Skip to main content
NCBI home page
Springer Nature - PMC COVID-19 Collection logoLink to Springer Nature - PMC COVID-19 Collection
. 2023 Feb 3:1–36. Online ahead of print. doi: 10.1007/s11427-021-2187-3

Innate and adaptive immune abnormalities underlying autoimmune diseases: the genetic connections

Xinxin Chi 1,#, Miaozhen Huang 1,#, Hailin Tu 1,#, Bin Zhang 1,#, Xin Lin 1,3,✉, Huji Xu 1,2,3,✉, Chen Dong 1,3,4,✉, Xiaoyu Hu 1,3,✉
PMCID: PMC9898710  PMID: 36738430

Abstract

With the exception of an extremely small number of cases caused by single gene mutations, most autoimmune diseases result from the complex interplay between environmental and genetic factors. In a nutshell, etiology of the common autoimmune disorders is unknown in spite of progress elucidating certain effector cells and molecules responsible for pathologies associated with inflammatory and tissue damage. In recent years, population genetics approaches have greatly enriched our knowledge regarding genetic susceptibility of autoimmunity, providing us with a window of opportunities to comprehensively re-examine autoimmunity-associated genes and possible pathways. In this review, we aim to discuss etiology and pathogenesis of common autoimmune disorders from the perspective of human genetics. An overview of the genetic basis of autoimmunity is followed by 3 chapters detailing susceptibility genes involved in innate immunity, adaptive immunity and inflammatory cell death processes respectively. With such attempts, we hope to expand the scope of thinking and bring attention to lesser appreciated molecules and pathways as important contributors of autoimmunity beyond the ‘usual suspects’ of a limited subset of validated therapeutic targets.

Keywords: autoimmune diseases, etiology, pathogenesis, innate immunity, adaptive immunity

Compliance and ethics

The author(s) declare that they have no conflict of interest.

Footnotes

Contributed equally to this work

Contributor Information

Xin Lin, Email: linxin307@tsinghua.edu.cn.

Huji Xu, Email: huji_xu@tsinghua.edu.cn.

Chen Dong, Email: chendong@tsinghua.edu.cn.

Xiaoyu Hu, Email: xiaoyuhu@tsinghua.edu.cn.

