Sexual dimorphism in autoimmunity

Journal of Clinical Investigation

Volumn 125, Issue 6, 2015, Pages 2187-2193

  Rubtsova, Kira ^a,b   Marrack, Philippa ^a,b,c,d   Rubtsov, Anatoly V ^a,b  

^a HOWARD HUGHES MEDICAL INSTITUTE   (United States)

^b DEPARTMENT OF MEDICINE   (United States)

^c UNIVERSITY OF COLORADO SCHOOL OF MEDICINE   (United States)

^d UNIVERSITY OF COLORADO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANDROGEN; ANDROGEN RECEPTOR; BRUTON TYROSINE KINASE; CD40 LIGAND; CHEMOKINE RECEPTOR CXCR3; ESTROGEN; ESTROGEN RECEPTOR; GAMMA INTERFERON; INTERFERON; INTERFERON REGULATORY FACTOR 5; INTERLEUKIN 2 RECEPTOR GAMMA; INTERLEUKIN 9 RECEPTOR; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 1; MEMBRANE PROTEIN; OGT PROTEIN; PATTERN RECOGNITION RECEPTOR; PROLACTIN; PROTEIN; SEX HORMONE; SPHINGOSINE 1 PHOSPHATE RECEPTOR; SPHINGOSINE 1 PHOSPHATE RECEPTOR 2; TESTOSTERONE; TOLL LIKE RECEPTOR 3; TOLL LIKE RECEPTOR 7; TOLL LIKE RECEPTOR 8; TOLL LIKE RECEPTOR 9; TRANSCRIPTION FACTOR FOXP3; TRANSCRIPTION FACTOR T BET; UNC 93 HOMOLOG B1; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ARTICLE; AUTOIMMUNE DISEASE; AUTOIMMUNITY; B LYMPHOCYTE; CASTRATION; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; DENDRITIC CELL; FEEDBACK SYSTEM; GENE EXPRESSION; HORMONE SUBSTITUTION; HUMAN; IMMUNOCOMPETENT CELL; INNATE IMMUNITY; INTESTINE FLORA; KARYOTYPE 47,XXY; KLINEFELTER SYNDROME; MACROPHAGE; MEMORY T LYMPHOCYTE; MONOCYTE; MULTIPLE SCLEROSIS; NATURAL KILLER CELL; NONHUMAN; PERIPHERAL BLOOD MONONUCLEAR CELL; POSITIVE FEEDBACK; PREGNANCY; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; RHEUMATOID ARTHRITIS; SCLERODERMA; SEX DIFFERENCE; SYSTEMIC LUPUS ERYTHEMATOSUS; TURNER SYNDROME; UPREGULATION; WILD TYPE; X CHROMOSOME; X CHROMOSOME INACTIVATION; Y CHROMOSOME; ANIMAL; AUTOIMMUNE DISEASES; FEMALE; GENE EXPRESSION REGULATION; IMMUNOLOGY; MALE; SEXUAL DEVELOPMENT; UNITED STATES;

ANIMALS; AUTOIMMUNE DISEASES; CHROMOSOMES, HUMAN, X; FEMALE; GENE EXPRESSION REGULATION; HUMANS; MALE; SEX CHARACTERISTICS; UNITED STATES;

EID: 84930411847     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI78082     Document Type: Article

References (124)

