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REVIEW ARTICLE

Sex differences in autoimmune disorders: Inspecting the roles of the X chromosome

Matteo Capici1* ,  Antonino Zito2,3*
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1 Department of Biomedicine, Neuroscience and Advanced Diagnostics, School of Medicine and Surgery, University of Palermo, Palermo, Italy
2 Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy
3 Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom
GPD, 8321 https://doi.org/10.36922/gpd.8321
Submitted: 31 December 2024 | Revised: 25 February 2025 | Accepted: 25 February 2025 | Published: 13 March 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Autoimmune disorders are complex, heterogeneous conditions that can severely impact an individual’s quality of life. These diseases are associated with a breakdown of central and peripheral processes controlling self-tolerance, causing the presence of circulating autoreactive immune cells that target the body’s own cells and tissues. Some data suggest that autoimmune diseases (ADs) are becoming increasingly prevalent in modern society. Possibly, both genetic and environmental factors contribute to the rise. ADs disproportionally affect females compared to males. Hormonal determinants, particularly sex-steroid hormones, have historically been proposed as key modulators of the differential susceptibility to ADs between the mammalian sexes. Emerging evidence has more recently generated significant focus on the X chromosome as a potential key player in ADs pathogenesis. The X chromosome, one of the largest chromosomes in the mammalian genome, exhibits a different pattern of inheritance between the sexes. In females, one X chromosome is typically silenced in somatic cells to balance the active X dosage between the sexes. The X-inactivation process is not fully efficient as a proportion of X-linked genes is capable to escape silencing and maintaining variable, biallelic expression degree within each cell. Notably, the X chromosome is rich in genes related to immune functions; variations in X chromosome dosage can alter the susceptibility of developing autoimmune traits. Both X-linked genes and X-linked mechanisms have been associated with ADs. In this review, we discuss the X chromosome’s crucial roles in ADs.

Graphical abstract
Keywords
Autoimmune diseases
Sex differences
X-chromosome inactivation
Skewed X-inactivation
Escape from X-inactivation
Systemic lupus erythematosus
Sjogren’s syndrome
Hashimoto’s thyroiditis
Funding
None.
Conflict of interest
The authors declare they have no competing interests.
References
  1. Pisetsky DS. Pathogenesis of autoimmune disease. Nat Rev Nephrol. 2023;19(8):509-524. doi: 10.1038/s41581-023-00720-1

 

  1. Wang L, Wang FS, Gershwin ME. Human autoimmune diseases: A comprehensive update. J Intern Med. 2015;278(4):369-395. doi: 10.1111/joim.12395

 

  1. Scherlinger M, Mertz P, Sagez F, et al. Worldwide trends in all-cause mortality of auto-immune systemic diseases between 2001 and 2014. Autoimmun Rev. 2020;19(6):102531. doi: 10.1016/j.autrev.2020.102531

 

  1. Roberts MH, Erdei E. Comparative United States autoimmune disease rates for 2010-2016 by sex, geographic region, and race. Autoimmun Rev. 2020;19(1):102423. doi: 10.1016/j.autrev.2019.102423

 

  1. Miller FW. The increasing prevalence of autoimmunity and autoimmune diseases: An urgent call to action for improved understanding, diagnosis, treatment, and prevention. Curr Opin Immunol. 2023;80:102266. doi: 10.1016/j.coi.2022.102266

 

  1. Spolarics Z. The X-files of inflammation: Cellular mosaicism of X-linked polymorphic genes and the female advantage in the host response to injury and infection. Shock. 2007;27(6):597-604. doi: 10.1097/SHK.0b013e31802e40bd

 

  1. Thompson DJ, Gezon HM, Rogers KD, Yee RB, Hatch TF. Excess risk of staphylococcal infection and disease in newborn males. Am J Epidemiol. 1966;84(2):314-328. doi: 10.1093/oxfordjournals.aje.a120645

 

  1. Purtilo DT, Sullivan JL. Immunological bases for superior survival of females. Am J Dis Child. 1979;133(12):1251-1253. doi: 10.1001/archpedi.1979.02130120043008

 

  1. Izmirly PM, Parton H, Wang L, et al. Prevalence of systemic lupus erythematosus in the United States: Estimates from a meta-analysis of the centers for disease control and prevention national lupus registries. Arthritis Rheumatol. 2021;73(6):991-996. doi: 10.1002/art.41632

 

  1. Ragusa F, Fallahi P, Elia G, et al. Hashimotos’ thyroiditis: Epidemiology, pathogenesis, clinic and therapy. Best Pract Res Clin Endocrinol Metab. 2019;33(6):101367. doi: 10.1016/j.beem.2019.101367

 

  1. Nalbandian G, Kovats S. Understanding sex biases in immunity: Effects of estrogen on the differentiation and function of antigen-presenting cells. Immunol Res. 2005;31(2):91-106. doi: 10.1385/IR:31:2:091

 