References

  1. Acosta-Herrera M, Kerick M, González-Serna D, Wijmenga C, Franke A, Gregersen PK, Padyukov L, Worthington J, Vyse T J, Alarcón-Riquelme ME, et al. Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases. Ann Rheum Dis. 2019;78:311–319. doi: 10.1136/annrheumdis-2018-214127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Adler SH, Chiffoleau E, Xu L, Dalton NM, Burg JM, Wells AD, Wolfe MS, Turka LA, Pear WS. Notch signaling augments T cell responsiveness by enhancing CD25 expression. J Immunol. 2003;171:2896–2903. doi: 10.4049/jimmunol.171.6.2896. [DOI] [PubMed] [Google Scholar]
  3. Almutairi KB, Nossent JC, Preen DB, Keen HI, Inderjeeth C A. The prevalence of rheumatoid arthritis: a systematic review of population-based studies. J Rheumatol. 2021;48:669–676. doi: 10.3899/jrheum.200367. [DOI] [PubMed] [Google Scholar]
  4. Amador-Patarroyo MJ, Rodriguez-Rodriguez A, Montoya-Ortiz G. How does age at onset influence the outcome of autoimmune diseases? Autoimmune Dis. 2012;2012:251730. doi: 10.1155/2012/251730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Amann J, Blasimme A, Vayena E, Frey D, Madai VI. Explainability for artificial intelligence in healthcare: a multidisciplinary perspective. BMC Med Inform Decis Mak. 2020;20:310. doi: 10.1186/s12911-020-01332-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ando DG, Clayton J, Kono D, Urban JL, Sercarz EE. Encephalitogenic T cells in the B10.PL model of experimental allergic encephalomyelitis (EAE) are of the Th-1 lymphokine subtype. Cell Immunol. 1989;124:132–143. doi: 10.1016/0008-8749(89)90117-2. [DOI] [PubMed] [Google Scholar]
  7. Ando K, Kanazawa S, Tetsuka T, Ohta S, Jiang X, Tada T, Kobayashi M, Matsui N, Okamoto T. Induction of Notch signaling by tumor necrosis factor in rheumatoid synovial fibroblasts. Oncogene. 2003;22:7796–7803. doi: 10.1038/sj.onc.1206965. [DOI] [PubMed] [Google Scholar]
  8. Ang QY, Alexander M, Newman JC, Tian Y, Cai J, Upadhyay V, Turnbaugh JA, Verdin E, Hall KD, Leibel RL, et al. Ketogenic diets alter the gut microbiome resulting in decreased intestinal Th17 cells. Cell. 2020;181:1263–1275.e16. doi: 10.1016/j.cell.2020.04.027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Angum F, Khan T, Kaler J, Siddiqui L, Hussain A. The prevalence of autoimmune disorders in women: a narrative review. Cureus. 2020;12:e8094. doi: 10.7759/cureus.8094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Apostolaki M, Armaka M, Victoratos P, Kollias G. Cellular mechanisms of TNF function in models of inflammation and autoimmunity. Curr Dir Autoimmun. 2010;11:1–26. doi: 10.1159/000289195. [DOI] [PubMed] [Google Scholar]
  11. Armingol E, Officer A, Harismendy O, Lewis NE. Deciphering cell-cell interactions and communication from gene expression. Nat Rev Genet. 2021;22:71–88. doi: 10.1038/s41576-020-00292-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Artyomov MN, Van den Bossche J. Immunometabolism in the Single-Cell Era. Cell Metab. 2020;32:710–725. doi: 10.1016/j.cmet.2020.09.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Asanuma K, Oliva Trejo JA, Tanaka E. The role of Notch signaling in kidney podocytes. Clin Exp Nephrol. 2017;21:1–6. doi: 10.1007/s10157-016-1247-y. [DOI] [PubMed] [Google Scholar]
  14. Baglaenko Y, Macfarlane D, Marson A, Nigrovic PA, Raychaudhuri S. Genome editing to define the function of risk loci and variants in rheumatic disease. Nat Rev Rheumatol. 2021;17:462–474. doi: 10.1038/s41584-021-00637-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Baranzini SE, Oksenberg JR. The genetics of multiple sclerosis: from 0 to 200 in 50 years. Trends Genet. 2017;33:960–970. doi: 10.1016/j.tig.2017.09.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Beavitt SJE, Harder KW, Kemp JM, Jones J, Quilici C, Casagranda F, Lam E, Turner D, Brennan S, Sly PD, et al. Lyn-deficient mice develop severe, persistent asthma: Lyn is a critical negative regulator of Th2 immunity. J Immunol. 2005;175:1867–1875. doi: 10.4049/jimmunol.175.3.1867. [DOI] [PubMed] [Google Scholar]
  17. Berger SB, Kasparcova V, Hoffman S, Swift B, Dare L, Schaeffer M, Capriotti C, Cook M, Finger J, Hughes-Earle A, et al. Cutting edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. J Immunol. 2014;192:5476–5480. doi: 10.4049/jimmunol.1400499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Billiard F, Lobry C, Darrasse-Jèze G, Waite J, Liu X, Mouquet H, DaNave A, Tait M, Idoyaga J, Leboeuf M, et al. Dll4-Notch signaling in Flt3-independent dendritic cell development and autoimmunity in mice. J Exp Med. 2012;209:1011–1028. doi: 10.1084/jem.20111615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Bing SJ, Silver PB, Jittayasothorn Y, Mattapallil MJ, Chan CC, Horai R, Caspi RR. Autoimmunity to neuroretina in the concurrent absence of IFN-γ and IL-17A is mediated by a GM-CSF-driven eosinophilic inflammation. J Autoimmun. 2020;114:102507. doi: 10.1016/j.jaut.2020.102507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Blanco P, Ueno H, Schmitt N. T follicular helper (Tfh) cells in lupus: activation and involvement in SLE pathogenesis. Eur J Immunol. 2016;46:281–290. doi: 10.1002/eji.201545760. [DOI] [PubMed] [Google Scholar]
  21. Blaser H, Dostert C, Mak TW, Brenner D. TNF and ROS crosstalk in inflammation. Trends Cell Biol. 2016;26:249–261. doi: 10.1016/j.tcb.2015.12.002. [DOI] [PubMed] [Google Scholar]
  22. Block KE, Zheng Z, Dent AL, Kee BL, Huang H. Gut microbiota regulates K/BxN autoimmune arthritis through follicular helper T but not Th17 cells. J Immunol. 2016;196:1550–1557. doi: 10.4049/jimmunol.1501904. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Bogdanos DP, Smyk DS, Rigopoulou EI, Mytilinaiou MG, Heneghan MA, Selmi C, Eric Gershwin M. Twin studies in autoimmune disease: genetics, gender and environment. J Autoimmun. 2012;38:J156–J169. doi: 10.1016/j.jaut.2011.11.003. [DOI] [PubMed] [Google Scholar]
  24. Boisson B, Laplantine E, Dobbs K, Cobat A, Tarantino N, Hazen M, Lidov HGW, Hopkins G, Du L, Belkadi A, et al. Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia. J Exp Med. 2015;212:939–951. doi: 10.1084/jem.20141130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Boisson B, Laplantine E, Prando C, Giliani S, Israelsson E, Xu Z, Abhyankar A, Israël L, Trevejo-Nunez G, Bogunovic D, et al. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat Immunol. 2012;13:1178–1186. doi: 10.1038/ni.2457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Bradfield JP, Qu HQ, Wang K, Zhang H, Sleiman PM, Kim CE, Mentch FD, Qiu H, Glessner JT, Thomas KA, et al. A genome-wide meta-analysis of six type 1 diabetes cohorts identifies multiple associated loci. PLoS Genet. 2011;7:e1002293. doi: 10.1371/journal.pgen.1002293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Bradley CP, Teng F, Felix KM, Sano T, Naskar D, Block KE, Huang H, Knox KS, Littman DR, Wu HJJ. Segmented filamentous bacteria provoke lung autoimmunity by inducing gut-lung axis Th17 cells expressing dual TCRs. Cell Host Microbe. 2017;22:697–704.e4. doi: 10.1016/j.chom.2017.10.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Brandt D, Hedrich CM. TCRαβ+CD3+CD4−CD8− (double negative) T cells in autoimmunity. Autoimmun Rev. 2018;17:422–430. doi: 10.1016/j.autrev.2018.02.001. [DOI] [PubMed] [Google Scholar]
  29. Breitkopf DM, Jankowski V, Ohl K, Hermann J, Hermert D, Tenbrock K, Liu X, Martin IV, Wang J, Groll F, et al. The YB-1:Notch-3 axis modulates immune cell responses and organ damage in systemic lupus erythematosus. Kidney Int. 2020;97:289–303. doi: 10.1016/j.kint.2019.09.031. [DOI] [PubMed] [Google Scholar]
  30. Brown MA, Kenna T, Wordsworth BP. Genetics of ankylosing spondylitis—insights into pathogenesis. Nat Rev Rheumatol. 2016;12:81–91. doi: 10.1038/nrrheum.2015.133. [DOI] [PubMed] [Google Scholar]
  31. Bungau SG, Behl T, Singh A, Sehgal A, Singh S, Chigurupati S, Vijayabalan S, Das S, Palanimuthu VR. Targeting probiotics in rheumatoid arthritis. Nutrients. 2021;13:3376. doi: 10.3390/nu13103376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Caielli S, Athale S, Domic B, Murat E, Chandra M, Banchereau R, Baisch J, Phelps K, Clayton S, Gong M, et al. Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. J Exp Med. 2016;213:697–713. doi: 10.1084/jem.20151876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Caliskan M, Brown CD, Maranville JC. A catalog of GWAS fine-mapping efforts in autoimmune disease. Am J Hum Genet. 2021;108:549–563. doi: 10.1016/j.ajhg.2021.03.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Cárdenas-Roldán J, Rojas-Villarraga A, Anaya JM. How do autoimmune diseases cluster in families? A systematic review and meta-analysis. BMC Med. 2013;11:73. doi: 10.1186/1741-7015-11-73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Charbonnier LM, Wang S, Georgiev P, Sefik E, Chatila TA. Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling. Nat Immunol. 2015;16:1162–1173. doi: 10.1038/ni.3288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Charles N, Hardwick D, Daugas E, Illei GG, Rivera J. Basophils and the T helper 2 environment can promote the development of lupus nephritis. Nat Med. 2010;16:701–707. doi: 10.1038/nm.2159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Chen J, He R, Sun W, Gao R, Peng Q, Zhu L, Du Y, Ma X, Guo X, Zhang H, et al. TAGAP instructs Th17 differentiation by bridging Dectin activation to EPHB2 signaling in innate antifungal response. Nat Commun. 2020;11:1913. doi: 10.1038/s41467-020-15564-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Chi X, Jin W, Zhao X, Xie T, Shao J, Bai X, Jiang Y, Wang X, Dong C. RORγt expression in mature TH17 cells safeguards their lineage specification by inhibiting conversion to TH2 cells. Sci Adv. 2022;8:eabn7774. doi: 10.1126/sciadv.abn7774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Chiou J, Geusz RJ, Okino ML, Han JY, Miller M, Melton R, Beebe E, Benaglio P, Huang S, Korgaonkar K, et al. Interpreting type 1 diabetes risk with genetics and single-cell epigenomics. Nature. 2021;594:398–402. doi: 10.1038/s41586-021-03552-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Cho JH, Feldman M. Heterogeneity of autoimmune diseases: pathophysiologic insights from genetics and implications for new therapies. Nat Med. 2015;21:730–738. doi: 10.1038/nm.3897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Choi BY, Choi Y, Park JS, Kang LJ, Baek SH, Park JS, Bahn G, Cho Y, Kim HK, Han J, et al. Inhibition of Notch1 induces population and suppressive activity of regulatory T cell in inflammatory arthritis. Theranostics. 2018;8:4795–4804. doi: 10.7150/thno.26093. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Choi SW, Mak TSH, O’Reilly PF. Tutorial: a guide to performing polygenic risk score analyses. Nat Protoc. 2020;15:2759–2772. doi: 10.1038/s41596-020-0353-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Chong WP, Mattapallil MJ, Raychaudhuri K, Bing SJ, Wu S, Zhong Y, Wang WW, Chen Z, Silver PB, Jittayasothorn Y, et al. The cytokine IL-17A limits Th17 pathogenicity via a negative feedback loop driven by autocrine induction of IL-24. Immunity. 2020;53:384–397.e5. doi: 10.1016/j.immuni.2020.06.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Chun HJ, Zheng L, Ahmad M, Wang J, Speirs CK, Siegel RM, Dale JK, Puck J, Davis J, Hall CG, et al. Pleiotropic defects in lymphocyte activation caused by Caspase-8 mutations lead to human immunodeficiency. Nature. 2002;419:395–399. doi: 10.1038/nature01063. [DOI] [PubMed] [Google Scholar]