1. Oertelt-Prigione S. The influence of sex and gender on the immune response. Autoimmun Rev. 2012;11(6): A479-A485.
2. Fish EN. The X-files in immunity: Sex-based differences predispose immune responses. Nat Rev Immunol. 2008;8(9): 737-744.
3. Klein SL. The effects of hormones on sex differences in infection: From genes to behavior. Neurosci Biobehav Rev. 2000;24(6): 627-638.
4. Chong JW, et al. Marked increase in type 1 diabetes mellitus incidence in children aged 0-14 yr in Victoria, Australia, from 1999 to 2002. Pediatr Diabetes. 2007;8(2): 67-73.
5. Whitacre CC. Sex differences in autoimmune disease. Nat Immunol. 2001;2(9): 777-780.
6. Lockshin MD. Sex differences in autoimmune disease. Lupus. 2006;15(11): 753-756.
7. Wandell PE, Carlsson AC. Time trends and gender differences in incidence and prevalence of type 1 diabetes in Sweden. Curr Diabetes Rev. 2013;9(4): 342-349.
8. Ostman J, et al. Gender differences and temporal variation in the incidence of type 1 diabetes: Results of 8012 cases in the nationwide Diabetes Incidence Study in Sweden 1983-2002. J Intern Med. 2008;263(4): 386-394.
9. Rubtsov AV, Rubtsova K, Kappler JW, Marrack P. Genetic and hormonal factors in femalebiased autoimmunity. Autoimmun Rev. 2010;9(7): 494-498.
10. Hughes GC, Choubey D. Modulation of autoimmune rheumatic diseases by oestrogen and progesterone. Nat Rev Rheumatol. 2014;10(12): 740-751.
11. Hench PS. Effect of jaundice on rheumatoid arthritis. Br Med J. 1938;2(4050): 394-398.
12. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med. 1998;339(5): 285-291.
13. Jara LJ, Medina G, Cruz-Dominguez P, Navarro C, Vera-Lastra O, Saavedra MA. Risk factors of systemic lupus erythematosus flares during pregnancy. Immunol Res. 2014;60(2): 184-192.
14. Roubinian JR, Talal N, Greenspan JS, Goodman JR, Siiteri PK. Effect of castration and sex hormone treatment on survival, anti-nucleic acid antibodies, and glomerulonephritis in NZB/ NZW F1 mice. J Exp Med. 1978;147(6): 1568-1583.
15. Elbourne KB, Keisler D, McMurray RW. Differential effects of estrogen and prolactin on autoimmune disease in the NZB/NZW F1 mouse model of systemic lupus erythematosus. Lupus. 1998;7(6): 420-427.
16. Li J, McMurray RW. Effects of estrogen receptor subtype-selective agonists on autoimmune disease in lupus-prone NZB/NZW F1 mouse model. Clin Immunol. 2007;123(2): 219-226.
17. Verheul HA, Verveld M, Hoefakker S, Schuurs AH. Effects of ethinylestradiol on the course of spontaneous autoimmune disease in NZB/W and NOD mice. Immunopharmacol Immunotoxicol. 1995;17(1): 163-180.
18. Gordon C, et al. Testosterone patches in the management of patients with mild/moderate systemic lupus erythematosus. Rheumatology (Oxford). 2008;47(3): 334-338.
19. Sicotte NL, et al. Testosterone treatment in multiple sclerosis: A pilot study. Arch Neurol. 2007;64(5): 683-688.
20. Melez KA, Reeves JP, Steinberg AD. Regulation of the expression of autoimmunity in NZB x NZW F1 mice by sex hormones. J Immunopharmacol. 1978;1(1): 27-42.
21. Makino S, Kunimoto K, Muraoka Y, Katagiri K. Effect of castration on the appearance of diabetes in NOD mouse. Jikken Dobutsu. 1981;30(2): 137-140.
22. Keith RC, et al. Testosterone is protective in the sexually dimorphic development of arthritis and lung disease in SKG mice. Arthritis Rheum. 2013;65(6): 1487-1493.
23. Young NA, et al. Estrogen modulation of endosomeassociated toll-like receptor 8: An IFNa-independent mechanism of sex-bias in systemic lupus erythematosus. Clin Immunol. 2014;151(1): 66-77.
24. Sakiani S, Olsen NJ, Kovacs WJ. Gonadal steroids and humoral immunity. Nat Rev Endocrinol. 2013;9(1): 56-62.
25. Sthoeger ZM, Chiorazzi N, Lahita RG. Regulation of the immune response by sex hormones. I. In vitro effects of estradiol and testosterone on pokeweed mitogen-induced human B cell differentiation. J Immunol. 1988;141(1): 91-98.