  1. Cutolo M, Capellino S, Sulli A, et al. Estrogens and autoimmune diseases. Ann N Y Acad Sci. 2006;1089:538-547. doi: 10.1196/annals.1386.043

 

  1. Hoffmann JP, Liu JA, Seddu K, Klein SL. Sex hormone signaling and regulation of immune function. Immunity. 2023;56(11):2472-2491. doi: 10.1016/j.immuni.2023.10.008

 

  1. Ross MT, Grafham DV, Coffey AJ, et al. The DNA sequence of the human X chromosome. Nature. 2005;434(7031):325-337. doi: 10.1038/nature03440

 

  1. Bianchi I, Lleo A, Gershwin ME, Invernizzi P. The X chromosome and immune associated genes. J Autoimmun. 2012;38(2-3):J187-J192. doi: 10.1016/j.jaut.2011.11.012

 

  1. Libert C, Dejager L, Pinheiro I. The X chromosome in immune functions: When a chromosome makes the difference. Nat Rev Immunol. 2010;10(8):594-604. doi: 10.1038/nri2815

 

  1. Scofield RH, Bruner GR, Namjou B, et al. Klinefelter’s syndrome (47,XXY) in male systemic lupus erythematosus patients: Support for the notion of a gene-dose effect from the X chromosome. Arthritis Rheum. 2008;58(8):2511-2517. doi: 10.1002/art.23701

 

  1. Liu K, Kurien BT, Zimmerman SL, et al. X chromosome dose and sex bias in autoimmune diseases: Increased prevalence of 47,XXX in Systemic lupus erythematosus and Sjogren’s syndrome. Arthritis Rheumatol. 2016;68(5):1290-1300. doi: 10.1002/art.39560

 

  1. Bhattacharya S, Sadhukhan D, Saraswathy R. Role of sex in immune response and epigenetic mechanisms. Epigenetics Chromatin. 2024;17(1):1. doi: 10.1186/s13072-024-00525-x

 

  1. Feng Z, Liao M, Zhang L. Sex differences in disease: Sex chromosome and immunity. J Transl Med. 2024;22(1):1150. doi: 10.1186/s12967-024-05990-2

 

  1. Lee JT, Bartolomei MS. X-inactivation, imprinting, and long noncoding RNAs in health and disease. Cell. 2013;152(6):1308-1323. doi: 10.1016/j.cell.2013.02.016

 

  1. Lyon MF. Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature. 1961;190:372-373. doi: 10.1038/190372a0

 

  1. Lyon MF. Sex chromatin and gene action in the mammalian X-chromosome. Am J Hum Genet. 1962;14(2):135-148.

 

  1. Jegu T, Aeby E, Lee JT. The X chromosome in space. Nat Rev Genet. 2017;18(6):377-389. doi: 10.1038/nrg.2017.17

 

  1. Zito A, Davies MN, Tsai PC, et al. Heritability of skewed X-inactivation in female twins is tissue-specific and associated with age. Nat Commun. 2019;10(1):5339. doi: 10.1038/s41467-019-13340-w

 

  1. Shvetsova E, Sofronova A, Monajemi R, et al. Skewed X-inactivation is common in the general female population. Eur J Hum Genet. 2019;27(3):455-465. doi: 10.1038/s41431-018-0291-3

 

  1. Roberts AL, Morea A, Amar A, et al. Age acquired skewed X chromosome inactivation is associated with adverse health outcomes in humans. Elife. 2022;11:e78263. doi: 10.7554/eLife.78263

 

  1. Minks J, Robinson WP, Brown CJ. A skewed view of X chromosome inactivation. J Clin Invest. 2008;118(1):20-23. doi: 10.1172/JCI34470

 

  1. Fearon ER, Kohn DB, Winkelstein JA, Vogelstein B, Blaese RM. Carrier detection in the Wiskott Aldrich syndrome. Blood. 1988;72(5):1735-1739.

 

  1. Balaton BP, Brown CJ. Escape artists of the X chromosome. Trends Genet. 2016;32(6):348-359. doi: 10.1016/j.tig.2016.03.007

 

  1. Tukiainen T, Villani AC, Yen A, et al. Landscape of X chromosome inactivation across human tissues. Nature. 2017;550(7675):244-248. doi: 10.1038/nature24265

 

  1. Sauteraud R, Stahl JM, James J, et al. Inferring genes that escape X-Chromosome inactivation reveals important contribution of variable escape genes to sex-biased diseases. Genome Res. 2021;31(9):1629-1637. doi: 10.1101/gr.275677.121

 

  1. Zito A, Roberts AL, Visconti A, et al. Escape from X-inactivation in twins exhibits intra- and inter-individual variability across tissues and is heritable. PLoS Genet. 2023;19(2):e1010556. doi: 10.1371/journal.pgen.1010556

 

  1. Peeters SB, Posynick BJ, Brown CJ. Out of the silence: Insights into how genes escape X-chromosome inactivation. Epigenomes. 2023;7(4):29. doi: 10.3390/epigenomes7040029