  45. Chung SA, Brown EE, Williams AH, Ramos PS, Berthier CC, Bhangale T, Alarcon-Riquelme ME, Behrens TW, Criswell LA, Graham DC, et al. Lupus nephritis susceptibility loci in women with systemic lupus erythematosus. J Am Soc Nephrol. 2014;25:2859–2870. doi: 10.1681/ASN.2013050446. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Chung SA, Taylor KE, Graham RR, Nititham J, Lee AT, Ortmann WA, Jacob CO, Alarcón-Riquelme ME, Tsao BP, Harley JB, et al. Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production. PLoS Genet. 2011;7:e1001323. doi: 10.1371/journal.pgen.1001323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, Rawal S, Wang YH, Lim H, Reynolds JM, Zhou X, et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med. 2011;17:983–988. doi: 10.1038/nm.2426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Clough JN, Omer OS, Tasker S, Lord GM, Irving PM. Regulatory T-cell therapy in Crohn’s disease: challenges and advances. Gut. 2020;69:942–952. doi: 10.1136/gutjnl-2019-319850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Codarri L, Gyülvészi G, Tosevski V, Hesske L, Fontana A, Magnenat L, Suter T, Becher B. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol. 2011;12:560–567. doi: 10.1038/ni.2027. [DOI] [PubMed] [Google Scholar]
  50. Conigliaro P, Triggianese P, De Martino E, Fonti GL, Chimenti MS, Sunzini F, Viola A, Canofari C, Perricone R. Challenges in the treatment of Rheumatoid Arthritis. Autoimmun Rev. 2019;18:706–713. doi: 10.1016/j.autrev.2019.05.007. [DOI] [PubMed] [Google Scholar]
  51. Conway JR, Lex A, Gehlenborg N. UpSetR: an R package for the visualization of intersecting sets and their properties. Bioinformatics. 2017;33:2938–2940. doi: 10.1093/bioinformatics/btx364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Cook AD, Braine EL, Campbell IK, Rich MJ, Hamilton JA. Blockade of collagen-induced arthritis post-onset by antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF): requirement for GM-CSF in the effector phase of disease. Arthritis Res. 2001;3:293–298. doi: 10.1186/ar318. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Cooles FAH, Anderson AE, Skelton A, Pratt AG, Kurowska-Stolarska MS, McInnes I, Hilkens CMU, Isaacs JD. Phenotypic and transcriptomic analysis of peripheral blood plasmacytoid and conventional dendritic cells in early drug naïve rheumatoid arthritis. Front Immunol. 2018;9:755. doi: 10.3389/fimmu.2018.00755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Cooper GS, Bynum MLK, Somers EC. Recent insights in the epidemiology of autoimmune diseases: improved prevalence estimates and understanding of clustering of diseases. J Autoimmun. 2009;33:197–207. doi: 10.1016/j.jaut.2009.09.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Cooper GS, Stroehla BC. The epidemiology of autoimmune diseases. Autoimmun Rev. 2003;2:119–125. doi: 10.1016/S1568-9972(03)00006-5. [DOI] [PubMed] [Google Scholar]
  56. Costa N, Marques O, Godinho SI, Carvalho C, Leal B, Figueiredo AM, Vasconcelos C, Marinho A, Moraes-Fontes MF, Gomes da Costa A, et al. Two separate effects contribute to regulatory T cell defect in systemic lupus erythematosus patients and their unaffected relatives. Clin Exp Immunol. 2017;189:318–330. doi: 10.1111/cei.12991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Cotch MF, Hoffman GS, Yerg DE, Kaufman GI, Targonski P, Kaslow RA. The epidemiology of Wegener’s granulomatosis. Estimates of the five-year period prevalence, annual mortality, and geographic disease distribution from population-based data sources. Arthritis Rheumatism. 1996;39:87–92. doi: 10.1002/art.1780390112. [DOI] [PubMed] [Google Scholar]
  58. Cotsapas C, Voight BF, Rossin E, Lage K, Neale BM, Wallace C, Abecasis GR, Barrett JC, Behrens T, Cho J, et al. Pervasive sharing of genetic effects in autoimmune disease. PLoS Genet. 2011;7:e1002254. doi: 10.1371/journal.pgen.1002254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Coutant F, Miossec P. Altered dendritic cell functions in autoimmune diseases: distinct and overlapping profiles. Nat Rev Rheumatol. 2016;12:703–715. doi: 10.1038/nrrheum.2016.147. [DOI] [PubMed] [Google Scholar]
  60. Crayne CB, Albeituni S, Nichols KE, Cron RQ. The immunology of macrophage activation syndrome. Front Immunol. 2019;10:119. doi: 10.3389/fimmu.2019.00119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Crotty S. Follicular helper CD4 T cells (TFH) Annu Rev Immunol. 2011;29:621–663. doi: 10.1146/annurev-immunol-031210-101400. [DOI] [PubMed] [Google Scholar]
  62. Crotty S. T follicular helper cell differentiation, function, and roles in disease. Immunity. 2014;41:529–542. doi: 10.1016/j.immuni.2014.10.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421:744–748. doi: 10.1038/nature01355. [DOI] [PubMed] [Google Scholar]
  64. Cuchet-Lourenço D, Eletto D, Wu C, Plagnol V, Papapietro O, Curtis J, Ceron-Gutierrez L, Bacon CM, Hackett S, Alsaleem B, et al. Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation. Science. 2018;361:810–813. doi: 10.1126/science.aar2641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Damgaard RB, Walker JA, Marco-Casanova P, Morgan NV, Titheradge HL, Elliott PR, McHale D, Maher ER, McKenzie ANJ, Komander D. The deubiquitinase OTULIN is an essential negative regulator of inflammation and autoimmunity. Cell. 2016;166:1215–1230.e20. doi: 10.1016/j.cell.2016.07.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. de Lange KM, Moutsianas L, Lee JC, Lamb CA, Luo Y, Kennedy NA, Jostins L, Rice DL, Gutierrez-Achury J, Ji SG, et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat Genet. 2017;49:256–261. doi: 10.1038/ng.3760. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Dean LE, Jones GT, MacDonald AG, Downham C, Sturrock RD, Macfarlane GJ. Global prevalence of ankylosing spondylitis. Rheumatology. 2014;53:650–657. doi: 10.1093/rheumatology/ket387. [DOI] [PubMed] [Google Scholar]
  68. Delanghe T, Dondelinger Y, Bertrand MJM. RIPK1 kinase-dependent death: a symphony of phosphorylation events. Trends Cell Biol. 2020;30:189–200. doi: 10.1016/j.tcb.2019.12.009. [DOI] [PubMed] [Google Scholar]
  69. Dillon CP, Weinlich R, Rodriguez DA, Cripps JG, Quarato G, Gurung P, Verbist KC, Brewer TL, Llambi F, Gong YN, et al. RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell. 2014;157:1189–1202. doi: 10.1016/j.cell.2014.04.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Doherty E, Oaks Z, Perl A. Increased mitochondrial electron transport chain activity at complex I is regulated by N-acetylcysteine in lymphocytes of patients with systemic lupus erythematosus. Antioxid Redox Signal. 2014;21:56–65. doi: 10.1089/ars.2013.5702. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Dondelinger Y, Delanghe T, Priem D, Wynosky-Dolfi MA, Sorobetea D, Rojas-Rivera D, Giansanti P, Roelandt R, Gropengiesser J, Ruckdeschel K, et al. Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation. Nat Commun. 2019;10:1729. doi: 10.1038/s41467-019-09690-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Dong C. Cytokine regulation and function in T cells. Annu Rev Immunol. 2021;39:51–76. doi: 10.1146/annurev-immunol-061020-053702. [DOI] [PubMed] [Google Scholar]
  73. Draber P, Kupka S, Reichert M, Draberova H, Lafont E, de Miguel D, Spilgies L, Surinova S, Taraborrelli L, Hartwig T, et al. LUBAC-recruited CYLD and A20 regulate gene activation and cell death by exerting opposing effects on linear ubiquitin in signaling complexes. Cell Rep. 2015;13:2258–2272. doi: 10.1016/j.celrep.2015.11.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Dziedzic SA, Su Z, Jean Barrett V, Najafov A, Mookhtiar AK, Amin P, Pan H, Sun L, Zhu H, Ma A, et al. ABIN-1 regulates RIPK1 activation by linking Met1 ubiquitylation with Lys63 deubiquitylation in TNF-RSC. Nat Cell Biol. 2018;20:58–68. doi: 10.1038/s41556-017-0003-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Edner NM, Carlesso G, Rush JS, Walker LSK. Targeting co-stimulatory molecules in autoimmune disease. Nat Rev Drug Discov. 2020;19:860–883. doi: 10.1038/s41573-020-0081-9. [DOI] [PubMed] [Google Scholar]
  76. Ellebrecht CT, Bhoj VG, Nace A, Choi EJ, Mao X, Cho MJ, Di Zenzo G, Lanzavecchia A, Seykora JT, Cotsarelis G, et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science. 2016;353:179–184. doi: 10.1126/science.aaf6756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Ellinghaus D, Ellinghaus E, Nair RP, Stuart PE, Esko T, Metspalu A, Debrus S, Raelson JV, Tejasvi T, Belouchi M, et al. Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci. Am J Hum Genet. 2012;90:636–647. doi: 10.1016/j.ajhg.2012.02.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Ellinghaus D, Jostins L, Spain SL, Cortes A, Bethune J, Han B, Park YR, Raychaudhuri S, Pouget JG, Hübenthal M, et al. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat Genet. 2016;48:510–518. doi: 10.1038/ng.3528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Ellinghaus U, Cortini A, Pinder CL, Le Friec G, Kemper C, Vyse TJ. Dysregulated CD46 shedding interferes with Th1-contraction in systemic lupus erythematosus. Eur J Immunol. 2017;47:1200–1210. doi: 10.1002/eji.201646822. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Emilsson L, Wijmenga C, Murray JA, Ludvigsson JF. Autoimmune disease in first-degree relatives and spouses of individuals with celiac disease. Clin Gastroenterol Hepatol. 2015;13:1271–1277.e2. doi: 10.1016/j.cgh.2015.01.026. [DOI] [PubMed] [Google Scholar]
  81. Evans PC, Ovaa H, Hamon M, Kilshaw PJ, Hamm S, Bauer S, Ploegh HL, Smith TS. Zinc-finger protein A20, a regulator of inflammation and cell survival, has de-ubiquitinating activity. Biochem J. 2004;378:727–734. doi: 10.1042/bj20031377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Eyre S, Bowes J, Diogo D, Lee A, Barton A, Martin P, Zhernakova A, Stahl E, Viatte S, McAllister K, et al. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat Genet. 2012;44:1336–1340. doi: 10.1038/ng.2462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Feng H, Zhao X, Xie J, Bai X, Fu W, Chen H, Tang H, Wang X, Dong C. Pathogen-associated T follicular helper cell plasticity is critical in anti-viral immunity. Sci China Life Sci. 2022;65:1075–1090. doi: 10.1007/s11427-021-2055-x. [DOI] [PubMed] [Google Scholar]
  84. Feng S, Yang Y, Mei Y, Ma L, Zhu D, Hoti N, Castanares M, Wu M. Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain. Cell Signal. 2007;19:2056–2067. doi: 10.1016/j.cellsig.2007.05.016. [DOI] [PubMed] [Google Scholar]
  85. Fernando MMA, Stevens CR, Walsh EC, De Jager PL, Goyette P, Plenge RM, Vyse TJ, Rioux JD. Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet. 2008;4:e1000024. doi: 10.1371/journal.pgen.1000024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Ferreira LMR, Muller YD, Bluestone JA, Tang Q. Next-generation regulatory T cell therapy. Nat Rev Drug Discov. 2019;18:749–769. doi: 10.1038/s41573-019-0041-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Fetterman JW, Jr., Zdanowicz MM. Therapeutic potential of n-3 polyunsaturated fatty acids in disease. Am J Health-Syst Pharmacy. 2009;66:1169–1179. doi: 10.2146/ajhp080411. [DOI] [PubMed] [Google Scholar]
  88. Fiil BK, Damgaard RB, Wagner SA, Keusekotten K, Fritsch M, Bekker-Jensen S, Mailand N, Choudhary C, Komander D, Gyrd-Hansen M. OTULIN restricts Met1-linked ubiquitination to control innate immune signaling. Mol Cell. 2013;50:818–830. doi: 10.1016/j.molcel.2013.06.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4 CD25 regulatory T cells. Nat Immunol. 2003;4:330–336. doi: 10.1038/ni904. [DOI] [PubMed] [Google Scholar]
  90. Fresneda Alarcon M, McLaren Z, Wright HL. Neutrophils in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus: same foe different M.O. Front Immunol. 2021;12:649693. doi: 10.3389/fimmu.2021.649693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Fritsch M, Günther SD, Schwarzer R, Albert MC, Schorn F, Werthenbach JP, Schiffmann LM, Stair N, Stocks H, Seeger JM, et al. Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature. 2019;575:683–687. doi: 10.1038/s41586-019-1770-6. [DOI] [PubMed] [Google Scholar]
  92. Fu W, Liu X, Lin X, Feng H, Sun L, Li S, Chen H, Tang H, Lu L, Jin W, et al. Deficiency in T follicular regulatory cells promotes autoimmunity. J Exp Med. 2018;215:815–825. doi: 10.1084/jem.20170901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Fujii W, Kawahito Y, Nagahara H, Kukida Y, Seno T, Yamamoto A, Kohno M, Oda R, Taniguchi D, Fujiwara H, et al. Monocarboxylate transporter 4, associated with the acidification of synovial fluid, is a novel therapeutic target for inflammatory arthritis. Arthritis Rheumatol. 2015;67:2888–2896. doi: 10.1002/art.39270. [DOI] [PubMed] [Google Scholar]