26. Calabrese LH, et al. The effects of anabolic steroids and strength training on the human immune response. Med Sci Sports Exerc. 1989;21(4): 386-392.
27. Callewaert DM, Moudgil VK, Radcliff G, Waite R. Hormone specific regulation of natural killer cells by cortisol. Direct inactivation of the cytotoxic function of cloned human NK cells without an effect on cellular proliferation. FEBS Lett. 1991;285(1): 108-110.
28. Theofilopoulos AN, Baccala R, Beutler B, Kono DH. Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol. 2005;23: 307-336.
29. Banchereau J, Pascual V. Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity. 2006;25(3): 383-392.
30. Crow MK. Type I interferon in the pathogenesis of lupus. J Immunol. 2014;192(12): 5459-5468.
31. Hooks JJ, Moutsopoulos HM, Geis SA, Stahl NI, Decker JL, Notkins AL. Immune interferon in the circulation of patients with autoimmune disease. N Engl J Med. 1979;301(1): 5-8.
32. Bennett L, et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med. 2003;197(6): 711-723.
33. Braun D, Geraldes P, Demengeot J. Type I Interferon controls the onset and severity of autoimmune manifestations in lpr mice. J Autoimmun. 2003;20(1): 15-25.
34. Santiago-Raber ML, et al. Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice. J Exp Med. 2003;197(6): 777-788.
35. Trinchieri G. Type I interferon: Friend or foe? J Exp Med. 2010;207(10): 2053-2063.
36. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: Update on Toll-like receptors. Nat Immunol. 2010;11(5): 373-384.
37. Graham RR, et al. A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat Genet. 2006;38(5): 550-555.
38. Feng D, et al. Genetic variants and disease-Associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus. Arthritis Rheum. 2010;62(2): 562-573.
39. Shen H, Panchanathan R, Rajavelu P, Duan X, Gould KA, Choubey D. Gender-dependent expression of murine Irf5 gene: Implications for sex bias in autoimmunity. J Mol Cell Biol. 2010;2(5): 284-290.
40. Haas C, Ryffel B, Le Hir M. IFN-gamma receptor deletion prevents autoantibody production and glomerulonephritis in lupus-prone (NZB × NZW) F1 mice. J Immunol. 1998;160(8): 3713-3718.
41. Gourdy P, et al. Relevance of sexual dimorphism to regulatory T cells: Estradiol promotes IFN-γ production by invariant natural killer T cells. Blood. 2005;105(6): 2415-2420.
42. Siracusa MC, Overstreet MG, Housseau F, Scott AL, Klein SL. 17β-estradiol alters the activity of conventional and IFN-producing killer dendritic cells. J Immunol. 2008;180(3): 1423-1431.
43. Nakaya M, Tachibana H, Yamada K. Effect of estrogens on the interferon-gamma producing cell population of mouse splenocytes. Biosci Biotechnol Biochem. 2006;70(1): 47-53.
44. Fox HS, Bond BL, Parslow TG. Estrogen regulates the IFN-γ promoter. J Immunol. 1991;146(12): 4362-4367.
45. Bynote KK, Hackenberg JM, Korach KS, Lubahn DB, Lane PH, Gould KA. Estrogen receptor-A deficiency attenuates autoimmune disease in (NZB × NZW)F1 mice. Genes Immun. 2008;9(2): 137-152.
46. Panchanathan R, Shen H, Zhang X, Ho SM, Choubey D. Mutually positive regulatory feedback loop between interferons and estrogen receptor-Alpha in mice: Implications for sex bias in autoimmunity. PLoS One. 2010;5(5): E10868.
47. Christensen SR, Shupe J, Nickerson K, Kashgarian M, Flavell RA, Shlomchik MJ. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity. 2006;25(3): 417-428.
48. Christensen SR, Kashgarian M, Alexopoulou L, Flavell RA, Akira S, Shlomchik MJ. Tolllike receptor 9 controls anti-DNA autoantibody production in murine lupus. J Exp Med. 2005;202(2): 321-331.
49. Rubtsov AV, et al. Toll-like receptor 7 (TLR7)- driven accumulation of a novel CD11c(+) B-cell population is important for the development of autoimmunity. Blood. 2011;118(5): 1305-1315.