 

  1. Youness A, Miquel CH, Guery JC. Escape from X chromosome inactivation and the female predominance in autoimmune diseases. Int J Mol Sci. 2021;22(3):1114. doi: 10.3390/ijms22031114

 

  1. Mousavi MJ, Mahmoudi M, Ghotloo S. Escape from X chromosome inactivation and female bias of autoimmune diseases. Mol Med. 2020;26(1):127. doi: 10.1186/s10020-020-00256-1

 

  1. Parodis I, Gatto M, Sjowall C. B cells in systemic lupus erythematosus: Targets of new therapies and surveillance tools. Front Med (Lausanne). 2022;9:952304. doi: 10.3389/fmed.2022.952304

 

  1. Moulton VR, Suarez-Fueyo A, Meidan E, Li H, Mizui M, Tsokos GC. Pathogenesis of human systemic lupus erythematosus: A cellular perspective. Trends Mol Med. 2017;23(7):615-635. doi: 10.1016/j.molmed.2017.05.006

 

  1. Chen PM, Tsokos GC. The role of CD8+ T-cell systemic lupus erythematosus pathogenesis: An update. Curr Opin Rheumatol. 2021;33(6):586-591. doi: 10.1097/BOR.0000000000000815

 

  1. Sharabi A, Tsokos GC. T cell metabolism: New insights in systemic lupus erythematosus pathogenesis and therapy. Nat Rev Rheumatol. 2020;16(2):100-112. doi: 10.1038/s41584-019-0356-x

 

  1. Syrett CM, Paneru B, Sandoval-Heglund D, et al. Altered X-chromosome inactivation in T cells may promote sex-biased autoimmune diseases. JCI Insight. 2019;4(7):e126751. doi: 10.1172/jci.insight.126751

 

  1. Hewagama A, Gorelik G, Patel D, et al. Overexpression of X-linked genes in T cells from women with lupus. J Autoimmun. 2013;41:60-71. doi: 10.1016/j.jaut.2012.12.006

 

  1. Negrini S, Emmi G, Greco M, et al. Sjogren’s syndrome: A systemic autoimmune disease. Clin Exp Med. 2022;22(1):9-25. doi: 10.1007/s10238-021-00728-6

 

  1. Barone F, Campos J, Bowman S, Fisher BA. The value of histopathological examination of salivary gland biopsies in diagnosis, prognosis and treatment of Sjogren’s syndrome. Swiss Med Wkly. 2015;145:w14168. doi: 10.4414/smw.2015.14168

 

  1. Reveille JD, Wilson RW, Provost TT, Bias WB, Arnett FC. Primary Sjogre’s syndrome and other autoimmune diseases in families. Prevalence and immunogenetic studies in six kindreds. Ann Intern Med. 1984;101(6):748-756. doi: 10.7326/0003-4819-101-6-748

 

  1. Lichtenfeld JL, Kirschner RH, Wiernik PH. Familial Sjogren’s syndrome with associated primary salivary gland lymphoma. Am J Med. 1976;60(2):286-292. doi: 10.1016/0002-9343(76)90439-3

 

  1. Doni A, Brancato R, Bartoletti L, Berni G. Familiarity characteristics of Sjogren’s disease. (Clinical contribution and considerations). La familiarita della malattia di Sjogren’s. (Contributo clinico e considerazioni). Riv Crit Clin Med. 1965;65(6):750-759.

 

  1. Koivukangas T, Simila S, Heikkinen E, Rasanen O, Wasz- Hockert O. Sjogren’s syndrome and achalasia of the cardia in two siblings. Pediatrics. 1973;51(5):943-945.

 

  1. Mason AM, Golding PL. Multiple immunological abnormalities in a family. J Clin Pathol. 1971;24(8):732-735. doi: 10.1136/jcp.24.8.732

 

  1. Boling EP, Wen J, Reveille JD, Bias WB, Chused TM, Arnett FC. Primary Sjogren’s syndrome and autoimmune hemolytic anemia in sisters. A family study. Am J Med. 1983;74(6):1066-1071. doi: 10.1016/0002-9343(83)90820-3

 

  1. Sabio JM, Milla E, Jimenez-Alonso J. A multicase family with primary Sjogren’s syndrome. J Rheumatol. 2001;28(8):1932-1934.

