The multiple pathways to autoimmunity

Nature Immunology

Volumn 18, Issue 7, 2017, Pages 716-724

  Theofilopoulos, Argyrios N ^a   Kono, Dwight H ^a   Baccala, Roberto ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AUTOANTIBODY; AUTOIMMUNE REGULATOR PROTEIN; FEZF2 PROTEIN; INTERFERON; INTERFERON INDUCED HELICASE C DOMAIN CONTAINING PROTEIN 1; INTERLEUKIN 10; INTERLEUKIN 2; NUCLEIC ACID; PROTEIN; RETINOIC ACID INDUCIBLE PROTEIN I; T LYMPHOCYTE RECEPTOR; TOLL LIKE RECEPTOR 3; TOLL LIKE RECEPTOR 7; TOLL LIKE RECEPTOR 8; TOLL LIKE RECEPTOR 9; TRANSCRIPTION FACTOR FOXP3; UNCLASSIFIED DRUG; UNTRANSLATED RNA; VIRUS ANTIGEN;

ADAPTIVE IMMUNITY; ALLELE; ANTIGEN PRESENTATION; AUTOIMMUNE DISEASE; AUTOIMMUNITY; CD4+ T LYMPHOCYTE; CELL ACTIVATION; CLONAL ANERGY; CROHN DISEASE; CYTOKINE PRODUCTION; DYSBIOSIS; GAIN OF FUNCTION MUTATION; GENE LINKAGE DISEQUILIBRIUM; GENETIC RISK; HUMAN; IMMUNOLOGICAL TOLERANCE; INNATE IMMUNITY; MICROFLORA; MOLECULAR MIMICRY; NONHUMAN; OXIDATIVE STRESS; PRE B LYMPHOCYTE; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REVIEW; SEX DIFFERENCE; ULCERATIVE COLITIS; X CHROMOSOME; Y CHROMOSOME; ANIMAL; B LYMPHOCYTE; IMMUNOLOGY; T LYMPHOCYTE;

ANIMALS; AUTOIMMUNE DISEASES; AUTOIMMUNITY; B-LYMPHOCYTES; CENTRAL TOLERANCE; HUMANS; PERIPHERAL TOLERANCE; SELF TOLERANCE; T-LYMPHOCYTES;

EID: 85020948093     PISSN: 15292908     EISSN: 15292916     Source Type: Journal    
DOI: 10.1038/ni.3731     Document Type: Review

References (144)

1. Kono, D.H. & Theofilopoulos, A.N. Autoimmunity. in Kelley and Firesteins Textbook of Rheumatology, 10th edn. (eds. Firestein, G.S., Budd, R.C., Gabriel, S.E., McInnes, I.B. & O'Dell, J.R.) 301-317 (Elsevier, Philadelphia, 2017).
2. Park, H., Bourla, A.B., Kastner, D.L., Colbert, R.A. & Siegel, R.M. Lighting the fires within: the cell biology of autoinflammatory diseases. Nat. Rev. Immunol. 12, 570-580 (2012).
3. Gutierrez-Arcelus, M., Rich, S.S. & Raychaudhuri, S. Autoimmune diseases-connecting risk alleles with molecular traits of the immune system. Nat. Rev. Genet. 17, 160-174 (2016).
4. Hunt, K.A. et al. Negligible impact of rare autoimmune-locus coding-region variants on missing heritability. Nature 498, 232-235 (2013).
5. Bouneaud, C., Kourilsky, P. & Bousso, P. Impact of negative selection on the T cell repertoire reactive to a self-peptide: a large fraction of T cell clones escapes clonal deletion. Immunity 13, 829-840 (2000).
6. Yu, W. et al. Clonal deletion prunes but does not eliminate self-specific CD8+ T lymphocytes. Immunity 42, 929-941 (2015).
7. Legoux, F.P. et al. CD4+ T cell tolerance to tissue-restricted self antigens is mediated by antigen-specific regulatory T cells rather than deletion. Immunity 43, 896-908 (2015).