50. Rubtsov AV, Rubtsova K, Kappler JW, Marrack P. TLR7 drives accumulation of ABCs and autoantibody production in autoimmune-prone mice. Immunol Res. 2013;55(1-3): 210-216.
51. Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol. 2006;6(11): 823-835.
52. Tabeta K, et al. The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nat Immunol. 2006;7(2): 156-164.
53. Kim YM, Brinkmann MM, Paquet ME, Ploegh HL. UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes. Nature. 2008;452(7184): 234-238.
54. Lee BL, Barton GM. Trafficking of endosomal Toll-like receptors. Trends Cell Biol. 2014;24(6): 360-369.
55. Fukui R, et al. Unc93B1 restricts systemic lethal inflammation by orchestrating Toll-like receptor 7 and 9 trafficking. Immunity. 2011;35(1): 69-81.
56. Panchanathan R, Liu H, Choubey D. Expression of murine Unc93b1 is up-regulated by interferon and estrogen signaling: Implications for sex bias in the development of autoimmunity. Int Immunol. 2013;25(9): 521-529.
57. McMurray RW, Hoffman RW, Nelson W, Walker SE. Cytokine mRNA expression in the B/W mouse model of systemic lupus erythematosus - Analyses of strain, gender, and age effects. Clin Immunol Immunopathol. 1997;84(3): 260-268.
58. Karpuzoglu E, Phillips RA, Gogal RM Jr, Ansar Ahmed S. IFN-γ-inducing transcription factor, T-bet is upregulated by estrogen in murine splenocytes: Role of IL-27 but not IL-12. Mol Immunol. 2007;44(7): 1808-1814.
59. Nakano S, Morimoto S, Suzuki S, Watanabe T, Amano H, Takasaki Y. Up-regulation of the endoplasmic reticulum transmembrane protein UNC93B in the B cells of patients with active systemic lupus erythematosus. Rheumatology (Oxford). 2010;49(5): 876-881.
60. Cruz-Orengo L, et al. Enhanced sphingosine-1- phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility. J Clin Invest. 2014;124(6): 2571-2584.
61. Garcia JG, et al. Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement. J Clin Invest. 2001;108(5): 689-701.
62. Lee MJ, et al. Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate. Cell. 1999;99(3): 301-312.
63. Lee MJ, et al. Akt-mediated phosphorylation of the G protein-coupled receptor EDG-1 is required for endothelial cell chemotaxis. Mol Cell. 2001;8(3): 693-704.
64. Zhang G, et al. Critical role of sphingosine-1- phosphate receptor 2 (S1PR2) in acute vascular inflammation. Blood. 2013;122(3): 443-455.
65. Skoura A, et al. Sphingosine-1-phosphate receptor- 2 function in myeloid cells regulates vascular inflammation and atherosclerosis. Arterioscler Thromb Vasc Biol. 2011;31(1): 81-85.
66. Kageyama Y, et al. Antagonism of sphingosine 1-phosphate receptor 2 causes a selective reduction of portal vein pressure in bile duct-ligated rodents. Hepatology. 2012;56(4): 1427-1438.
67. Lyon MF. Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature. 1961;190: 372-373.
68. Carrel L, Willard HF. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature. 2005;434(7031): 400-404.
69. Stochholm K, Juul S, Juel K, Naeraa RW, Gravholt CH. Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab. 2006;91(10): 3897-3902.
70. Bondy CA, Cheng C. Monosomy for the X chromosome. Chromosome Res. 2009;17(5): 649-658.
71. Ranke MB, Saenger P. Turner's syndrome. Lancet. 2001;358(9278): 309-314.
72. Jorgensen KT, et al. Autoimmune diseases in women with Turner's syndrome. Arthritis Rheum. 2010;62(3): 658-666.
73. Rakfal SM, Deutsch M. Radiotherapy for malignancies associated with lupus: Case reports of acute and late reactions. Am J Clin Oncol. 1998;21(1): 54-57.
74. Takegami T, et al. [A case of SLE associated with Turner's syndrome of 45, XO/46, XXq+ mosaicism (author's transl)]. Nihon Naika Gakkai Zasshi. 1980;69(7): 861-866.
75. Cooney CM, 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.
76. Scofield RH, 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.