 

  1. Cobb BL, Lessard CJ, Harley JB, Moser KL. Genes and Sjogren’s syndrome. Rheum Dis Clin North Am. 2008;34(4):847-868, vii. doi: 10.1016/j.rdc.2008.08.003

 

  1. Harley JB, Reichlin M, Arnett FC, Alexander EL, Bias WB, Provost TT. Gene interaction at HLA-DQ enhances autoantibody production in primary Sjogren’s syndrome. Science. 1986;232(4754):1145-1147. doi: 10.1126/science.3458307

 

  1. Cruz-Tapias P, Rojas-Villarraga A, Maier-Moore S, Anaya JM. HLA and Sjogren’s syndrome susceptibility. A meta-analysis of worldwide studies. Autoimmun Rev. 2012;11(4):281-287. doi: 10.1016/j.autrev.2011.10.002

 

  1. Lessard CJ, Li H, Adrianto I, et al. Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjogren’s syndrome. Nat Genet. 2013;45(11):1284-1292. doi: 10.1038/ng.2792

 

  1. Taylor KE, Wong Q, Levine DM, et al. Genome-wide association analysis reveals genetic heterogeneity of Sjogren’s syndrome according to ancestry. Arthritis Rheumatol. 2017;69(6):1294-1305. doi: 10.1002/art.40040

 

  1. Imgenberg-Kreuz J, Rasmussen A, Sivils K, Nordmark G. Genetics and epigenetics in primary Sjogren’s syndrome. Rheumatology (Oxford). 2021;60(5):2085-2098. doi: 10.1093/rheumatology/key330

 

  1. Nordmark G, Kristjansdottir G, Theander E, et al. Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjogren’s syndrome. Genes Immun. 2009;10(1):68-76. doi: 10.1038/gene.2008.94

 

  1. Miceli-Richard C, Comets E, Loiseau P, Puechal X, Hachulla E, Mariette X. Association of an IRF5 gene functional polymorphism with Sjogren’s syndrome. Arthritis Rheum. 2007;56(12):3989-3994. doi: 10.1002/art.23142

 

  1. Fogel O, Riviere E, Seror R, et al. Role of the IL-12/IL-35 balance in patients with Sjogren syndrome. J Allergy Clin Immunol. 2018;142(1):258-268.e5. doi: 10.1016/j.jaci.2017.07.041

 

  1. Gestermann N, Mekinian A, Comets E, et al. STAT4 is a confirmed genetic risk factor for Sjogren’s syndrome and could be involved in type 1 interferon pathway signaling. Genes Immun. 2010;11(5):432-438. doi: 10.1038/gene.2010.29

 

  1. Li H, Reksten TR, Ice JA, et al. Identification of a Sjogren’s syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons. PLoS Genet. 2017;13(6):e1006820. doi: 10.1371/journal.pgen.1006820

 

  1. Chatzis L, Pezoulas VC, Ferro F, et al. Sjogren’s syndrome: The clinical spectrum of male patients. J Clin Med. 2020;9(8):2620. doi: 10.3390/jcm9082620

 

  1. Harris VM, Sharma R, Cavett J, et al. Klinefelter’s syndrome (47,XXY) is in excess among men with Sjogren’s syndrome. Clin Immunol. 2016;168:25-29. doi: 10.1016/j.clim.2016.04.002

 

  1. Sharma R, Harris VM, Cavett J, et al. Rare X chromosome abnormalities in systemic lupus erythematosus and Sjogren’s syndrome. Arthritis Rheumatol. 2017;69(11):2187-2192. doi: 10.1002/art.40207

 

  1. Kaur J, Jialal I. Hashimoto thyroiditis. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2025.

 

  1. Zaletel K, Gaberscek S. Hashimoto’s thyroiditis: From genes to the disease. Curr Genomics. 2011;12(8):576-588. doi: 10.2174/138920211798120763

 

  1. Hansen PS, Brix TH, Iachine I, Kyvik KO, Hegedus L. The relative importance of genetic and environmental effects for the early stages of thyroid autoimmunity: A study of healthy Danish twins. Eur J Endocrinol. 2006;154(1):29-38. doi: 10.1530/eje.1.02060

 

  1. Villanueva R, Greenberg DA, Davies TF, Tomer Y. Sibling recurrence risk in autoimmune thyroid disease. Thyroid. 2003;13(8):761-764. doi: 10.1089/105072503768499653

 

  1. Dittmar M, Libich C, Brenzel T, Kahaly GJ. Increased familial clustering of autoimmune thyroid diseases. Horm Metab Res. 2011;43(3):200-204. doi: 10.1055/s-0031-1271619

 

  1. Invernizzi P, Miozzo M, Selmi C, et al. X chromosome monosomy: A common mechanism for autoimmune diseases. J Immunol. 2005;175(1):575-578. doi: 10.4049/jimmunol.175.1.575

 

  1. Brix TH, Knudsen GP, Kristiansen M, Kyvik KO, Orstavik KH, Hegedus L. High frequency of skewed X-chromosome inactivation in females with autoimmune thyroid disease: A possible explanation for the female predisposition to thyroid autoimmunity. J Clin Endocrinol Metab. 2005;90(11):5949-5953. doi: 10.1210/jc.2005-1366

 

  1. Ozcelik T, Uz E, Akyerli CB, et al. Evidence from autoimmune thyroiditis of skewed X-chromosome inactivation in female predisposition to autoimmunity. Eur J Hum Genet. 2006;14(6):791-797. doi: 10.1038/sj.ejhg.5201614