8. Malhotra, D. et al. Tolerance is established in polyclonal CD4+ T cells by distinct mechanisms, according to self-peptide expression patterns. Nat. Immunol. 17, 187-195 (2016).
9. Mathis, D. & Benoist, C. Aire. Annu. Rev. Immunol. 27, 287-312 (2009).
10. Anderson, M.S. & Su, M.A. AIRE expands: new roles in immune tolerance and beyond. Nat. Rev. Immunol. 16, 247-258 (2016).
11. Bansal, K., Yoshida, H., Benoist, C. & Mathis, D. The transcriptional regulator Aire binds to and activates super-enhancers. Nat. Immunol. 18, 263-273 (2017).
12. Lei, Y. et al. Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development. J. Exp. Med. 208, 383-394 (2011).
13. Yamano, T. et al. Thymic B cells are licensed to present self antigens for central T cell tolerance induction. Immunity 42, 1048-1061 (2015).
14. Oftedal, B.E. et al. Dominant mutations in the autoimmune regulator AIRE are associated with common organ-specific autoimmune diseases. Immunity 42, 1185-1196 (2015).
15. Anderson, M.S. & Casanova, J.L. More than meets the eye: monogenic autoimmunity strikes again. Immunity 42, 986-988 (2015).
16. Takaba, H. et al. Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell 163, 975-987 (2015).
17. Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374-1377 (2003).
18. Meffre, E. The establishment of early B cell tolerance in humans: lessons from primary immunodeficiency diseases. Ann. NY Acad. Sci. 1246, 1-10 (2011).
19. Nemazee, D. Mechanisms of central tolerance for B cells. Nat. Rev. Immunol. 17, 281-294 (2017).
20. Avrameas, S. Natural autoantibodies: from 'horror autotoxicus' to 'gnothi seauton'. Immunol. Today 12, 154-159 (1991).
21. Paterson, A.M. & Sharpe, A.H. Taming tissue-specific T cells: CTLA-4 reins in self-reactive T cells. Nat. Immunol. 11, 109-111 (2010).
22. Okazaki, T., Chikuma, S., Iwai, Y., Fagarasan, S. & Honjo, T. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat. Immunol. 14, 1212-1218 (2013).
23. Pincetic, A. et al. Type I and type II Fc receptors regulate innate and adaptive immunity. Nat. Immunol. 15, 707-716 (2014).
24. Macauley, M.S., Crocker, P.R. & Paulson, J.C. Siglec-mediated regulation of immune cell function in disease. Nat. Rev. Immunol. 14, 653-666 (2014).
25. Ceeraz, S. et al. VISTA deficiency accelerates the development of fatal murine lupus nephritis. Arthritis Rheumatol. 69, 814-825 (2017).
26. Schmitt, H. et al. Siglec-H protects from virus-triggered severe systemic autoimmunity. J. Exp. Med. 213, 1627-1644 (2016).
27. Sharma, P. & Allison, J.P. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205-214 (2015).
28. Fathman, C.G. & Lineberry, N.B. Molecular mechanisms of CD4+ T-cell anergy. Nat. Rev. Immunol. 7, 599-609 (2007).
29. Friesen, T.J., Ji, Q. & Fink, P.J. Recent thymic emigrants are tolerized in the absence of inflammation. J. Exp. Med. 213, 913-920 (2016).
30. Kalekar, L.A. et al. CD4+ T cell anergy prevents autoimmunity and generates regulatory T cell precursors. Nat. Immunol. 17, 304-314 (2016).
31. Yarkoni, Y., Getahun, A. & Cambier, J.C. Molecular underpinning of B-cell anergy. Immunol. Rev. 237, 249-263 (2010).
32. Zikherman, J., Parameswaran, R. & Weiss, A. Endogenous antigen tunes the responsiveness of naive B cells but not T cells. Nature 489, 160-164 (2012).