  94. Gagliani N, Amezcua Vesely MC, Iseppon A, Brockmann L, Xu H, Palm NW, de Zoete MR, Licona-Limón P, Paiva RS, Ching T, et al. TH17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature. 2015;523:221–225. doi: 10.1038/nature14452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Galindo-Izquierdo M, Pablos Alvarez JL. Complement as a therapeutic target in systemic autoimmune diseases. Cells. 2021;10:148. doi: 10.3390/cells10010148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Gallagher MD, Chen-Plotkin AS. The Post-GWAS Era: from association to function. Am J Hum Genet. 2018;102:717–730. doi: 10.1016/j.ajhg.2018.04.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  97. Gao W, McCormick J, Connolly M, Balogh E, Veale DJ, Fearon U. Hypoxia and STAT3 signalling interactions regulate pro-inflammatory pathways in rheumatoid arthritis. Ann Rheum Dis. 2015;74:1275–1283. doi: 10.1136/annrheumdis-2013-204105. [DOI] [PubMed] [Google Scholar]
  98. Gao W, Sweeney C, Connolly M, Kennedy A, Ng CT, McCormick J, Veale DJ, Fearon U. Notch-1 mediates hypoxia-induced angiogenesis in rheumatoid arthritis. Arthritis Rheumatism. 2012;64:2104–2113. doi: 10.1002/art.34397. [DOI] [PubMed] [Google Scholar]
  99. Gensous N, Charrier M, Duluc D, Contin-Bordes C, Truchetet ME, Lazaro E, Duffau P, Blanco P, Richez C. T follicular helper cells in autoimmune disorders. Front Immunol. 2018;9:1637. doi: 10.3389/fimmu.2018.01637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Gergely P, Grossman C, Niland B, Puskas F, Neupane H, Allam F, Banki K, Phillips PE, Perl A. Mitochondrial hyperpolarization and ATP depletion in patients with systemic lupus erythematosus. Arthritis Rheumatism. 2002;46:175–190. doi: 10.1002/1529-0131(200201)46:1<175::AID-ART10015>3.0.CO;2-H. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Gioia C, Lucchino B, Tarsitano MG, Iannuccelli C, Di Franco M. Dietary habits and nutrition in rheumatoid arthritis: can diet influence disease development and clinical manifestations? Nutrients. 2020;12:1456. doi: 10.3390/nu12051456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  102. Gorlova O, Martin JE, Rueda B, Koeleman BPC, Ying J, Teruel M, Diaz-Gallo LM, Broen JC, Vonk MC, Simeon CP, et al. Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy. PLoS Genet. 2011;7:e1002178. doi: 10.1371/journal.pgen.1002178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Gowthaman U, Chen JS, Zhang B, Flynn WF, Lu Y, Song W, Joseph J, Gertie JA, Xu L, Collet MA, et al. Identification of a T follicular helper cell subset that drives anaphylactic IgE. Science. 2019;365:eaaw6433. doi: 10.1126/science.aaw6433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  104. Grazioli P, Felli MP, Screpanti I, Campese AF. The mazy case of Notch and immunoregulatory cells. J Leukoc Biol. 2017;102:361–368. doi: 10.1189/jlb.1VMR1216-505R. [DOI] [PubMed] [Google Scholar]
  105. Greig SL. Brodalumab: first global approval. Drugs. 2016;76:1403–1412. doi: 10.1007/s40265-016-0634-8. [DOI] [PubMed] [Google Scholar]
  106. Grosveld GC. γ-secretase inhibitors: Notch so bad. Nat Med. 2009;15:20–21. doi: 10.1038/nm0109-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  107. Gu Z, Gu L, Eils R, Schlesner M, Brors B. circlize Implements and enhances circular visualization in R. Bioinformatics. 2014;30:2811–2812. doi: 10.1093/bioinformatics/btu393. [DOI] [PubMed] [Google Scholar]
  108. Guerra SG, Vyse TJ, Cunninghame Graham DS. The genetics of lupus: a functional perspective. Arthritis Res Ther. 2012;14:211. doi: 10.1186/ar3844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  109. Guo X, Dong C. Zooming on T cells in cancer. Sci China Life Sci. 2022;65:1466–1468. doi: 10.1007/s11427-022-2100-2. [DOI] [PubMed] [Google Scholar]
  110. Ha E, Bae SC, Kim K. Large-scale meta-analysis across East Asian and European populations updated genetic architecture and variant-driven biology of rheumatoid arthritis, identifying 11 novel susceptibility loci. Ann Rheum Dis. 2021;80:558–565. doi: 10.1136/annrheumdis-2020-219065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  111. Haas R, Smith J, Rocher-Ros V, Nadkarni S, Montero-Melendez T, D’Acquisto F, Bland EJ, Bombardieri M, Pitzalis C, Perretti M, et al. Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions. PLoS Biol. 2015;13:e1002202. doi: 10.1371/journal.pbio.1002202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  112. Han H, Yi B, Zhong R, Wang M, Zhang S, Ma J, Yin Y, Yin J, Chen L, Zhang H. From gut microbiota to host appetite: gut microbiota-derived metabolites as key regulators. Microbiome. 2021;9:162. doi: 10.1186/s40168-021-01093-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. Hanson EP, Monaco-Shawver L, Solt LA, Madge LA, Banerjee PP, May MJ, Orange JS. Hypomorphic nuclear factor-κB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity. J Allergy Clin Immunol. 2008;122:1169–1177.e16. doi: 10.1016/j.jaci.2008.08.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  114. He S, Wang L, Miao L, Wang T, Du F, Zhao L, Wang X. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-α. Cell. 2009;137:1100–1111. doi: 10.1016/j.cell.2009.05.021. [DOI] [PubMed] [Google Scholar]
  115. Heger K, Wickliffe KE, Ndoja A, Zhang J, Murthy A, Dugger DL, Maltzman A, de Sousa E Melo F, Hung J, Zeng Y, et al. OTULIN limits cell death and inflammation by deubiquitinating LUBAC. Nature. 2018;559:120–124. doi: 10.1038/s41586-018-0256-2. [DOI] [PubMed] [Google Scholar]
  116. Hildebrand JM, Kauppi M, Majewski IJ, Liu Z, Cox AJ, Miyake S, Petrie EJ, Silk MA, Li Z, Tanzer MC, et al. A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction. Nat Commun. 2020;11:3150. doi: 10.1038/s41467-020-16819-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  117. Hirota K, Turner JE, Villa M, Duarte JH, Demengeot J, Steinmetz OM, Stockinger B. Plasticity of TH17 cells in Peyer’s patches is responsible for the induction of T cell-dependent IgA responses. Nat Immunol. 2013;14:372–379. doi: 10.1038/ni.2552. [DOI] [PMC free article] [PubMed] [Google Scholar]
  118. Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K. A comprehensive review of genetic association studies. Genet Med. 2002;4:45–61. doi: 10.1097/00125817-200203000-00002. [DOI] [PubMed] [Google Scholar]
  119. Horwitz DA. Identity of mysterious CD4+CD25-Foxp3+ cells in SLE. Arthritis Res Ther. 2010;12:101. doi: 10.1186/ar2894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  120. Huang N, Perl A. Metabolism as a target for modulation in autoimmune diseases. Trends Immunol. 2018;39:562–576. doi: 10.1016/j.it.2018.04.006. [DOI] [PubMed] [Google Scholar]
  121. Huber S, Gagliani N, Esplugues E, O’Connor W, Jr., Huber FJ, Chaudhry A, Kamanaka M, Kobayashi Y, Booth CJ, Rudensky A Y, et al. Th17 cells express interleukin-10 receptor and are controlled by Foxp3 and Foxp3+ regulatory CD4+ T cells in an interleukin 10 dependent manner. Immunity. 2011;34:554–565. doi: 10.1016/j.immuni.2011.01.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  122. Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PDR, Wehkamp J, Feagan BG, Yao MD, Karczewski M, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut. 2012;61:1693–1700. doi: 10.1136/gutjnl-2011-301668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  123. Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16:448–457. doi: 10.1038/ni.3153. [DOI] [PubMed] [Google Scholar]
  124. Huseby ES, Liggitt D, Brabb T, Schnabel B, Ohlén C, Goverman J. A pathogenic role for myelin-specific CD8+ T cells in a model for multiple sclerosis. J Exp Med. 2001;194:669–676. doi: 10.1084/jem.194.5.669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  125. Iberg CA, Jones A, Hawiger D. Dendritic cells as inducers of peripheral tolerance. Trends Immunol. 2017;38:793–804. doi: 10.1016/j.it.2017.07.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  126. Inshaw JRJ, Cutler AJ, Burren OS, Stefana MI, Todd JA. Approaches and advances in the genetic causes of autoimmune disease and their implications. Nat Immunol. 2018;19:674–684. doi: 10.1038/s41590-018-0129-8. [DOI] [PubMed] [Google Scholar]
  127. International Genetics of Ankylosing Spondylitis Consortium IGAS Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet. 2013;45:730–738. doi: 10.1038/ng.2667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  128. International Multiple Sclerosis Genetics Consortium Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science. 2019;365:eaav7188. doi: 10.1126/science.aav7188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  129. Ishii H, Nakazawa M, Yoshino SI, Nakamura H, Nishioka K, Nakajima T. Expression of notch homologues in the synovium of rheumatoid arthritis and osteoarthritis patients. Rheumatol Int. 2001;21:10–14. doi: 10.1007/s002960100119. [DOI] [PubMed] [Google Scholar]
  130. Ishikawa Y, Terao C. The impact of cigarette smoking on risk of rheumatoid arthritis: a narrative review. Cells. 2020;9:475. doi: 10.3390/cells9020475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  131. Jacobs SR, Herman CE, Maciver NJ, Wofford JA, Wieman HL, Hammen JJ, Rathmell JC. Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. J Immunol. 2008;180:4476–4486. doi: 10.4049/jimmunol.180.7.4476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  132. Jameson JL, Longo DL. Precision medicine—personalized, problematic, and promising. N Engl J Med. 2015;372:2229–2234. doi: 10.1056/NEJMsb1503104. [DOI] [PubMed] [Google Scholar]
  133. Jeffery LE, Raza K, Hewison M. Vitamin D in rheumatoid arthritis—towards clinical application. Nat Rev Rheumatol. 2016;12:201–210. doi: 10.1038/nrrheum.2015.140. [DOI] [PubMed] [Google Scholar]
  134. Jiao Z, Wang W, Guo M, Zhang T, Chen L, Wang Y, You H, Li J. Expression analysis of Notch-related molecules in peripheral blood T helper cells of patients with rheumatoid arthritis. Scand J Rheumatol. 2010;39:26–32. doi: 10.3109/03009740903124424. [DOI] [PubMed] [Google Scholar]
  135. Jiao Z, Wang W, Hua S, Liu M, Wang H, Wang X, Chen Y, Xu H, Lu L. Blockade of Notch signaling ameliorates murine collagen-induced arthritis via suppressing Th1 and Th17 cell responses. Am J Pathol. 2014;184:1085–1093. doi: 10.1016/j.ajpath.2013.12.010. [DOI] [PubMed] [Google Scholar]
  136. Jiao Z, Wang W, Ma J, Wang S, Su Z, Xu H. Notch signaling mediates TNF-α-induced IL-6 production in cultured fibroblast-like synoviocytes from rheumatoid arthritis. Clin Dev Immunol. 2012;2012:350209. doi: 10.1155/2012/350209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  137. Jiao Z, Wang W, Xu H, Wang S, Guo M, Chen Y, Gao J. Engagement of activated Notch signalling in collagen II-specific T helper type 1 (Th1)- and Th17-type expansion involving Notch3 and Delta-like1. Clin Exp Immunol. 2011;164:66–71. doi: 10.1111/j.1365-2249.2010.04310.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  138. Jongbloed SL, Benson RA, Nickdel MB, Garside P, McInnes IB, Brewer JM. Plasmacytoid dendritic cells regulate breach of self-tolerance in autoimmune arthritis. J Immunol. 2009;182:963–968. doi: 10.4049/jimmunol.182.2.963. [DOI] [PubMed] [Google Scholar]
  139. Juyal G, Negi S, Sood A, Gupta A, Prasad P, Senapati S, Zaneveld J, Singh S, Midha V, van Sommeren S, et al. Genome-wide association scan in north Indians reveals three novel HLA-independent risk loci for ulcerative colitis. Gut. 2015;64:571–579. doi: 10.1136/gutjnl-2013-306625. [DOI] [PubMed] [Google Scholar]
  140. Kaiser WJ, Upton JW, Long AB, Livingston-Rosanoff D, Daley-Bauer LP, Hakem R, Caspary T, Mocarski ES. RIP3 mediates the embryonic lethality of Caspase-8-deficient mice. Nature. 2011;471:368–372. doi: 10.1038/nature09857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  141. Kamali AN, Noorbakhsh SM, Hamedifar H, Jadidi-Niaragh F, Yazdani R, Bautista JM, Azizi G. A role for Th1-like Th17 cells in the pathogenesis of inflammatory and autoimmune disorders. Mol Immunol. 2019;105:107–115. doi: 10.1016/j.molimm.2018.11.015. [DOI] [PubMed] [Google Scholar]