 

  1. Massaad MJ, Ramesh N, Geha RS. Wiskott-Aldrich syndrome: A comprehensive review. Ann N Y Acad Sci. 2013;1285:26-43. doi: 10.1111/nyas.12049

 

  1. El-Sayed ZA, Abramova I, Aldave JC, et al. X-linked agammaglobulinemia (XLA):Phenotype, diagnosis, and therapeutic challenges around the world. World Allergy Organ J. 2019;12(3):100018. doi: 10.1016/j.waojou.2019.100018

 

  1. Conley ME, Buckley RH, Hong R, et al. X-linked severe combined immunodeficiency. Diagnosis in males with sporadic severe combined immunodeficiency and clarification of clinical findings. J Clin Invest. 1990; 85(5):1548-1554. doi: 10.1172/JCI114603

 

  1. Cooney CM, Bruner GR, Aberle T, et al. 46,X,del(X) (q13) Turner’s syndrome women with systemic lupus erythematosus in a pedigree multiplex for SLE. Genes Immun. 2009;10(5):478-481. doi: 10.1038/gene.2009.37

 

  1. Ranke MB, Saenger P. Turner’s syndrome. Lancet. 2001;358(9278):309-314. doi: 10.1016/S0140-6736(01)05487-3

 

  1. Elsheikh M, Wass JA, Conway GS. Autoimmune thyroid syndrome in women with Turner’s syndrome- -the association with karyotype. Clin Endocrinol (Oxf). 2001;55(2):223-226. doi: 10.1046/j.1365-2265.2001.01296.x

 

  1. Bondy CA, Cheng C. Monosomy for the X chromosome. Chromosome Res. 2009;17(5):649-658. doi: 10.1007/s10577-009-9052-z

 

  1. Chitnis S, Monteiro J, Glass D, et al. The role of X-chromosome inactivation in female predisposition to autoimmunity. Arthritis Res. 2000;2(5):399-406. doi: 10.1186/ar118

 

  1. Kast RE. Predominance of autoimmune and rheumatic diseases in females. J Rheumatol. 1977;4(3):288-292.

 

  1. Chabchoub G, Uz E, Maalej A, et al. Analysis of skewed X-chromosome inactivation in females with rheumatoid arthritis and autoimmune thyroid diseases. Arthritis Res Ther. 2009;11(4):R106. doi: 10.1186/ar2759

 

  1. Ozbalkan Z, Bagislar S, Kiraz S, et al. Skewed X chromosome inactivation in blood cells of women with scleroderma. Arthritis Rheum. 2005;52(5):1564-1570. doi: 10.1002/art.21026

 

  1. Brix TH, Hansen PS, Bennedbak FN, et al. X Chromosome inactivation pattern is not associated with interindividual variations in thyroid volume: A study of euthyroid Danish female twins. Twin Res Hum Genet. 2009;12(5):502-506. doi: 10.1375/twin.12.5.502

 

  1. Brix TH, Hansen PS, Kyvik KO, Hegedus L. The pituitary-thyroid axis set point in women is uninfluenced by X chromosome inactivation pattern? A twin study. Clin Endocrinol (Oxf). 2010;73(5):666-670. doi: 10.1111/j.1365-2265.2010.03848.x

 

  1. Roberts AL, Morea A, Amar A, et al. Haematopoietic stem cell-derived immune cells have reduced X chromosome inactivation skewing in systemic lupus erythematosus. Ann Rheum Dis. 2024;83(10):1315-1321. doi: 10.1136/ard-2024-225585

 

  1. Niu H, Fang G, Tang Y, et al. The function of hematopoietic stem cells is altered by both genetic and inflammatory factors in lupus mice. Blood. 2013;121(11):1986-1994. doi: 10.1182/blood-2012-05-433755

 

  1. Grigoriou M, Banos A, Filia A, et al. Transcriptome reprogramming and myeloid skewing in haematopoietic stem and progenitor cells in systemic lupus erythematosus. Ann Rheum Dis. 2020;79(2):242-253. doi: 10.1136/annrheumdis-2019-215782

 

  1. Price JD, Tarbell KV. The role of dendritic cell subsets and innate immunity in the pathogenesis of type 1 diabetes and other autoimmune diseases. Front Immunol. 2015;6:288. doi: 10.3389/fimmu.2015.00288

 

  1. Labelle A, Boulay LJ, Lapierre YD. Retention rates in placebo- and nonplacebo-controlled clinical trials of schizophrenia. Can J Psychiatry. 1999;44(9):887-892. doi: 10.1177/070674379904400904

 

  1. Huret C, Ferraye L, David A, et al. Altered X-chromosome inactivation predisposes to autoimmunity. Sci Adv. 2024;10(18):eadn6537. doi: 10.1126/sciadv.adn6537

 