33. Getahun, A., Beavers, N.A., Larson, S.R., Shlomchik, M.J. & Cambier, J.C. Continuous inhibitory signaling by both SHP-1 and SHIP-1 pathways is required to maintain unresponsiveness of anergic B cells. J. Exp. Med. 213, 751-769 (2016).
34. Lamagna, C., Hu, Y., DeFranco, A.L. & Lowell, C.A. B cell-specific loss of Lyn kinase leads to autoimmunity. J. Immunol. 192, 919-928 (2014).
35. Prasad, S., Starck, S.R. & Shastri, N. Presentation of cryptic peptides by MHC Class I is enhanced by inflammatory stimuli. J. Immunol. 197, 2981-2991 (2016).
36. Doyle, H.A. & Mamula, M.J. Autoantigenesis: the evolution of protein modifications in autoimmune disease. Curr. Opin. Immunol. 24, 112-118 (2012).
37. Delong, T. et al. Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science 351, 711-714 (2016).
38. Oldstone, M.B. Molecular mimicry and autoimmune disease. Cell 50, 819-820 (1987).
39. Wucherpfennig, K.W. & Strominger, J.L. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 80, 695-705 (1995).
40. Sanderson, N.S. et al. Cocapture of cognate and bystander antigens can activate autoreactive B cells. Proc. Natl. Acad. Sci. USA 114, 734-739 (2017).
41. Morikawa, H. & Sakaguchi, S. Genetic and epigenetic basis of Treg cell development and function: from a FoxP3-centered view to an epigenome-defined view of natural Treg cells. Immunol. Rev. 259, 192-205 (2014).
42. Li, M.O. & Rudensky, A.Y. T cell receptor signalling in the control of regulatory T cell differentiation and function. Nat. Rev. Immunol. 16, 220-233 (2016).
43. Thiault, N. et al. Peripheral regulatory T lymphocytes recirculating to the thymus suppress the development of their precursors. Nat. Immunol. 16, 628-634 (2015).
44. Weist, B.M., Kurd, N., Boussier, J., Chan, S.W. & Robey, E.A. Thymic regulatory T cell niche size is dictated by limiting IL-2 from antigen-bearing dendritic cells and feedback competition. Nat. Immunol. 16, 635-641 (2015).
45. Liu, Z. et al. Immune homeostasis enforced by co-localized effector and regulatory T cells. Nature 528, 225-230 (2015).
46. Procaccini, C. et al. The proteomic landscape of human ex vivo regulatory and conventional T cells reveals specific metabolic requirements. Immunity 44, 406-421 (2016).
47. Newton, R., Priyadharshini, B. & Turka, L.A. Immunometabolism of regulatory T cells. Nat. Immunol. 17, 618-625 (2016).
48. Yang, S., Fujikado, N., Kolodin, D., Benoist, C. & Mathis, D. Immune tolerance. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance. Science 348, 589-594 (2015).
49. Su, L.F., Del Alcazar, D., Stelekati, E., Wherry, E.J. & Davis, M.M. Antigen exposure shapes the ratio between antigen-specific Tregs and conventional T cells in human peripheral blood. Proc. Natl. Acad. Sci. USA 113, E6192-E6198 (2016).
50. Arpaia, N. et al. A distinct function of regulatory T cells in tissue protection. Cell 162, 1078-1089 (2015).
51. Dombrowski, Y. et al. Regulatory T cells promote myelin regeneration in the central nervous system. Nat. Neurosci. 20, 674-680 (2017).
52. Kitagawa, Y. et al. Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment. Nat. Immunol. 18, 173-183 (2017).
53. Apostolidis, S.A. et al. Phosphatase PP2A is requisite for the function of regulatory T cells. Nat. Immunol. 17, 556-564 (2016).
54. Kieback, E. et al. Thymus-derived regulatory T cells are positively selected on natural self-antigen through cognate interactions of high functional avidity. Immunity 44, 1114-1126 (2016).
55. Malchow, S. et al. Aire enforces immune tolerance by directing autoreactive T cells into the regulatory T cell lineage. Immunity 44, 1102-1113 (2016).