  142. Kanamori M, Nakatsukasa H, Okada M, Lu Q, Yoshimura A. Induced regulatory T cells: their development, stability, and applications. Trends Immunol. 2016;37:803–811. doi: 10.1016/j.it.2016.08.012. [DOI] [PubMed] [Google Scholar]
  143. Kang JY, Kang AHY, Green A, Gwee KA, Ho KY. Systematic review: worldwide variation in the frequency of coeliac disease and changes over time. Aliment Pharmacol Ther. 2013;38:226–245. doi: 10.1111/apt.12373. [DOI] [PubMed] [Google Scholar]
  144. Kariuki SN, Ghodke-Puranik Y, Dorschner JM, Chrabot BS, Kelly JA, Tsao BP, Kimberly RP, Alarcón-Riquelme ME, Jacob CO, Criswell LA, et al. Genetic analysis of the pathogenic molecular sub-phenotype interferon-alpha identifies multiple novel loci involved in systemic lupus erythematosus. Genes Immun. 2015;16:15–23. doi: 10.1038/gene.2014.57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  145. Kavousanaki M, Makrigiannakis A, Boumpas D, Verginis P. Novel role of plasmacytoid dendritic cells in humans: induction of interleukin-10—producing treg cells by plasmacytoid dendritic cells in patients with rheumatoid arthritis responding to therapy. Arthritis Rheum. 2010;62:53–63. doi: 10.1002/art.25037. [DOI] [PubMed] [Google Scholar]
  146. Kelly B, O’Neill LAJ. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 2015;25:771–784. doi: 10.1038/cr.2015.68. [DOI] [PMC free article] [PubMed] [Google Scholar]
  147. Khan MF, Wang H. Environmental exposures and autoimmune diseases: contribution of gut microbiome. Front Immunol. 2019;10:3094. doi: 10.3389/fimmu.2019.03094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  148. Kim K, Bang SY, Lee HS, Cho SK, Choi CB, Sung YK, Kim T H, Jun JB, Yoo DH, Kang YM, et al. High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci. Ann Rheum Dis. 2015;74:e13. doi: 10.1136/annrheumdis-2013-204749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  149. Kim S, Hwang J, Xuan J, Jung YH, Cha HS, Kim KH. Global metabolite profiling of synovial fluid for the specific diagnosis of rheumatoid arthritis from other inflammatory arthritis. PLoS ONE. 2014;9:e97501. doi: 10.1371/journal.pone.0097501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  150. Kitamoto S, Nagao-Kitamoto H, Jiao Y, Gillilland Iii MG, Hayashi A, Imai J, Sugihara K, Miyoshi M, Brazil JC, Kuffa P, et al. The intermucosal connection between the mouth and gut in commensal pathobiont-driven colitis. Cell. 2020;182:447–462.e14. doi: 10.1016/j.cell.2020.05.048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  151. Kjeldsen-Kragh J, Borchgrevink CF, Laerum E, Haugen M, Eek M, Førre O, Mowinkel P, Hovi K. Controlled trial of fasting and one-year vegetarian diet in rheumatoid arthritis. Lancet. 1991;338:899–902. doi: 10.1016/0140-6736(91)91770-U. [DOI] [PubMed] [Google Scholar]
  152. Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker R A, Muller DN, Hafler DA. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature. 2013;496:518–522. doi: 10.1038/nature11868. [DOI] [PMC free article] [PubMed] [Google Scholar]
  153. Kochi Y. Genetics of autoimmune diseases: perspectives from genome-wide association studies. Int Immunol. 2016;28:155–161. doi: 10.1093/intimm/dxw002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  154. Koga T, Sato T, Furukawa K, Morimoto S, Endo Y, Umeda M, Sumiyoshi R, Fukui S, Kawashiri SY, Iwamoto N, et al. Promotion of calcium/calmodulin-dependent protein kinase 4 by GLUT1-dependent glycolysis in systemic lupus erythematosus. Arthritis Rheumatol. 2019;71:766–772. doi: 10.1002/art.40785. [DOI] [PubMed] [Google Scholar]
  155. Komuczki J, Tuzlak S, Friebel E, Hartwig T, Spath S, Rosenstiel P, Waisman A, Opitz L, Oukka M, Schreiner B, et al. Fatemapping of GM-CSF expression identifies a discrete subset of inflammation-driving T helper cells regulated by cytokines IL-23 and IL-1β. Immunity. 2019;50:1289–1304.e6. doi: 10.1016/j.immuni.2019.04.006. [DOI] [PubMed] [Google Scholar]
  156. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annu Rev Immunol. 2009;27:485–517. doi: 10.1146/annurev.immunol.021908.132710. [DOI] [PubMed] [Google Scholar]
  157. Kroenke MA, Carlson TJ, Andjelkovic AV, Segal BM. IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. J Exp Med. 2008;205:1535–1541. doi: 10.1084/jem.20080159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  158. Kuo D, Ding J, Cohn IS, Zhang F, Wei K, Rao DA, Rozo C, Sokhi UK, Shanaj S, Oliver DJ, et al. HBEGF+ macrophages in rheumatoid arthritis induce fibroblast invasiveness. Sci Transl Med. 2019;11:eaau8587. doi: 10.1126/scitranslmed.aau8587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  159. Kuusisto H, Kaprio J, Kinnunen E, Luukkaala T, Koskenvuo M, Elovaara I. Concordance and heritability of multiple sclerosis in Finland: study on a nationwide series of twins. Eur J Neurol. 2008;15:1106–1110. doi: 10.1111/j.1468-1331.2008.02262.x. [DOI] [PubMed] [Google Scholar]
  160. Lalaoui N, Boyden SE, Oda H, Wood GM, Stone DL, Chau D, Liu L, Stoffels M, Kratina T, Lawlor KE, et al. Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease. Nature. 2020;577:103–108. doi: 10.1038/s41586-019-1828-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  161. Langefeld CD, Ainsworth HC, Cunninghame Graham DS, Kelly J A, Comeau ME, Marion MC, Howard TD, Ramos PS, Croker J A, Morris DL, et al. Transancestral mapping and genetic load in systemic lupus erythematosus. Nat Commun. 2017;8:16021. doi: 10.1038/ncomms16021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  162. Lasagni L, Ballerini L, Angelotti ML, Parente E, Sagrinati C, Mazzinghi B, Peired A, Ronconi E, Becherucci F, Bani D, et al. Notch activation differentially regulates renal progenitors proliferation and differentiation toward the podocyte lineage in glomerular disorders. Stem Cells. 2010;28:1674–1685. doi: 10.1002/stem.492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  163. Lee JE, Choi G, Cho M, Kim D, Lee MO, Chung Y. A critical regulation of Th2 cell responses by RORα in allergic asthma. Sci China Life Sci. 2021;64:1326–1335. doi: 10.1007/s11427-020-1825-3. [DOI] [PubMed] [Google Scholar]
  164. Lemos FS, Pereira JX, Carvalho VF, Bernardes ES, Chammas R, Pereira TM, Carvalho RS, Luisetto R, El-Cheikh MC, Calil-Elias S, et al. Galectin-3 orchestrates the histology of mesentery and protects liver during lupus-like syndrome induced by pristane. Sci Rep. 2019;9:14620. doi: 10.1038/s41598-019-50564-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  165. León B, Ballesteros-Tato A. Modulating Th2 cell immunity for the treatment of asthma. Front Immunol. 2021;12:637948. doi: 10.3389/fimmu.2021.637948. [DOI] [PMC free article] [PubMed] [Google Scholar]
  166. Li CY, Ou RW, Shang HF. Rheumatoid arthritis decreases risk for Parkinson’s disease: a Mendelian randomization study. npj Parkinsons Dis. 2021;7:17. doi: 10.1038/s41531-021-00166-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  167. Li J, Zaslavsky M, Su Y, Guo J, Sikora MJ, van Unen V, Christophersen A, Chiou SH, Chen L, Li J, et al. KIR+CD8+ T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19. Science. 2022;376:eabi9591. doi: 10.1126/science.abi9591. [DOI] [PMC free article] [PubMed] [Google Scholar]
  168. Li P, Huang P, Yang Y, Hao M, Peng H, Li F. Updated understanding of Autoimmune Lymphoproliferative Syndrome (ALPS) Clinic Rev Allerg Immunol. 2016;50:55–63. doi: 10.1007/s12016-015-8466-y. [DOI] [PubMed] [Google Scholar]
  169. Li X, Sundquist J, Sundquist K. Subsequent risks of Parkinson disease in patients with autoimmune and related disorders: a nationwide epidemiological study from Sweden. Neurodegener Dis. 2012;10:277–284. doi: 10.1159/000333222. [DOI] [PubMed] [Google Scholar]
  170. Li Y, Führer M, Bahrami E, Socha P, Klaudel-Dreszler M, Bouzidi A, Liu Y, Lehle AS, Magg T, Hollizeck S, et al. Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases. Proc Natl Acad Sci USA. 2019;116:970–975. doi: 10.1073/pnas.1813582116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  171. Li Y, Shen Y, Hohensinner P, Ju J, Wen Z, Goodman SB, Zhang H, Goronzy JJ, Weyand CM. Deficient activity of the nuclease MRE11A induces T cell aging and promotes arthritogenic effector functions in patients with rheumatoid arthritis. Immunity. 2016;45:903–916. doi: 10.1016/j.immuni.2016.09.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  172. Li Y, Shen Y, Jin K, Wen Z, Cao W, Wu B, Wen R, Tian L, Berry GJ, Goronzy JJ, et al. The DNA repair nuclease MRE11A functions as a mitochondrial protector and prevents T cell pyroptosis and tissue inflammation. Cell Metab. 2019;30:477–492.e6. doi: 10.1016/j.cmet.2019.06.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  173. Li Z, Wu X, Leo PJ, De Guzman E, Akkoc N, Breban M, Macfarlane GJ, Mahmoudi M, Marzo-Ortega H, Anderson LK, et al. Polygenic Risk Scores have high diagnostic capacity in ankylosing spondylitis. Ann Rheum Dis. 2021;80:1168–1174. doi: 10.1136/annrheumdis-2020-219446. [DOI] [PMC free article] [PubMed] [Google Scholar]
  174. Liang S, Ji L, Kang L, Hu X. Metabolic regulation of innate immunity. Adv Immunol. 2020;145:129–157. doi: 10.1016/bs.ai.2019.11.005. [DOI] [PubMed] [Google Scholar]
  175. Lin J, Kumari S, Kim C, Van TM, Wachsmuth L, Polykratis A, Pasparakis M. RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation. Nature. 2016;540:124–128. doi: 10.1038/nature20558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  176. Linterman MA, Rigby RJ, Wong RK, Yu D, Brink R, Cannons J L, Schwartzberg PL, Cook MC, Walters GD, Vinuesa CG. Follicular helper T cells are required for systemic autoimmunity. J Exp Med. 2009;206:561–576. doi: 10.1084/jem.20081886. [DOI] [PMC free article] [PubMed] [Google Scholar]
  177. Lippens S, Lefebvre S, Gilbert B, Sze M, Devos M, Verhelst K, Vereecke L, Mc Guire C, Guérin C, Vandenabeele P, et al. Keratinocyte-specific ablation of the NF-κB regulatory protein A20 (TNFAIP3) reveals a role in the control of epidermal homeostasis. Cell Death Differ. 2011;18:1845–1853. doi: 10.1038/cdd.2011.55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  178. Littlewood-Evans A, Sarret S, Apfel V, Loesle P, Dawson J, Zhang J, Muller A, Tigani B, Kneuer R, Patel S, et al. GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis. J Exp Med. 2016;213:1655–1662. doi: 10.1084/jem.20160061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  179. Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C, De Ravin S S, Smith CK, Malech HL, Ledbetter JA, Elkon KB, Kaplan MJ. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med. 2016;22:146–153. doi: 10.1038/nm.4027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  180. Lork M, Verhelst K, Beyaert R. CYLD, A20 and OTULIN deubiquitinases in NF-κB signaling and cell death: so similar, yet so different. Cell Death Differ. 2017;24:1172–1183. doi: 10.1038/cdd.2017.46. [DOI] [PMC free article] [PubMed] [Google Scholar]
  181. Lotfi N, Thome R, Rezaei N, Zhang GX, Rezaei A, Rostami A, Esmaeil N. Roles of GM-CSF in the pathogenesis of autoimmune diseases: an update. Front Immunol. 2019;10:1265. doi: 10.3389/fimmu.2019.01265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  182. Maahs DM, West NA, Lawrence JM, Mayer-Davis EJ. Epidemiology of type 1 diabetes. Endocrinol Metab Clin N Am. 2010;39:481–497. doi: 10.1016/j.ecl.2010.05.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  183. Makris C, Godfrey VL, Krähn-Senftleben G, Takahashi T, Roberts J L, Schwarz T, Feng L, Johnson RS, Karin M. Female mice heterozygous for IKKγ/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol Cell. 2000;5:969–979. doi: 10.1016/S1097-2765(00)80262-2. [DOI] [PubMed] [Google Scholar]
  184. Mancini AJ, Lawley LP, Uzel G. X-linked ectodermal dysplasia with immunodeficiency caused by NEMO mutation. Arch Dermatol. 2008;144:342–346. doi: 10.1001/archderm.144.3.342. [DOI] [PubMed] [Google Scholar]