  1. Lu Q, Wu A, Tesmer L, Ray D, Yousif N, Richardson B. Demethylation of CD40LG on the inactive X in T cells from women with lupus. J Immunol. 2007;179(9):6352-6358. doi: 10.4049/jimmunol.179.9.6352

 

  1. Lambert NC. Nonendocrine mechanisms of sex bias in rheumatic diseases. Nat Rev Rheumatol. 2019;15(11):673-686. doi: 10.1038/s41584-019-0307-6

 

  1. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C. Innate antiviral responses by means of TLR7- mediated recognition of single-stranded RNA. Science. 2004;303(5663):1529-1531. doi: 10.1126/science.1093616

 

  1. Pisitkun P, Deane JA, Difilippantonio MJ, Tarasenko T, Satterthwaite AB, Bolland S. Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science. 2006;312(5780):1669-1672. doi: 10.1126/science.1124978

 

  1. Deane JA, Pisitkun P, Barrett RS, et al. Control of toll-like receptor 7 expression is essential to restrict autoimmunity and dendritic cell proliferation. Immunity. 2007;27(5):801-810. doi: 10.1016/j.immuni.2007.09.009

 

  1. Brown GJ, Canete PF, Wang H, et al. TLR7 gain-of-function genetic variation causes human lupus. Nature. 2022;605(7909):349-356. doi: 10.1038/s41586-022-04642-z

 

  1. Mishra H, Schlack-Leigers C, Lim EL, et al. Disrupted degradative sorting of TLR7 is associated with human lupus. Sci Immunol. 2024;9(92):eadi9575. doi: 10.1126/sciimmunol.adi9575

 

  1. Souyris M, Cenac C, Azar P, et al. TLR7 escapes X chromosome inactivation in immune cells. Sci Immunol. 2018;3(19):eaap8855. doi: 10.1126/sciimmunol.aap8855

 

  1. Wang Y, Roussel-Queval A, Chasson L, et al. TLR7 signaling drives the development of Sjogren’s syndrome. Front Immunol. 2021;12:676010. doi: 10.3389/fimmu.2021.676010

 

  1. Karlsen M, Jakobsen K, Jonsson R, Hammenfors D, Hansen T, Appel S. Expression of toll-like receptors in peripheral blood mononuclear cells of patients with primary Sjogren’s syndrome. Scand J Immunol. 2017;85(3):220-226. doi: 10.1111/sji.12520

 

  1. Zheng L, Zhang Z, Yu C, Yang C. Expression of toll-like receptors 7, 8, and 9 in primary Sjogren’s syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010;109(6):844-850. doi: 10.1016/j.tripleo.2010.01.006

 

  1. Maria NI, Steenwijk EC, IJpma AS, et al. Contrasting expression pattern of RNA-sensing receptors TLR7, RIG-I and MDA5 in interferon-positive and interferon-negative patients with primary Sjogren’s syndrome. Ann Rheum Dis. 2017;76(4):721-730. doi: 10.1136/annrheumdis-2016-209589

 

  1. Cancro MP. Age-associated B cells. Annu Rev Immunol. 2020;38:315-340. doi: 10.1146/annurev-immunol-092419-031130

 

  1. Alexopoulou L. Nucleic acid-sensing toll-like receptors: Important players in Sjogren’s syndrome. Front Immunol. 2022;13:980400. doi: 10.3389/fimmu.2022.980400

 

  1. Odhams CA, Roberts AL, Vester SK, et al. Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in systemic lupus erythematosus. Nat Commun. 2019;10(1):2164. doi: 10.1038/s41467-019-10106-2

 

  1. Bentham J, Morris DL, Graham DSC, et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet. 2015;47(12):1457-1464. doi: 10.1038/ng.3434

 

  1. Mackay M, Oswald M, Sanchez-Guerrero J, et al. Molecular signatures in systemic lupus erythematosus: Distinction between disease flare and infection. Lupus Sci Med. 2016;3(1):e000159. doi: 10.1136/lupus-2016-000159

 

  1. Harris VM, Koelsch KA, Kurien BT, et al. Characterization of cxorf21 provides molecular insight into female-bias immune response in SLE pathogenesis. Front Immunol. 2019;10:2160. doi: 10.3389/fimmu.2019.02160

 

  1. Song Y, Zhou W. Role of TLR7 in the pathogenesis of primary Sjogren’s syndrome. Clin Exp Rheumatol. 2024; 42(12):2513-2519. doi: 10.55563/clinexprheumatol/cmmkod

 

  1. Harris VM, Scofield RH, Sivils KL. Genetics in Sjogren’s syndrome: Where we are and where we go. Clin Exp Rheumatol. 2019;118(3, 37 Suppl):234-239.