56. Miyara, M., Ito, Y. & Sakaguchi, S. TREG-cell therapies for autoimmune rheumatic diseases. Nat. Rev. Rheumatol. 10, 543-551 (2014).
57. Spence, A., Klementowicz, J.E., Bluestone, J.A. & Tang, Q. Targeting Treg signaling for the treatment of autoimmune diseases. Curr. Opin. Immunol. 37, 11-20 (2015).
58. Visperas, A. & Vignali, D.A. Are regulatory T cells defective in type 1 diabetes and can we fix them? J. Immunol. 197, 3762-3770 (2016).
59. Zhou, X. et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat. Immunol. 10, 1000-1007 (2009).
60. Guo, J. & Zhou, X. Regulatory T cells turn pathogenic. Cell. Mol. Immunol. 12, 525-532 (2015).
61. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805-820 (2010).
62. Blasius, A.L. & Beutler, B. Intracellular toll-like receptors. Immunity 32, 305-315 (2010).
63. Iwasaki, A. & Medzhitov, R. Control of adaptive immunity by the innate immune system. Nat. Immunol. 16, 343-353 (2015).
64. Theofilopoulos, A.N., Kono, D.H., Beutler, B. & Baccala, R. Intracellular nucleic acid sensors and autoimmunity. J. Interferon Cytokine Res. 31, 867-886 (2011).
65. Chen, Q., Sun, L. & Chen, Z.J. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat. Immunol. 17, 1142-1149 (2016).
66. Barber, G.N. STING-dependent cytosolic DNA sensing pathways. Trends Immunol. 35, 88-93 (2014).
67. Crow, M.K. Type I interferon in the pathogenesis of lupus. J. Immunol. 192, 5459-5468 (2014).
68. Rönnblom, L. The type I interferon system in the etiopathogenesis of autoimmune diseases. Ups. J. Med. Sci. 116, 227-237 (2011).
69. Marshak-Rothstein, A. Toll-like receptors in systemic autoimmune disease. Nat. Rev. Immunol. 6, 823-835 (2006).
70. Santiago-Raber, M.L. et al. Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice. J. Exp. Med. 197, 777-788 (2003).
71. Baccala, R. et al. Anti-IFN-/receptor antibody treatment ameliorates disease in lupus-predisposed mice. J. Immunol. 189, 5976-5984 (2012).
72. Christensen, S.R. et al. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 25, 417-428 (2006).
73. Pisitkun, P. et al. Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 312, 1669-1672 (2006).
74. Subramanian, S. et al. A Tlr7 translocation accelerates systemic autoimmunity in murine lupus. Proc. Natl. Acad. Sci. USA 103, 9970-9975 (2006).
75. Weindel, C.G. et al. B cell autophagy mediates TLR7-dependent autoimmunity and inflammation. Autophagy 11, 1010-1024 (2015).
76. Martinez, J. et al. Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells. Nature 533, 115-119 (2016).
77. Kono, D.H. et al. Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus. Proc. Natl. Acad. Sci. USA 106, 12061-12066 (2009).
78. Blasius, A.L. et al. Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling in plasmacytoid dendritic cells. Proc. Natl. Acad. Sci. USA 107, 19973-19978 (2010).
79. Koh, Y.T. et al. Role of nucleic acid-sensing TLRs in diverse autoantibody specificities and anti-nuclear antibody-producing B cells. J. Immunol. 190, 4982-4990 (2013).
80. Baccala, R. et al. Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus. Proc. Natl. Acad. Sci. USA 110, 2940-2945 (2013).
81. Rowland, S.L. et al. Early, transient depletion of plasmacytoid dendritic cells ameliorates autoimmunity in a lupus model. J. Exp. Med. 211, 1977-1991 (2014).
82. Sisirak, V. et al. Genetic evidence for the role of plasmacytoid dendritic cells in systemic lupus erythematosus. J. Exp. Med. 211, 1969-1976 (2014).