77. 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.
78. Hewagama A, et al. Overexpression of X-linked genes in T cells from women with lupus. J Autoimmun. 2013;41: 60-71.
79. 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.
80. Lartigue A, et al. Role of TLR9 in anti-nucleosome and anti-DNA antibody production in lpr mutation-induced murine lupus. J Immunol. 2006;177(2): 1349-1354.
81. Berland R, et al. Toll-like receptor 7-dependent loss of B cell tolerance in pathogenic autoantibody knockin mice. Immunity. 2006;25(3): 429-440.
82. Nickerson KM, et al. TLR9 regulates TLR7- And MyD88-dependent autoantibody production and disease in a murine model of lupus. J Immunol. 2010;184(4): 1840-1848.
83. Wu X, Peng SL. Toll-like receptor 9 signaling protects against murine lupus. Arthritis Rheum. 2006;54(1): 336-342.
84. Umiker BR, et al. Dosage of X-linked Toll-like receptor 8 determines gender differences in the development of systemic lupus erythematosus. Eur J Immunol. 2014;44(5): 1503-1516.
85. Garcia-Ortiz H, Velazquez-Cruz R, Espinosa- Rosales F, Jimenez-Morales S, Baca V, Orozco L. Association of TLR7 copy number variation with susceptibility to childhood-onset systemic lupus erythematosus in Mexican population. Ann Rheum Dis. 2010;69(10): 1861-1865.
86. Shen N, et al. Sex-specific association of X-linked Toll-like receptor 7 (TLR7) with male systemic lupus erythematosus. Proc Natl Acad Sci U S A. 2010;107(36): 15838-15843.
87. Subramanian S, et al. A Tlr7 translocation accelerates systemic autoimmunity in murine lupus. Proc Natl Acad Sci U S A. 2006;103(26): 9970-9975.
88. Prchal JT, et al. Clonal stability of blood cell lineages indicated by X-chromosomal transcriptional polymorphism. J Exp Med. 1996;183(2): 561-567.
89. Ozbalkan Z, et al. Skewed X chromosome inactivation in blood cells of women with scleroderma. Arthritis Rheum. 2005;52(5): 1564-1570.
90. Ozcelik T, 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.
91. 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.
92. Chagnon P, Provost S, Belisle C, Bolduc V, Gingras M, Busque L. Age-Associated skewing of X-inactivation ratios of blood cells in normal females: A candidate-gene analysis approach. Exp Hematol. 2005;33(10): 1209-1214.
93. Hatakeyama C, Anderson CL, Beever CL, Penaherrera MS, Brown CJ, Robinson WP. The dynamics of X-inactivation skewing as women age. Clin Genet. 2004;66(4): 327-332.
94. Sandovici I, Naumova AK, Leppert M, Linares Y, Sapienza C. A longitudinal study of X-inactivation ratio in human females. Hum Genet. 2004;115(5): 387-392.
95. Morgan CP, Bale TL. Sex differences in microRNA regulation of gene expression: No smoke, just miRs. Biol Sex Differ. 2012;3(1): 22.
96. Cheung L, Gustavsson C, Norstedt G, Tollet- Egnell P. Sex-different and growth hormoneregulated expression of microRNA in rat liver. BMC Mol Biol. 2009;10: 13.
97. Mishima T, et al. MicroRNA (miRNA) cloning analysis reveals sex differences in miRNA expression profiles between adult mouse testis and ovary. Reproduction. 2008;136(6): 811-822.
98. Shen N, Liang D, Tang Y, de Vries N, Tak PP. MicroRNAs-novel regulators of systemic lupus erythematosus pathogenesis. Nat Rev Rheumatol. 2012;8(12): 701-709.
99. Ceribelli A, Yao B, Dominguez-Gutierrez PR, Nahid MA, Satoh M, Chan EK. MicroRNAs in systemic rheumatic diseases. Arthritis Res Ther. 2011;13(4): 229.
100. Dai R, McReynolds S, Leroith T, Heid B, Liang Z, Ahmed SA. Sex differences in the expression of lupus-Associated miRNAs in splenocytes from lupus-prone NZB/WF1 mice. Biol Sex Differ. 2013;4(1): 19.
101. Xie T, et al. MicroRNA-127 inhibits lung inflammation by targeting IgG Fc? receptor I. J Immunol. 2012;188(5): 2437-2444.
102. Rouas R, et al. Human natural Treg microRNA signature: Role of microRNA-31 and microRNA-21 in FOXP3 expression. Eur J Immunol. 2009;39(6): 1608-1618.