 

  1. Martin MU, Wesche H. Summary and comparison of the signaling mechanisms of the toll/interleukin-1 receptor family. Biochim Biophys Acta. 2002;1592(3):265-280. doi: 10.1016/s0167-4889(02)00320-8

 

  1. Gottipati S, Rao NL, Fung-Leung WP. IRAK1: A critical signaling mediator of innate immunity. Cell Signal. 2008;20(2):269-276. doi: 10.1016/j.cellsig.2007.08.009

 

  1. Jacob CO, Zhu J, Armstrong DL, et al. Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus. Proc Natl Acad Sci U S A. 2009;106(15):6256-6261. doi: 10.1073/pnas.0901181106

 

  1. Kaufman KM, Zhao J, Kelly JA, et al. Fine mapping of Xq28: Both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups. Ann Rheum Dis. 2013;72(3):437-444. doi: 10.1136/annrheumdis-2012-201851

 

  1. Zhai Y, Xu K, Leng RX, et al. Association of interleukin-1 receptor-associated kinase (IRAK1) gene polymorphisms (rs3027898, rs1059702) with systemic lupus erythematosus in a Chinese Han population. Inflamm Res. 2013;62(6):555-560. doi: 10.1007/s00011-013-0607-2

 

  1. Zilahi E, Tarr T, Papp G, Griger Z, Sipka S, Zeher M. Increased microRNA-146a/b, TRAF6 gene and decreased IRAK1 gene expressions in the peripheral mononuclear cells of patients with Sjogren’s syndrome. Immunol Lett. 2012;141(2):165-168. doi: 10.1016/j.imlet.2011.09.006

 

  1. Balaton BP, Cotton AM, Brown CJ. Derivation of consensus inactivation status for X-linked genes from genome-wide studies. Biol Sex Differ. 2015;6:35. doi: 10.1186/s13293-015-0053-7

 

  1. O’Driscoll DN, De Santi C, McKiernan PJ, McEneaney V, Molloy EJ, Greene CM. Expression of X-linked toll-like receptor 4 signaling genes in female vs. male neonates. Pediatr Res. 2017;81(5):831-837. doi: 10.1038/pr.2017.2

 

  1. Pyfrom S, Paneru B, Knox JJ, et al. The dynamic epigenetic regulation of the inactive X chromosome in healthy human B cells is dysregulated in lupus patients. Proc Natl Acad Sci U S A. 2021;118(24):e2024624118. doi: 10.1073/pnas.2024624118

 

  1. Groom JR, Luster AD. CXCR3 in T cell function. Exp Cell Res. 2011;317(5):620-631. doi: 10.1016/j.yexcr.2010.12.017

 

  1. Loetscher M, Loetscher P, Brass N, Meese E, Moser B. Lymphocyte-specific chemokine receptor CXCR3: Regulation, chemokine binding and gene localization. Eur J Immunol. 1998;28(11):3696-3705. doi: 10.1002/(SICI)1521-4141(199811)28:11<3696:AID-IMMU3696>3.0.CO;2-W

 

  1. Lacotte S, Brun S, Muller S, Dumortier H. CXCR3, inflammation, and autoimmune diseases. Ann N Y Acad Sci. 2009;1173:310-317. doi: 10.1111/j.1749-6632.2009.04813.x

 

  1. Yoon KC, Park CS, You IC, et al. Expression of CXCL9, -10, -11, and CXCR3 in the tear film and ocular surface of patients with dry eye syndrome. Invest Ophthalmol Vis Sci. 2010;51(2):643-650. doi: 10.1167/iovs.09-3425

 

  1. Ogawa N, Ping L, Zhenjun L, Takada Y, Sugai S. 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 Sjogren’s syndrome. Arthritis Rheum. 2002;46(10):2730-2741. doi: 10.1002/art.10577

 

  1. Kim JW, Ahn MH, Jung JY, Suh CH, Han JH, Kim HA. Role of chemokines CXCL9, CXCL10, CXCL11, and CXCR3 in the serum and minor salivary gland tissues of patients with Sjogren’s syndrome. Clin Exp Med. 2024;24(1):133. doi: 10.1007/s10238-024-01401-4

 

  1. Blokland SLM, Kislat A, Homey B, et al. Decreased circulating CXCR3+ CCR9+T helper cells are associated with elevated levels of their ligands CXCL10 and CCL25 in the salivary gland of patients with Sjogren’s syndrome to facilitate their concerted migration. Scand J Immunol. 2020;91(3):e12852. doi: 10.1111/sji.12852

 

  1. Liao X, Pirapakaran T, Luo XM. Chemokines and chemokine receptors in the development of lupus nephritis. Mediators Inflamm. 2016;2016:6012715. doi: 10.1155/2016/6012715

 

  1. Enghard P, Humrich JY, Rudolph B, et al. CXCR3+CD4+ T cells are enriched in inflamed kidneys and urine and provide a new biomarker for acute nephritis flares in systemic lupus erythematosus patients. Arthritis Rheum. 2009;60(1):199-206. doi: 10.1002/art.24136

 