83. Kobayashi, T. et al. The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. Immunity 41, 375-388 (2014).
84. Teichmann, L.L. et al. Dendritic cells in lupus are not required for activation of T and B cells but promote their expansion, resulting in tissue damage. Immunity 33, 967-978 (2010).
85. Teichmann, L.L., Schenten, D., Medzhitov, R., Kashgarian, M. & Shlomchik, M.J. Signals via the adaptor MyD88 in B cells and DCs make distinct and synergistic contributions to immune activation and tissue damage in lupus. Immunity 38, 528-540 (2013).
86. Funabiki, M. et al. Autoimmune disorders associated with gain of function of the intracellular sensor MDA5. Immunity 40, 199-212 (2014).
87. Buskiewicz, I.A. et al. Reactive oxygen species induce virus-independent MAVS oligomerization in systemic lupus erythematosus. Sci. Signal. 9, ra115 (2016).
88. Sisirak, V. et al. Digestion of chromatin in apoptotic cell microparticles prevents autoimmunity. Cell 166, 88-101 (2016).
89. Stetson, D.B., Ko, J.S., Heidmann, T. & Medzhitov, R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134, 587-598 (2008).
90. Hung, T. et al. The Ro60 autoantigen binds endogenous retroelements and regulates inflammatory gene expression. Science 350, 455-459 (2015).
91. Garcia-Romo, G.S. et al. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci. Transl. Med. 3, 73ra20 (2011).
92. Lande, R. et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci. Transl. Med. 3, 73ra19 (2011).
93. Caielli, S. et al. Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. J. Exp. Med. 213, 697-713 (2016).
94. Lood, C. et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22, 146-153 (2016).
95. Henault, J. et al. Self-reactive IgE exacerbates interferon responses associated with autoimmunity. Nat. Immunol. 17, 196-203 (2016).
96. Honda, K. & Littman, D.R. The microbiota in adaptive immune homeostasis and disease. Nature 535, 75-84 (2016).
97. Ruff, W.E. & Kriegel, M.A. Autoimmune host-microbiota interactions at barrier sites and beyond. Trends Mol. Med. 21, 233-244 (2015).
98. Huttenhower, C., Kostic, A.D. & Xavier, R.J. Inflammatory bowel disease as a model for translating the microbiome. Immunity 40, 843-854 (2014).
99. Smith, P.M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569-573 (2013).
100. Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451-455 (2013).
101. Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446-450 (2013).
102. Koh, A., De Vadder, F., Kovatcheva-Datchary, P. & Bäckhed, F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 165, 1332-1345 (2016).
103. Mazmanian, S.K., Round, J.L. & Kasper, D.L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620-625 (2008).
104. Neff, C.P. et al. Diverse intestinal bacteria contain putative zwitterionic capsular polysaccharides with anti-inflammatory properties. Cell Host Microbe 20, 535-547 (2016).
105. Monteleone, I. et al. Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology 141, 237-248 (2011).
106. Zelante, T. et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39, 372-385 (2013).
107. Qiu, J. et al. Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora. Immunity 39, 386-399 (2013).
108. Knip, M. & Siljander, H. The role of the intestinal microbiota in type 1 diabetes mellitus. Nat. Rev. Endocrinol. 12, 154-167 (2016).
109. Vatanen, T. et al. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell 165, 1551 (2016).
110. Haghikia, A. et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity 43, 817-829 (2015).
111. Rothhammer, V. et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat. Med. 22, 586-597 (2016).
112. Glenn, J.D. & Mowry, E.M. Emerging concepts on the gut microbiome and multiple sclerosis. J. Interferon Cytokine Res. 36, 347-357 (2016).
113. Scher, J.U., Littman, D.R. & Abramson, S.B. Microbiome in inflammatory arthritis and human rheumatic diseases. Arthritis Rheumatol. 68, 35-45 (2016).
114. Wegner, N. et al. Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum. 62, 2662-2672 (2010).
115. Zhang, X. et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat. Med. 21, 895-905 (2015).
116. Konig, M.F. et al. Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. Sci. Transl. Med. 8, 369ra176 (2016).
117. Thaiss, C.A. et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell 159, 514-529 (2014).
118. Korem, T. et al. Growth dynamics of gut microbiota in health and disease inferred from single metagenomic samples. Science 349, 1101-1106 (2015).