  185. Marquez A, Kerick M, Zhernakova A, Gutierrez-Achury J, Chen W M, Onengut-Gumuscu S, González-Álvaro I, Rodriguez-Rodriguez L, Rios-Fernández R, González-Gay MA, et al. Meta-analysis of Immunochip data of four autoimmune diseases reveals novel single-disease and cross-phenotype associations. Genome Med. 2018;10:97. doi: 10.1186/s13073-018-0604-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  186. McGarry T, Biniecka M, Veale DJ, Fearon U. Hypoxia, oxidative stress and inflammation. Free Radical Biol Med. 2018;125:15–24. doi: 10.1016/j.freeradbiomed.2018.03.042. [DOI] [PubMed] [Google Scholar]
  187. Meng L, Hu S, Wang J, He S, Zhang Y. DLL4+ dendritic cells: key regulators of Notch Signaling in effector T cell responses. Pharmacol Res. 2016;113:449–457. doi: 10.1016/j.phrs.2016.09.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  188. Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell. 2003;114:181–190. doi: 10.1016/S0092-8674(03)00521-X. [DOI] [PubMed] [Google Scholar]
  189. Mina R, Brunner HI. Update on differences between childhood-onset and adult-onset systemic lupus erythematosus. Arthritis Res Ther. 2013;15:218. doi: 10.1186/ar4256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  190. Miragaia RJ, Gomes T, Chomka A, Jardine L, Riedel A, Hegazy A N, Whibley N, Tucci A, Chen X, Lindeman I, et al. Single-cell transcriptomics of regulatory T cells reveals trajectories of tissue adaptation. Immunity. 2019;50:493–504.e7. doi: 10.1016/j.immuni.2019.01.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  191. Miserocchi E, Fogliato G, Modorati G, Bandello F. Review on the worldwide epidemiology of uveitis. Eur J Ophthalmol. 2013;23:705–717. doi: 10.5301/ejo.5000278. [DOI] [PubMed] [Google Scholar]
  192. Mohan C, Putterman C. Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis. Nat Rev Nephrol. 2015;11:329–341. doi: 10.1038/nrneph.2015.33. [DOI] [PubMed] [Google Scholar]
  193. Mohr A, Atif M, Balderas R, Gorochov G, Miyara M. The role of FOXP3+ regulatory T cells in human autoimmune and inflammatory diseases. Clin Exp Immunol. 2019;197:24–35. doi: 10.1111/cei.13288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  194. Momozawa Y, Dmitrieva J, Théâtre E, Deffontaine V, Rahmouni S, Charloteaux B, Crins F, Docampo E, Elansary M, Gori AS, et al. IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes. Nat Commun. 2018;9:2427. doi: 10.1038/s41467-018-04365-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  195. Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
  196. Murea M, Park JK, Sharma S, Kato H, Gruenwald A, Niranjan T, Si H, Thomas DB, Pullman JM, Melamed ML, et al. Expression of Notch pathway proteins correlates with albuminuria, glomerulosclerosis, and renal function. Kidney Int. 2010;78:514–522. doi: 10.1038/ki.2010.172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  197. Murphy MP, O’Neill LAJ. Krebs cycle reimagined: the emerging roles of succinate and itaconate as signal transducers. Cell. 2018;174:780–784. doi: 10.1016/j.cell.2018.07.030. [DOI] [PubMed] [Google Scholar]
  198. Nakazawa M, Ishii H, Aono H, Takai M, Honda T, Aratani S, Fukamizu A, Nakamura H, Yoshino SI, Kobata T, et al. Role of Notch-1 intracellular domain in activation of rheumatoid synoviocytes. Arthritis Rheumatism. 2001;44:1545–1554. doi: 10.1002/1529-0131(200107)44:7<1545::AID-ART278>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
  199. Nakazawa M, Ishii H, Nakamura H, Yoshino SI, Fukamizu A, Nishioka K, Nakajima T. NFkappaB2 (p52) promoter activation via Notch signaling pathway in rheumatoid synoviocytes. Int J Mol Med. 2001;7:31–35. doi: 10.3892/ijmm.7.1.31. [DOI] [PubMed] [Google Scholar]
  200. Navegantes KC, de Souza Gomes R, Pereira PAT, Czaikoski PG, Azevedo CHM, Monteiro MC. Immune modulation of some autoimmune diseases: the critical role of macrophages and neutrophils in the innate and adaptive immunity. J Transl Med. 2017;15:36. doi: 10.1186/s12967-017-1141-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  201. Nenci A, Huth M, Funteh A, Schmidt-Supprian M, Bloch W, Metzger D, Chambon P, Rajewsky K, Krieg T, Haase I, et al. Skin lesion development in a mouse model of incontinentia pigmenti is triggered by NEMO deficiency in epidermal keratinocytes and requires TNF signaling. Hum Mol Genet. 2006;15:531–542. doi: 10.1093/hmg/ddi470. [DOI] [PubMed] [Google Scholar]
  202. Neurath MF. Targeting immune cell circuits and trafficking in inflammatory bowel disease. Nat Immunol. 2019;20:970–979. doi: 10.1038/s41590-019-0415-0. [DOI] [PubMed] [Google Scholar]
  203. Newton K. Multitasking kinase RIPK1 regulates cell death and inflammation. Cold Spring Harb Perspect Biol. 2020;12:a036368. doi: 10.1101/cshperspect.a036368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  204. Newton K, Dugger DL, Wickliffe KE, Kapoor N, de Almagro MC, Vucic D, Komuves L, Ferrando RE, French DM, Webster J, et al. Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science. 2014;343:1357–1360. doi: 10.1126/science.1249361. [DOI] [PubMed] [Google Scholar]
  205. Newton K, Wickliffe KE, Dugger DL, Maltzman A, Roose-Girma M, Dohse M, Kőműves L, Webster JD, Dixit VM. Cleavage of RIPK1 by Caspase-8 is crucial for limiting apoptosis and necroptosis. Nature. 2019;574:428–431. doi: 10.1038/s41586-019-1548-x. [DOI] [PubMed] [Google Scholar]
  206. Newton K, Wickliffe KE, Maltzman A, Dugger DL, Reja R, Zhang Y, Roose-Girma M, Modrusan Z, Sagolla MS, Webster JD, et al. Activity of Caspase-8 determines plasticity between cell death pathways. Nature. 2019;575:679–682. doi: 10.1038/s41586-019-1752-8. [DOI] [PubMed] [Google Scholar]
  207. Newton K, Wickliffe KE, Maltzman A, Dugger DL, Strasser A, Pham VC, Lill JR, Roose-Girma M, Warming S, Solon M, et al. RIPK1 inhibits ZBP1-driven necroptosis during development. Nature. 2016;540:129–133. doi: 10.1038/nature20559. [DOI] [PubMed] [Google Scholar]
  208. Niemela J, Kuehn HS, Kelly C, Zhang M, Davies J, Melendez J, Dreiling J, Kleiner D, Calvo K, Oliveira JB, et al. Caspase-8 deficiency presenting as late-onset multi-organ lymphocytic infiltration with granulomas in two adult siblings. J Clin Immunol. 2015;35:348–355. doi: 10.1007/s10875-015-0150-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  209. O’Connor RA, Prendergast CT, Sabatos CA, Lau CWZ, Leech M D, Wraith DC, Anderton SM. Cutting edge: Th1 cells facilitate the entry of Th17 cells to the central nervous system during experimental autoimmune encephalomyelitis. J Immunol. 2008;181:3750–3754. doi: 10.4049/jimmunol.181.6.3750. [DOI] [PMC free article] [PubMed] [Google Scholar]
  210. O’Donnell JA, Lehman J, Roderick JE, Martinez-Marin D, Zelic M, Doran C, Hermance N, Lyle S, Pasparakis M, Fitzgerald KA, et al. Dendritic cell RIPK1 maintains immune homeostasis by preventing inflammation and autoimmunity. J Immunol. 2018;200:737–748. doi: 10.4049/jimmunol.1701229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  211. O’Neill LAJ, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016;16:553–565. doi: 10.1038/nri.2016.70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  212. Ohkura N, Yasumizu Y, Kitagawa Y, Tanaka A, Nakamura Y, Motooka D, Nakamura S, Okada Y, Sakaguchi S. Regulatory T cell-specific epigenomic region variants are a key determinant of susceptibility to common autoimmune diseases. Immunity. 2020;52:1119–1132.e4. doi: 10.1016/j.immuni.2020.04.006. [DOI] [PubMed] [Google Scholar]
  213. Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, Kochi Y, Ohmura K, Suzuki A, Yoshida S, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014;506:376–381. doi: 10.1038/nature12873. [DOI] [PMC free article] [PubMed] [Google Scholar]
  214. Omenetti S, Bussi C, Metidji A, Iseppon A, Lee S, Tolaini M, Li Y, Kelly G, Chakravarty P, Shoaie S, et al. The intestine harbors functionally distinct homeostatic tissue-resident and inflammatory Th17 cells. Immunity. 2019;51:77–89.e6. doi: 10.1016/j.immuni.2019.05.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  215. Onizawa M, Oshima S, Schulze-Topphoff U, Oses-Prieto JA, Lu T, Tavares R, Prodhomme T, Duong B, Whang MI, Advincula R, et al. The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis. Nat Immunol. 2015;16:618–627. doi: 10.1038/ni.3172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  216. Orning P, Weng D, Starheim K, Ratner D, Best Z, Lee B, Brooks A, Xia S, Wu H, Kelliher MA, et al. Pathogen blockade of TAK1 triggers Caspase-8-dependent cleavage of gasdermin D and cell death. Science. 2018;362:1064–1069. doi: 10.1126/science.aau2818. [DOI] [PMC free article] [PubMed] [Google Scholar]
  217. Orozco G, Viatte S, Bowes J, Martin P, Wilson AG, Morgan AW, Steer S, Wordsworth P, Hocking LJ, Barton A, et al. Novel rheumatoid arthritis susceptibility locus at 22q12 identified in an extended UK genome-wide association study. Arthritis Rheumatol. 2014;66:24–30. doi: 10.1002/art.38196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  218. Park JS, Kim SH, Kim K, Jin CH, Choi KY, Jang J, Choi Y, Gwon AR, Baik SH, Yun UJ, et al. Inhibition of notch signalling ameliorates experimental inflammatory arthritis. Ann Rheum Dis. 2015;74:267–274. doi: 10.1136/annrheumdis-2013-203467. [DOI] [PubMed] [Google Scholar]
  219. Pattison DJ, Symmons DPM, Lunt M, Welch A, Luben R, Bingham SA, Khaw KT, Day NE, Silman AJ. Dietary risk factors for the development of inflammatory polyarthritis: evidence for a role of high level of red meat consumption. Arthritis Rheum. 2004;50:3804–3812. doi: 10.1002/art.20731. [DOI] [PubMed] [Google Scholar]
  220. Peltzer N, Darding M, Montinaro A, Draber P, Draberova H, Kupka S, Rieser E, Fisher A, Hutchinson C, Taraborrelli L, et al. LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis. Nature. 2018;557:112–117. doi: 10.1038/s41586-018-0064-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  221. Peltzer N, Darding M, Walczak H. Holding RIPK1 on the ubiquitin leash in TNFR1 signaling. Trends Cell Biol. 2016;26:445–461. doi: 10.1016/j.tcb.2016.01.006. [DOI] [PubMed] [Google Scholar]
  222. Peltzer N, Rieser E, Taraborrelli L, Draber P, Darding M, Pernaute B, Shimizu Y, Sarr A, Draberova H, Montinaro A, et al. HOIP deficiency causes embryonic lethality by aberrant TNFR1-mediated endothelial cell death. Cell Rep. 2014;9:153–165. doi: 10.1016/j.celrep.2014.08.066. [DOI] [PubMed] [Google Scholar]
  223. Peng HY, Lucavs J, Ballard D, Das JK, Kumar A, Wang L, Ren Y, Xiong X, Song J. Metabolic reprogramming and reactive oxygen species in T cell immunity. Front Immunol. 2021;12:652687. doi: 10.3389/fimmu.2021.652687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  224. Perl A. Oxidative stress in the pathology and treatment of systemic lupus erythematosus. Nat Rev Rheumatol. 2013;9:674–686. doi: 10.1038/nrrheum.2013.147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  225. Perl A, Hanczko R, Lai ZW, Oaks Z, Kelly R, Borsuk R, Asara J M, Phillips PE. Comprehensive metabolome analyses reveal N-acetylcysteine-responsive accumulation of kynurenine in systemic lupus erythematosus: implications for activation of the mechanistic target of rapamycin. Metabolomics. 2015;11:1157–1174. doi: 10.1007/s11306-015-0772-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  226. Pérol L, Lindner JM, Caudana P, Nunez NG, Baeyens A, Valle A, Sedlik C, Loirat D, Boyer O, Créange A, et al. Loss of immune tolerance to IL-2 in type 1 diabetes. Nat Commun. 2016;7:13027. doi: 10.1038/ncomms13027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  227. Peyrot WJ, Price AL. Identifying loci with different allele frequencies among cases of eight psychiatric disorders using CCGWAS. Nat Genet. 2021;53:445–454. doi: 10.1038/s41588-021-00787-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  228. Pierce SE, Booms A, Prahl J, van der Schans EJC, Tyson T, Coetzee GA. Post-GWAS knowledge gap: the how, where, and when. npj Parkinsons Dis. 2020;6:23. doi: 10.1038/s41531-020-00125-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  229. Pitzalis C, Jones GW, Bombardieri M, Jones SA. Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat Rev Immunol. 2014;14:447–462. doi: 10.1038/nri3700. [DOI] [PubMed] [Google Scholar]