  1. Ohlsson M, Szodoray P, Loro LL, Johannessen AC, Jonsson R. CD40, CD154, Bax and Bcl-2 expression in Sjogren’s syndrome salivary glands: A putative anti-apoptotic role during its effector phases. Scand J Immunol. 2002;56(6):561-571. doi: 10.1046/j.1365-3083.2002.01168.x

 

  1. Dimitriou ID, Kapsogeorgou EK, Moutsopoulos HM, Manoussakis MN. CD40 on salivary gland epithelial cells: High constitutive expression by cultured cells from Sjogren’s syndrome patients indicating their intrinsic activation. Clin Exp Immunol. 2002;127(2):386-392. doi: 10.1046/j.1365-2249.2002.01752.x

 

  1. Van Kooten C, Banchereau J. CD40-CD40 ligand. J Leukoc Biol. 2000;67(1):2-17. doi: 10.1002/jlb.67.1.2

 

  1. Kawabe T, Naka T, Yoshida K, et al. The immune responses in CD40-deficient mice: Impaired immunoglobulin class switching and germinal center formation. Immunity. 1994;1(3):167-178. doi: 10.1016/1074-7613(94)90095-7

 

  1. Armitage RJ, Fanslow WC, Strockbine L, et al. Molecular and biological characterization of a murine ligand for CD40. Nature. 1992;357(6373):80-82. doi: 10.1038/357080a0

 

  1. Goules A, Tzioufas AG, Manousakis MN, Kirou KA, Crow MK, Routsias JG. Elevated levels of soluble CD40 ligand (sCD40L) in serum of patients with systemic autoimmune diseases. J Autoimmun. 2006;26(3):165-171. doi: 10.1016/j.jaut.2006.02.002

 

  1. Stergiou IE, Poulaki A, Voulgarelis M. Pathogenetic mechanisms implicated in sjogren’s syndrome lymphomagenesis: A review of the literature. J Clin Med. 2020;9(12):3794. doi: 10.3390/jcm9123794

 

  1. Ramanujam M, Steffgen J, Visvanathan S, Mohan C, Fine JS, Putterman C. Phoenix from the flames: Rediscovering the role of the CD40-CD40L pathway in systemic lupus erythematosus and lupus nephritis. Autoimmun Rev. 2020;19(11):102668. doi: 10.1016/j.autrev.2020.102668

 

  1. Allard CC, Salti S, Mourad W, Hassan GS. Implications of CD154 and its receptors in the pathogenesis and treatment of systemic lupus erythematosus. Cells. 2024;13(19):1621. doi: 10.3390/cells13191621

 

  1. Desai-Mehta A, Lu L, Ramsey-Goldman R, Datta SK. Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. J Clin Invest. 1996;97(9):2063-2073. doi: 10.1172/JCI118643

 

  1. Koshy M, Berger D, Crow MK. Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes. J Clin Invest. 1996;98(3):826-837. doi: 10.1172/JCI118855

 

  1. Katsiari CG, Liossis SN, Souliotis VL, Dimopoulos AM, Manoussakis MN, Sfikakis PP. Aberrant expression of the costimulatory molecule CD40 ligand on monocytes from patients with systemic lupus erythematosus. Clin Immunol. 2002;103(1):54-62. doi: 10.1006/clim.2001.5172

 

  1. Higuchi T, Aiba Y, Nomura T, et al. Cutting edge: Ectopic expression of CD40 ligand on B cells induces lupus-like autoimmune disease. J Immunol. 2002;168(1):9-12. doi: 10.4049/jimmunol.168.1.9

 

  1. Watanabe R, Berry GJ, Liang DH, Goronzy JJ, Weyand CM. Pathogenesis of giant cell arteritis and takayasu arteritis-similarities and differences. Curr Rheumatol Rep. 2020;22(10):68. doi: 10.1007/s11926-020-00948-x

 

  1. Hughes M, Pauling JD, Armstrong-James L, Denton CP, Galdas P, Flurey C. Gender-related differences in systemic sclerosis. Autoimmun Rev. 2020;19(4):102494. doi: 10.1016/j.autrev.2020.102494

 

  1. Van Vollenhoven RF. Sex differences in rheumatoid arthritis: More than meets the eye. BMC Med. 2009;7:12. doi: 10.1186/1741-7015-7-12

 

  1. Linos A, Worthington JW, O’Fallon WM, Kurland LT. The epidemiology of rheumatoid arthritis in Rochester, Minnesota: A study of incidence, prevalence, and mortality. Am J Epidemiol. 1980;111(1):87-98. doi: 10.1093/oxfordjournals.aje.a112878

 

  1. Taylor PN, Albrecht D, Scholz A, et al. Global epidemiology of hyperthyroidism and hypothyroidism. Nat Rev Endocrinol. 2018;14(5):301-316. doi: 10.1038/nrendo.2018.18

 

  1. Ngo ST, Steyn FJ, McCombe PA. Gender differences in autoimmune disease. Front Neuroendocrinol. 2014;35(3):347-369. doi: 10.1016/j.yfrne.2014.04.004

 

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