119. Mehta, A. & Baltimore, D. MicroRNAs as regulatory elements in immune system logic. Nat. Rev. Immunol. 16, 279-294 (2016).
120. Atianand, M.K. & Fitzgerald, K.A. Long non-coding RNAs and control of gene expression in the immune system. Trends Mol. Med. 20, 623-631 (2014).
121. Satpathy, A.T. & Chang, H.Y. Long noncoding RNA in hematopoiesis and immunity. Immunity 42, 792-804 (2015).
122. Xiao, C. et al. Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nat. Immunol. 9, 405-414 (2008).
123. Lai, M. et al. Regulation of B-cell development and tolerance by different members of the miR-17~92 family microRNAs. Nat. Commun. 7, 12207 (2016).
124. Gonzalez-Martin, A. et al. The microRNA miR-148a functions as a critical regulator of B cell tolerance and autoimmunity. Nat. Immunol. 17, 433-440 (2016).
125. Garo, L.P. & Murugaiyan, G. Contribution of MicroRNAs to autoimmune diseases. Cell. Mol. Life Sci. 73, 2041-2051 (2016).
126. Wu, G.C. et al. Emerging role of long noncoding RNAs in autoimmune diseases. Autoimmun. Rev. 14, 798-805 (2015).
127. Castellanos-Rubio, A. et al. A long noncoding RNA associated with susceptibility to celiac disease. Science 352, 91-95 (2016).
128. Rubtsova, K., Marrack, P. & Rubtsov, A.V. Sexual dimorphism in autoimmunity. J. Clin. Invest. 125, 2187-2193 (2015).
129. Markle, J.G. & Fish, E.N. SeXX matters in immunity. Trends Immunol. 35, 97-104 (2014).
130. Ter Horst, R. et al. Host and environmental factors influencing individual human cytokine responses. Cell 167, 1111-1124 (2016).
131. Grimaldi, C.M., Jeganathan, V. & Diamond, B. Hormonal regulation of B cell development: 17 estradiol impairs negative selection of high-affinity DNA-reactive B cells at more than one developmental checkpoint. J. Immunol. 176, 2703-2710 (2006).
132. Dragin, N. et al. Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases. J. Clin. Invest. 126, 1525-1537 (2016).
133. Zhu, M.L. et al. Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator. Nat. Commun. 7, 11350 (2016).
134. Markle, J.G. et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339, 1084-1088 (2013).
135. Yurkovetskiy, L. et al. Gender bias in autoimmunity is influenced by microbiota. Immunity 39, 400-412 (2013).
136. Smith-Bouvier, D.L. et al. A role for sex chromosome complement in the female bias in autoimmune disease. J. Exp. Med. 205, 1099-1108 (2008).
137. Carrel, L. & Willard, H.F. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434, 400-404 (2005).
138. Brooks, W.H. X chromosome inactivation and autoimmunity. Clin. Rev. Allergy Immunol. 39, 20-29 (2010).
139. Berletch, J.B., Yang, F. & Disteche, C.M. Escape from X inactivation in mice and humans. Genome Biol. 11, 213 (2010).
140. Zhang, Y. et al. Genes that escape X-inactivation in humans have high intraspecific variability in expression, are associated with mental impairment but are not slow evolving. Mol. Biol. Evol. 30, 2588-2601 (2013).
141. Harris, V.M. et al. Klinefelter's syndrome (47,XXY) is in excess among men with Sjögren's syndrome. Clin. Immunol. 168, 25-29 (2016).
142. Hughes, T. et al. Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus. Ann. Rheum. Dis. 71, 694-699 (2012).
143. Ellebrecht, C.T. et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 353, 179-184 (2016).
144. Clemente-Casares, X. et al. Expanding antigen-specific regulatory networks to treat autoimmunity. Nature 530, 434-440 (2016).