitive commensal Lactobacillus strain mediates TLR7-dependent systemic autoimmunity","volume":"25","author":"Zegarra-Ruiz","year":"2019","journal-title":"Cell Host Microbe"},{"key":"B107","doi-asserted-by":"publisher","first-page":"910561","DOI":"10.3389\/fmed.2022.910561","article-title":"Mini-Review: gut-Microbiota and the sex-bias in autoimmunity\u2014lessons learnt from animal models","volume":"9","author":"Rosser","year":"2022","journal-title":"Front Med (Lausanne)"},{"key":"B108","doi-asserted-by":"publisher","first-page":"102436","DOI":"10.1016\/j.jaut.2020.102436","article-title":"Multi-omics: differential expression of IFN-gamma results in distinctive mechanistic features linking chronic inflammation, gut dysbiosis, and autoimmune diseases","volume":"111","author":"Bae","year":"2020","journal-title":"J Autoimmun"},{"key":"B109","doi-asserted-by":"publisher","first-page":"111352","DOI":"10.1016\/j.celrep.2022.111352","article-title":"Microbiota dysbiosis in primary Sj\u00f6gren's syndrome and the ameliorative effect of hydroxychloroquine","volume":"40","author":"Wang","year":"2022","journal-title":"Cell Rep"},{"key":"B110","doi-asserted-by":"publisher","first-page":"852918","DOI":"10.3389\/fmed.2022.852918","article-title":"Gut Microbiota from Sj\u00f6gren syndrome patients causes decreased T regulatory cells in the lymphoid organs and desiccation-induced corneal barrier disruption in mice","volume":"9","author":"Schaefer","year":"2022","journal-title":"Front Med (Lausanne)"},{"key":"B111","doi-asserted-by":"publisher","first-page":"2551","DOI":"10.3390\/pharmaceutics14122551","article-title":"Biologic functions of hydroxychloroquine in disease: from COVID-19 to cancer","volume":"14","author":"Niemann","year":"2022","journal-title":"Pharmaceutics"},{"key":"B112","doi-asserted-by":"publisher","first-page":"e167","DOI":"10.1016\/j.lpm.2014.03.007","article-title":"Hydroxychloroquine: a multifaceted treatment in lupus","volume":"43","author":"Costedoat-Chalumeau","year":"2014","journal-title":"Presse Med"},{"key":"B113","doi-asserted-by":"publisher","first-page":"361ra137","DOI":"10.1126\/scitranslmed.aag0367","article-title":"Autoimmune manifestations in aged mice arise from early-life immune dysregulation","volume":"8","author":"Mahmoud","year":"2016","journal-title":"Sci Transl Med"},{"key":"B114","doi-asserted-by":"publisher","first-page":"974","DOI":"10.1136\/annrheumdis-2018-213929","article-title":"Blockade of CD40-CD154 pathway interactions suppresses ectopic lymphoid structures and inhibits pathology in the NOD\/ShiLtJ mouse model of sjogren's syndrome","volume":"78","author":"Wieczorek","year":"2019","journal-title":"Ann Rheum Dis"},{"key":"B115","doi-asserted-by":"publisher","first-page":"54","DOI":"10.4049\/immunohorizons.1700069","article-title":"Requirement for CD40\/CD40L interactions for development of autoimmunity differs depending on specific checkpoint and costimulatory pathways","volume":"2","author":"Voynova","year":"2018","journal-title":"Immunohorizons"},{"key":"B116","article-title":"A Study to Evaluate the Efficacy and Safety of VIB4920 in Participants With Sj\u00f6gren's Syndrome (SS) (2023)","year":""},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0000000000004469","article-title":"CD40-CD40L Blockade: update on novel investigational therapeutics for transplantation","author":"Singh","year":"2022","journal-title":"Transplantation"},{"key":"B118","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1097\/MOT.0000000000000844.","article-title":"Developments in immunosuppression","volume":"26","author":"Viklicky","year":"2021","journal-title":"Curr Opin Organ Transplant"},{"key":"B119","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1007\/s40259-021-00505-7","article-title":"Targeted therapy for primary Sj\u00f6gren's syndrome: where are we now?","volume":"35","author":"Wang","year":"2021","journal-title":"BioDrugs"},{"key":"B120","article-title":"Study of Safety and Tolerability of CFZ533 in Patients With Sj\u00f6gren's Syndrome (TWINSS Extn) (2023)","year":""},{"key":"B121","doi-asserted-by":"publisher","first-page":"705307","DOI":"10.3389\/fimmu.2021.705307","article-title":"Impaired B cell apoptosis results in autoimmunity that is alleviated by ablation of btk","volume":"12","author":"Wright","year":"2021","journal-title":"Front Immunol"},{"key":"B122","article-title":"A Phase 2 Study to Evaluate the Safety and Efficacy of LOU064 in Patients With Moderate to Severe Sj\u00f6gren's Syndrome (LOUiSSe) (2023)","year":""},{"key":"B123","doi-asserted-by":"publisher","first-page":"2807","DOI":"10.3390\/jcm11102807","article-title":"Bruton's kinase inhibitors for the treatment of immunological diseases: current Status and perspectives","volume":"11","author":"Robak","year":"2022","journal-title":"J