  230. Pocovi-Gerardino G, Correa-Rodríguez M, Callejas-Rubio JL, Ríos-Fernández R, Martín-Amada M, Cruz-Caparros MG, Rueda-Medina B, Ortego-Centeno N. Beneficial effect of Mediterranean diet on disease activity and cardiovascular risk in systemic lupus erythematosus patients: a cross-sectional study. Rheumatology. 2021;60:160–169. doi: 10.1093/rheumatology/keaa210. [DOI] [PubMed] [Google Scholar]
  231. Polykratis A, Martens A, Eren RO, Shirasaki Y, Yamagishi M, Yamaguchi Y, Uemura S, Miura M, Holzmann B, Kollias G, et al. A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis through its ZnF7 ubiquitin-binding domain. Nat Cell Biol. 2019;21:731–742. doi: 10.1038/s41556-019-0324-3. [DOI] [PubMed] [Google Scholar]
  232. Pot C, Apetoh L, Kuchroo VK. Type 1 regulatory T cells (Tr1) in autoimmunity. Semin Immunol. 2011;23:202–208. doi: 10.1016/j.smim.2011.07.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  233. Qiu R, Zhou L, Ma Y, Zhou L, Liang T, Shi L, Long J, Yuan D. Regulatory T cell plasticity and stability and autoimmune diseases. Clinic Rev Allerg Immunol. 2020;58:52–70. doi: 10.1007/s12016-018-8721-0. [DOI] [PubMed] [Google Scholar]
  234. Ramos PS, Shedlock AM, Langefeld CD. Genetics of autoimmune diseases: insights from population genetics. J Hum Genet. 2015;60:657–664. doi: 10.1038/jhg.2015.94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  235. Rao DA, Gurish MF, Marshall JL, Slowikowski K, Fonseka CY, Liu Y, Donlin LT, Henderson LA, Wei K, Mizoguchi F, et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature. 2017;542:110–114. doi: 10.1038/nature20810. [DOI] [PMC free article] [PubMed] [Google Scholar]
  236. Raphael I, Nalawade S, Eagar TN, Forsthuber TG. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine. 2015;74:5–17. doi: 10.1016/j.cyto.2014.09.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  237. Rauen T, Grammatikos AP, Hedrich CM, Floege J, Tenbrock K, Ohl K, Kyttaris VC, Tsokos GC. cAMP-responsive element modulator α (CREMα) contributes to decreased Notch-1 expression in T cells from patients with active systemic lupus erythematosus (SLE) J Biol Chem. 2012;287:42525–42532. doi: 10.1074/jbc.M112.425371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  238. Rehker J, Rodhe J, Nesbitt RR, Boyle EA, Martin BK, Lord J, Karaca I, Naj A, Jessen F, Helisalmi S, et al. Caspase-8, association with Alzheimer’s Disease and functional analysis of rare variants. PLoS ONE. 2017;12:e0185777. doi: 10.1371/journal.pone.0185777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  239. Reizis B. Plasmacytoid dendritic cells: development, regulation, and function. Immunity. 2019;50:37–50. doi: 10.1016/j.immuni.2018.12.027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  240. Reynolds ND, Lukacs NW, Long N, Karpus WJ. Delta-like ligand 4 regulates central nervous system T cell accumulation during experimental autoimmune encephalomyelitis. J Immunol. 2011;187:2803–2813. doi: 10.4049/jimmunol.1100160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  241. Rezaei N. TNF-receptor-associated periodic syndrome (TRAPS): an autosomal dominant multisystem disorder. Clin Rheumatol. 2006;25:773–777. doi: 10.1007/s10067-005-0198-6. [DOI] [PubMed] [Google Scholar]
  242. Richard-Miceli C, Criswell LA. Emerging patterns of genetic overlap across autoimmune disorders. Genome Med. 2012;4:6. doi: 10.1186/gm305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  243. Rickard JA, O’Donnell JA, Evans JM, Lalaoui N, Poh AR, Rogers TW, Vince JE, Lawlor KE, Ninnis RL, Anderton H, et al. RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell. 2014;157:1175–1188. doi: 10.1016/j.cell.2014.04.019. [DOI] [PubMed] [Google Scholar]
  244. Rioux JD, Abbas AK. Paths to understanding the genetic basis of autoimmune disease. Nature. 2005;435:584–589. doi: 10.1038/nature03723. [DOI] [PubMed] [Google Scholar]
  245. Rong H, Shen H, Xu Y, Yang H. Notch signalling suppresses regulatory T-cell function in murine experimental autoimmune uveitis. Immunology. 2016;149:447–459. doi: 10.1111/imm.12663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  246. Russell JT, Roesch LFW, Ördberg M, Ilonen J, Atkinson MA, Schatz DA, Triplett EW, Ludvigsson J. Genetic risk for autoimmunity is associated with distinct changes in the human gut microbiome. Nat Commun. 2019;10:3621. doi: 10.1038/s41467-019-11460-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  247. Ryan GE, Harris JE, Richmond JM. Resident memory T cells in autoimmune skin diseases. Front Immunol. 2021;12:652191. doi: 10.3389/fimmu.2021.652191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  248. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133:775–787. doi: 10.1016/j.cell.2008.05.009. [DOI] [PubMed] [Google Scholar]
  249. Salgado E, Bes-Rastrollo M, de Irala J, Carmona L, Gómez-Reino JJ. High sodium intake is associated with self-reported rheumatoid arthritis. Medicine. 2015;94:e0924. doi: 10.1097/MD.0000000000000924. [DOI] [PMC free article] [PubMed] [Google Scholar]
  250. Saravia J, Raynor JL, Chapman NM, Lim SA, Chi H. Signaling networks in immunometabolism. Cell Res. 2020;30:328–342. doi: 10.1038/s41422-020-0301-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  251. Scavuzzi BM, Simão ANC, Iriyoda TMV, Lozovoy MAB, Stadtlober NP, Franchi Santos LFR, Flauzino T, de Medeiros F A, de Sá MC, Consentin L, et al. Increased lipid and protein oxidation and lowered anti-oxidant defenses in systemic lupus erythematosus are associated with severity of illness, autoimmunity, increased adhesion molecules, and Th1 and Th17 immune shift. Immunol Res. 2018;66:158–171. doi: 10.1007/s12026-017-8960-9. [DOI] [PubMed] [Google Scholar]
  252. Schaid DJ, Chen W, Larson NB. From genome-wide associations to candidate causal variants by statistical fine-mapping. Nat Rev Genet. 2018;19:491–504. doi: 10.1038/s41576-018-0016-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  253. Schmitt H, Billmeier U, Dieterich W, Rath T, Sonnewald S, Reid S, Hirschmann S, Hildner K, Waldner MJ, Mudter J, et al. Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn’s disease. Gut. 2019;68:814–828. doi: 10.1136/gutjnl-2017-315671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  254. Schulert GS, Cron RQ. The genetics of macrophage activation syndrome. Genes Immun. 2020;21:169–181. doi: 10.1038/s41435-020-0098-4. [DOI] [PubMed] [Google Scholar]
  255. Schwehr NA, Kuntz KM, Butler M, Enns EA, Shippee ND, Kingwell E, Tremlett H, Carpenter AF. Age-related decreases in relapses among adults with relapsing-onset multiple sclerosis. Mult Scler. 2019;26:1510–1518. doi: 10.1177/1352458519866613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  256. Sekine C, Koyanagi A, Koyama N, Hozumi K, Chiba S, Yagita H. Differential regulation of osteoclastogenesis by Notch2/Delta-like 1 and Notch1/Jagged1 axes. Arthritis Res Ther. 2012;14:R45. doi: 10.1186/ar3758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  257. Seymour RE, Hasham MG, Cox GA, Shultz LD, Hogenesch H, Roopenian DC, Sundberg JP. Spontaneous mutations in the mouse Sharpin gene result in multiorgan inflammation, immune system dysregulation and dermatitis. Genes Immun. 2007;8:416–421. doi: 10.1038/sj.gene.6364403. [DOI] [PubMed] [Google Scholar]
  258. Shang Y, Smith S, Hu X. Role of Notch signaling in regulating innate immunity and inflammation in health and disease. Protein Cell. 2016;7:159–174. doi: 10.1007/s13238-016-0250-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  259. Shin SH, Bode AM, Dong Z. Precision medicine: the foundation of future cancer therapeutics. npj Precision Onc. 2017;1:12. doi: 10.1038/s41698-017-0016-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  260. Simone D, Penkava F, Ridley A, Sansom S, Al-Mossawi MH, Bowness P. Single cell analysis of spondyloarthritis regulatory T cells identifies distinct synovial gene expression patterns and clonal fates. Commun Biol. 2021;4:1395. doi: 10.1038/s42003-021-02931-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  261. Smahi A, Courtois G, Vabres P, Yamaoka S, Heuertz S, Munnich A, Israël A, Heiss NS, Klauck SM, Kioschis P, et al. Genomic rearrangement in NEMO impairs NF-κB activation and is a cause of incontinentia pigmenti. Nature. 2000;405:466–472. doi: 10.1038/35013114. [DOI] [PubMed] [Google Scholar]
  262. Soni C, Reizis B. Self-DNA at the epicenter of SLE: immunogenic forms, regulation, and effects. Front Immunol. 2019;10:1601. doi: 10.3389/fimmu.2019.01601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  263. Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP, Li Y, Kurreeman FAS, Zhernakova A, Hinks A, et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet. 2010;42:508–514. doi: 10.1038/ng.582. [DOI] [PMC free article] [PubMed] [Google Scholar]
  264. Steinbach K, Vincenti I, Egervari K, Kreutzfeldt M, van der Meer F, Page N, Klimek B, Rossitto-Borlat I, Di Liberto G, Muschaweckh A, et al. Brain-resident memory T cells generated early in life predispose to autoimmune disease in mice. Sci Transl Med. 2019;11:eaav5519. doi: 10.1126/scitranslmed.aav5519. [DOI] [PubMed] [Google Scholar]
  265. Stewart BJ, Ferdinand JR, Clatworthy MR. Using single-cell technologies to map the human immune system—implications for nephrology. Nat Rev Nephrol. 2020;16:112–128. doi: 10.1038/s41581-019-0227-3. [DOI] [PubMed] [Google Scholar]
  266. Stuart T, Satija R. Integrative single-cell analysis. Nat Rev Genet. 2019;20:257–272. doi: 10.1038/s41576-019-0093-7. [DOI] [PubMed] [Google Scholar]
  267. Subbarayal B, Chauhan SK, Di Zazzo A, Dana R. IL-17 augments B cell activation in ocular surface autoimmunity. J Immunol. 2016;197:3464–3470. doi: 10.4049/jimmunol.1502641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  268. Subramanian M, Wojtusciszyn A, Favre L, Boughorbel S, Shan J, Letaief KB, Pitteloud N, Chouchane L. Precision medicine in the era of artificial intelligence: implications in chronic disease management. J Transl Med. 2020;18:472. doi: 10.1186/s12967-020-02658-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  269. Sun W, Zhang H, Wang H, Chiu YG, Wang M, Ritchlin CT, Kiernan A, Boyce BF, Xing L. Targeting Notch-activated M1 macrophages attenuates joint tissue damage in a mouse model of inflammatory arthritis. J Bone Miner Res. 2017;32:1469–1480. doi: 10.1002/jbmr.3117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  270. Suthers AN, Sarantopoulos S. TLR7/TLR9- and B cell receptor-signaling crosstalk: promotion of potentially dangerous B cells. Front Immunol. 2017;8:775. doi: 10.3389/fimmu.2017.00775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  271. Symmons DPM. Epidemiology of rheumatoid arthritis: determinants of onset, persistence and outcome. Best Pract Res Clin Rheumatol. 2002;16:707–722. doi: 10.1053/berh.2002.0257. [DOI] [PubMed] [Google Scholar]
  272. Syreeni A, Sandholm N, Sidore C, Cucca F, Haukka J, Harjutsalo V, Groop PH. Genome-wide search for genes affecting the age at diagnosis of type 1 diabetes. J Intern Med. 2021;289:662–674. doi: 10.1111/joim.13187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  273. Takakubo Y, Takagi M, Maeda K, Tamaki Y, Sasaki A, Asano T, Fukushima S, Kiyoshige Y, Orui H, Ogino T, et al. Distribution of myeloid dendritic cells and plasmacytoid dendritic cells in the synovial tissues of rheumatoid arthritis. J Rheumatol. 2008;35:1919–1931. [PubMed] [Google Scholar]
  274. Tan EK, Chao YX, West A, Chan LL, Poewe W, Jankovic J. Parkinson disease and the immune system—associations, mechanisms and therapeutics. Nat Rev Neurol. 2020;16:303–318. doi: 10.1038/s41582-020-0344-4. [DOI] [PubMed] [Google Scholar]
  275. Tang Y, Tu H, Zhang J, Zhao X, Wang Y, Qin J, Lin X. K63-linked ubiquitination regulates RIPK1 kinase activity to prevent cell death during embryogenesis and inflammation. Nat Commun. 2019;10:4157. doi: 10.1038/s41467-019-12033-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  276. Tangtanatakul P, Thumarat C, Satproedprai N, Kunhapan P, Chaiyasung T, Klinchanhom S, Wang YF, Wei W, Wongshinsri J, Chiewchengchol D, et al. Meta-analysis of genome-wide association study identifies FBN2 as a novel locus associated with systemic lupus erythematosus in Thai population. Arthritis Res Ther. 2020;22:185. doi: 10.1186/s13075-020-02276-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  277. Tao P, Sun J, Wu Z, Wang S, Wang J, Li W, Pan H, Bai R, Zhang J, Wang Y, et al. A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1. Nature. 2020;577:109–114. doi: 10.1038/s41586-019-1830-y. [DOI] [PubMed] [Google Scholar]