103. Fan W, et al. Identification of microRNA-31 as a novel regulator contributing to impaired interleukin- 2 production in T cells from patients with systemic lupus erythematosus. Arthritis Rheum. 2012;64(11): 3715-3725.
104. Dai R, et al. Identification of a common lupus disease-Associated microRNA expression pattern in three different murine models of lupus. PLoS One. 2010;5(12): E14302.
105. Pinheiro I, Dejager L, Libert C. X-chromosomelocated microRNAs in immunity: Might they explain male/female differences? The X chromosome- genomic context may affect X-located miRNAs and downstream signaling, thereby contributing to the enhanced immune response of females. Bioessays. 2011;33(11): 791-802.
106. Fazi F, et al. A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPa regulates human granulopoiesis. Cell. 2005;123(5): 819-831.
107. Fulci V, et al. miR-223 is overexpressed in T-lymphocytes of patients affected by rheumatoid arthritis. Hum Immunol. 2010;71(2): 206-211.
108. Wang H, Peng W, Ouyang X, Li W, Dai Y. Circulating microRNAs as candidate biomarkers in patients with systemic lupus erythematosus. Transl Res. 2012;160(3): 198-206.
109. Pandis I, et al. Identification of microRNA-221/222 and microRNA-323-3p association with rheumatoid arthritis via predictions using the human tumour necrosis factor transgenic mouse model. Ann Rheum Dis. 2012;71(10): 1716-1723.
110. Lu C, et al. miR-221 and miR-155 regulate human dendritic cell development, apoptosis, and IL-12 production through targeting of p27kip1, KPC1, and SOCS-1. Blood. 2011;117(16): 4293-4303.
111. Grigoryev YA, et al. MicroRNA regulation of molecular networks mapped by global microRNA, mRNA, and protein expression in activated T lymphocytes. J Immunol. 2011;187(5): 2233-2243.
112. Pozzilli P, Signore A, Williams AJ, Beales PE. NOD mouse colonies around the world - recent facts and figures. Immunol Today. 1993;14(5): 193-196.
113. Wen L, et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature. 2008;455(7216): 1109-1113.
114. Markle JG, et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science. 2013;339(6123): 1084-1088.
115. Yurkovetskiy L, et al. Gender bias in autoimmunity is influenced by microbiota. Immunity. 2013;39(2): 400-412.
116. Rehakova Z, et al. Germ-free mice do not develop ankylosing enthesopathy, a spontaneous joint disease. Hum Immunol. 2000;61(6): 555-558.
117. Abdollahi-Roodsaz S, et al. Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis. J Clin Invest. 2008;118(1): 205-216.
118. Maldonado MA, et al. The role of environmental antigens in the spontaneous development of autoimmunity in MRL-lpr mice. J Immunol. 1999;162(11): 6322-6330.
119. Yan J, et al. The effect of ageing on human lymphocyte subsets: Comparison of males and females. Immun Ageing. 2010;7: 4.
120. Hirokawa K, Utsuyama M, Hayashi Y, Kitagawa M, Makinodan T, Fulop T. Slower immune system aging in women versus men in the Japanese population. Immun Ageing. 2013;10(1): 19.
121. Hao Y, O'Neill P, Naradikian MS, Scholz JL, Cancro MP. A B-cell subset uniquely responsive to innate stimuli accumulates in aged mice. Blood. 2011;118(5): 1294-1304.
122. Rubtsova K, Marrack P, Rubtsov AV. Age-Associated B cells: Are they the key to understanding why autoimmune diseases are more prevalent in women? Expert Rev Clin Immunol. 2012;8(1): 5-7.
123. Rubtsova K, Marrack P, Rubtsov AV. TLR7, IFNγ, and T-bet: Their roles in the development of ABCs in female-biased autoimmunity [published online ahead of print December 13, 2014]. Cell Immunol. doi: 10.1016/j.cellimm.2014.12.002.
124. Rubtsova K, Rubtsov AV, van Dyk LF, Kappler JW, Marrack P. T-box transcription factor T-bet, a key player in a unique type of B-cell activation essential for effective viral clearance. Proc Natl Acad Sci U S A. 2013;110(34): E3216-E3224.