Clin Med"},{"key":"B124","article-title":"The WILLOW Study With M5049 in SLE and CLE (SCLE and\/or DLE) (WILLOW) (2023)","year":""},{"key":"B125","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1002\/cpt.2606","article-title":"Applying modeling and simulations for rational dose selection of novel toll-like receptor 7\/8 inhibitor enpatoran for indications of high medical need","volume":"112","author":"Klopp-Schulze","year":"2022","journal-title":"Clin Pharmacol Ther"},{"key":"B126","doi-asserted-by":"publisher","first-page":"e00842","DOI":"10.1002\/prp2.842","article-title":"Phase 1 study in healthy participants of the safety, pharmacokinetics, and pharmacodynamics of enpatoran (M5049), a dual antagonist of toll-like receptors 7 and 8","volume":"9","author":"Port","year":"2021","journal-title":"Pharmacol Res Perspect"},{"key":"B127","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1002\/acr.25048","article-title":"Female sex, age, and unfavorable response to tumor necrosis factor inhibitors in patients with axial spondyloarthritis: results of statistical and artificial intelligence-based data analyses of a national multicenter prospective registry","volume":"75","author":"Fernandez-Carballido","year":"2023","journal-title":"Arthritis Care Res (Hoboken)"},{"key":"B128","doi-asserted-by":"publisher","first-page":"195","DOI":"10.3899\/jrheum.170666","article-title":"The sex influence on response to tumor necrosis factor-alpha inhibitors and remission in axial spondyloarthritis","volume":"45","author":"Lubrano","year":"2018","journal-title":"J Rheumatol"},{"key":"B129","doi-asserted-by":"publisher","first-page":"e0266816","DOI":"10.1371\/journal.pone.0266816","article-title":"Sex difference in disease burden of inflammatory arthritis patients treated with tumor necrosis factor inhibitors as part of standard care","volume":"17","author":"Michelsen","year":"2022","journal-title":"PLoS One"},{"key":"B130","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1080\/09546634.2019.1656797","article-title":"Characterization of insufficient responders to anti-tumor necrosis factor therapies in patients with moderate to severe psoriasis: real-world data from the US corrona psoriasis registry","volume":"32","author":"Van Voorhees","year":"2021","journal-title":"J Dermatolog Treat"},{"key":"B131","doi-asserted-by":"publisher","first-page":"885","DOI":"10.3899\/jrheum.211037","article-title":"Potential impact of sex and BMI on response to therapy in psoriatic arthritis: post hoc analysis of results from the SEAM-PsA trial","volume":"49","author":"Mease","year":"2022","journal-title":"J Rheumatol"},{"key":"B132","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1080\/03009742.2019.1602670","article-title":"Association of female sex and positive rheumatoid factor with low serum infliximab and anti-drug antibodies, related to treatment failure in early rheumatoid arthritis: results from the SWEFOT trial population","volume":"48","author":"Hambardzumyan","year":"2019","journal-title":"Scand J Rheumatol"},{"key":"B133","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1111\/apt.15380","article-title":"Earlier discontinuation of TNF-alpha inhibitor therapy in female patients with inflammatory bowel disease is related to a greater risk of side effects","volume":"50","author":"Schultheiss","year":"2019","journal-title":"Aliment Pharmacol Ther"},{"key":"B134","doi-asserted-by":"publisher","first-page":"1913","DOI":"10.1111\/jdv.15733","article-title":"Female patients are less satisfied with biological treatment for psoriasis and experience more side-effects than male patients: results from the prospective BioCAPTURE registry","volume":"33","author":"van der Schoot","year":"2019","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"B135","doi-asserted-by":"publisher","first-page":"801532","DOI":"10.3389\/fmed.2021.801532","article-title":"Relationship between patient sex and serum tumor necrosis factor antagonist drug and anti-drug antibody concentrations in inflammatory bowel disease; a nationwide cohort study","volume":"8","author":"Shehab","year":"2021","journal-title":"Front Med (Lausanne)"}],"container-title":["Frontiers in Dental Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fdmed.2023.1168645\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T14:25:18Z","timestamp":1722522318000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fdmed.2023.1168645\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,16]]},"references-count":135,"alternative-id":["10.3389\/fdmed.2023.1168645"],"URL":"https:\/\/doi.org\/10.3389\/fdmed.2023.1168645","relation":{},"ISSN":["2673-4915"],"issn-type":[{"value":"2673-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,16]]},"article-number":"1168645"}}