  278. Teachey DT, Seif AE, Brown VI, Bruno M, Bunte RM, Chang Y J, Choi JK, Fish JD, Hall J, Reid GS, et al. Targeting Notch signaling in autoimmune and lymphoproliferative disease. Blood. 2008;111:705–714. doi: 10.1182/blood-2007-05-087353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  279. Teng F, Klinger CN, Felix KM, Bradley CP, Wu E, Tran NL, Umesaki Y, Wu HJJ. Gut microbiota drive autoimmune arthritis by promoting differentiation and migration of Peyer’s Patch T follicular helper cells. Immunity. 2016;44:875–888. doi: 10.1016/j.immuni.2016.03.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  280. Theofilopoulos AN, Kono DH, Baccala R. The multiple pathways to autoimmunity. Nat Immunol. 2017;18:716–724. doi: 10.1038/ni.3731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  281. Timón-Gómez A, Nývltová E, Abriata LA, Vila AJ, Hosler J, Barrientos A. Mitochondrial cytochrome c oxidase biogenesis: recent developments. Semin Cell Dev Biol. 2018;76:163–178. doi: 10.1016/j.semcdb.2017.08.055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  282. Tindemans I, Peeters MJW, Hendriks RW. Notch signaling in T helper cell subsets: instructor or unbiased amplifier? Front Immunol. 2017;8:419. doi: 10.3389/fimmu.2017.00419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  283. Tomer Y, Dolan LM, Kahaly G, Divers J, D’Agostino RB, Jr., Imperatore G, Dabelea D, Marcovina S, Black MH, Pihoker C, et al. Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes. J Autoimmun. 2015;60:32–39. doi: 10.1016/j.jaut.2015.03.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  284. Tortola L, Jacobs A, Pohlmeier L, Obermair FJ, Ampenberger F, Bodenmiller B, Kopf M. High-dimensional T helper cell profiling reveals a broad diversity of stably committed effector states and uncovers interlineage relationships. Immunity. 2020;53:597–613.e6. doi: 10.1016/j.immuni.2020.07.001. [DOI] [PubMed] [Google Scholar]
  285. Travis MA, Sheppard D. TGF-β activation and function in immunity. Annu Rev Immunol. 2014;32:51–82. doi: 10.1146/annurev-immunol-032713-120257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  286. Tsokos GC. Autoimmunity and organ damage in systemic lupus erythematosus. Nat Immunol. 2020;21:605–614. doi: 10.1038/s41590-020-0677-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  287. Tu H, Tang Y, Zhang J, Cheng L, Joo D, Zhao X, Lin X. Linear ubiquitination of RIPK1 on Lys612 regulates systemic inflammation via preventing cell death. J Immunol. 2021;207:602–612. doi: 10.4049/jimmunol.2100299. [DOI] [PubMed] [Google Scholar]
  288. Ueno H, Banchereau J, Vinuesa CG. Pathophysiology of T follicular helper cells in humans and mice. Nat Immunol. 2015;16:142–152. doi: 10.1038/ni.3054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  289. Valencia X, Yarboro C, Illei G, Lipsky PE. Deficient CD4+ CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol. 2007;178:2579–2588. doi: 10.4049/jimmunol.178.4.2579. [DOI] [PubMed] [Google Scholar]
  290. Valenti L, Fracanzani AL, Dongiovanni P, Santorelli G, Branchi A, Taioli E, Fiorelli G, Fargion S. Tumor necrosis factor a promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease. Gastroenterology. 2002;122:274–280. doi: 10.1053/gast.2002.31065. [DOI] [PubMed] [Google Scholar]
  291. Van Assche G, Van Ranst M, Sciot R, Dubois B, Vermeire S, Noman M, Verbeeck J, Geboes K, Robberecht W, Rutgeerts P. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med. 2005;353:362–368. doi: 10.1056/NEJMoa051586. [DOI] [PubMed] [Google Scholar]
  292. Vanderbeck A, Maillard I. Notch signaling at the crossroads of innate and adaptive immunity. J Leukoc Biol. 2021;109:535–548. doi: 10.1002/JLB.1RI0520-138R. [DOI] [PubMed] [Google Scholar]
  293. Varfolomeev EE, Schuchmann M, Luria V, Chiannilkulchai N, Beckmann JS, Mett IL, Rebrikov D, Brodianski VM, Kemper OC, Kollet O, et al. Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity. 1998;9:267–276. doi: 10.1016/S1074-7613(00)80609-3. [DOI] [PubMed] [Google Scholar]
  294. Vargas-Rojas MI, Crispín JC, Richaud-Patin Y, Alcocer-Varela J. Quantitative and qualitative normal regulatory T cells are not capable of inducing suppression in SLE patients due to T-cell resistance. Lupus. 2008;17:289–294. doi: 10.1177/0961203307088307. [DOI] [PubMed] [Google Scholar]
  295. Venigalla RK, Tretter T, Krienke S, Max R, Eckstein V, Blank N, Fiehn C, Dick Ho A, Lorenz H. Reduced CD4+,CD25− T cell sensitivity to the suppressive function of CD4+,CD25high, CD127−/low regulatory T cells in patients with active systemic lupus erythematosus. Arthritis Rheum. 2008;58:2120–2130. doi: 10.1002/art.23556. [DOI] [PubMed] [Google Scholar]
  296. Verstappen GM, Corneth OBJ, Bootsma H, Kroese FGM. Th17 cells in primary Sjögren’s syndrome: pathogenicity and plasticity. J Autoimmun. 2018;87:16–25. doi: 10.1016/j.jaut.2017.11.003. [DOI] [PubMed] [Google Scholar]
  297. Visscher PM, Brown MA, McCarthy MI, Yang J. Five years of GWAS discovery. Am J Hum Genet. 2012;90:7–24. doi: 10.1016/j.ajhg.2011.11.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  298. Visscher PM, Wray NR, Zhang Q, Sklar P, McCarthy MI, Brown MA, Yang J. 10 years of GWAS discovery: biology, function, and translation. Am J Hum Genet. 2017;101:5–22. doi: 10.1016/j.ajhg.2017.06.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  299. Vlantis K, Wullaert A, Polykratis A, Kondylis V, Dannappel M, Schwarzer R, Welz P, Corona T, Walczak H, Weih F, et al. NEMO prevents RIP kinase 1-mediated epithelial cell death and chronic intestinal inflammation by NF-κB-dependent and -independent functions. Immunity. 2016;44:553–567. doi: 10.1016/j.immuni.2016.02.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  300. Vojdani A. A potential link between environmental triggers and autoimmunity. Autoimmun Dis. 2014;2014:1–18. doi: 10.1155/2014/798029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  301. Wagner A, Wang C, Fessler J, DeTomaso D, Avila-Pacheco J, Kaminski J, Zaghouani S, Christian E, Thakore P, Schellhaass B, et al. Metabolic modeling of single Th17 cells reveals regulators of autoimmunity. Cell. 2021;184:4168–4185.e21. doi: 10.1016/j.cell.2021.05.045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  302. Wang L, Du F, Wang X. TNF-α induces two distinct caspase-8 activation pathways. Cell. 2008;133:693–703. doi: 10.1016/j.cell.2008.03.036. [DOI] [PubMed] [Google Scholar]
  303. Wang L, Wang FS, Gershwin ME. Human autoimmune diseases: a comprehensive update. J Intern Med. 2015;278:369–395. doi: 10.1111/joim.12395. [DOI] [PubMed] [Google Scholar]
  304. Wang X, Ni L, Wan S, Zhao X, Ding X, Dejean A, Dong C. Febrile temperature critically controls the differentiation and pathogenicity of T helper 17 cells. Immunity. 2020;52:328–341.e5. doi: 10.1016/j.immuni.2020.01.006. [DOI] [PubMed] [Google Scholar]
  305. Wei K, Korsunsky I, Marshall JL, Gao A, Watts GFM, Major T, Croft AP, Watts J, Blazar PE, Lange JK, et al. Notch signalling drives synovial fibroblast identity and arthritis pathology. Nature. 2020;582:259–264. doi: 10.1038/s41586-020-2222-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  306. Wellcome Trust Case Control Consortium Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661–678. doi: 10.1038/nature05911. [DOI] [PMC free article] [PubMed] [Google Scholar]
  307. Wellcome Trust Case Control Consortium,The Australo-Anglo-American Spondylitis Consortium TASC Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet. 2007;39:1329–1337. doi: 10.1038/ng.2007.17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  308. Weyand CM, Goronzy JJ. The immunology of rheumatoid arthritis. Nat Immunol. 2021;22:10–18. doi: 10.1038/s41590-020-00816-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  309. Wijmenga C, Zhernakova A. The importance of cohort studies in the post-GWAS era. Nat Genet. 2018;50:322–328. doi: 10.1038/s41588-018-0066-3. [DOI] [PubMed] [Google Scholar]
  310. Witoelar A, Jansen IE, Wang Y, Desikan RS, Gibbs JR, Blauwendraat C, Thompson WK, Hernandez DG, Djurovic S, Schork AJ, et al. Genome-wide pleiotropy between parkinson disease and autoimmune diseases. JAMA Neurol. 2017;74:780–792. doi: 10.1001/jamaneurol.2017.0469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  311. Xu H, Yin J. HLA risk alleles and gut microbiome in ankylosing spondylitis and rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2019;33:101499. doi: 10.1016/j.berh.2020.101499. [DOI] [PubMed] [Google Scholar]
  312. Yabe Y, Matsumoto T, Tsurumoto T, Shindo H. Immunohistological localization of Notch receptors and their ligands Delta and Jagged in synovial tissues of rheumatoid arthritis. J Orthop Sci. 2005;10:589–594. doi: 10.1007/s00776-005-0943-3. [DOI] [PubMed] [Google Scholar]
  313. Yamazaki K, Umeno J, Takahashi A, Hirano A, Johnson TA, Kumasaka N, Morizono T, Hosono N, Kawaguchi T, Takazoe M, et al. A genome-wide association study identifies 2 susceptibility loci for Crohn’s disease in a Japanese population. Gastroenterology. 2013;144:781–788. doi: 10.1053/j.gastro.2012.12.021. [DOI] [PubMed] [Google Scholar]
  314. Yang Z, Fujii H, Mohan SV, Goronzy JJ, Weyand CM. Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells. J Exp Med. 2013;210:2119–2134. doi: 10.1084/jem.20130252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  315. Yang Z, Shen Y, Oishi H, Matteson EL, Tian L, Goronzy JJ, Weyand CM. Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Sci Transl Med. 2016;8:331ra38. doi: 10.1126/scitranslmed.aad7151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  316. Yin J, Sternes PR, Wang M, Song J, Morrison M, Li T, Zhou L, Wu X, He F, Zhu J, et al. Shotgun metagenomics reveals an enrichment of potentially cross-reactive bacterial epitopes in ankylosing spondylitis patients, as well as the effects of TNFi therapy upon microbiome composition. Ann Rheum Dis. 2020;79:132–140. doi: 10.1136/annrheumdis-2019-215763. [DOI] [PubMed] [Google Scholar]
  317. Yin Y, Choi SC, Xu Z, Perry DJ, Seay H, Croker BP, Sobel ES, Brusko TM, Morel L. Normalization of CD4+ T cell metabolism reverses lupus. Sci Transl Med. 2015;7:274ra218. doi: 10.1126/scitranslmed.aaa0835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  318. Yu F, Sharma S, Edwards J, Feigenbaum L, Zhu J. Dynamic expression of transcription factors T-bet and GATA-3 by regulatory T cells maintains immunotolerance. Nat Immunol. 2015;16:197–206. doi: 10.1038/ni.3053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  319. Yu Y, Ma X, Gong R, Zhu J, Wei L, Yao J. Recent advances in CD8+ regulatory T cell research (Review) Oncol Lett. 2018;15:8187–8194. doi: 10.3892/ol.2018.8378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  320. Yuan J, Amin P, Ofengeim D. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat Rev Neurosci. 2019;20:19–33. doi: 10.1038/s41583-018-0093-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  321. Zaiss MM, Joyce Wu HJ, Mauro D, Schett G, Ciccia F. The gut-joint axis in rheumatoid arthritis. Nat Rev Rheumatol. 2021;17:224–237. doi: 10.1038/s41584-021-00585-3. [DOI] [PubMed] [Google Scholar]
  322. Zeggini E, Ioannidis JPA. Meta-analysis in genome-wide association studies. Pharmacogenomics. 2009;10:191–201. doi: 10.2217/14622416.10.2.191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  323. Zhang F, Wei K, Slowikowski K, Fonseka CY, Rao DA, Kelly S, Goodman SM, Tabechian D, Hughes LB, Salomon-Escoto K, et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol. 2019;20:928–942. doi: 10.1038/s41590-019-0378-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  324. Zhang J, Webster JD, Dugger DL, Goncharov T, Roose-Girma M, Hung J, Kwon YC, Vucic D, Newton K, Dixit VM. Ubiquitin ligases cIAP1 and cIAP2 limit cell death to prevent inflammation. Cell Rep. 2019;27:2679–2689.e3. doi: 10.1016/j.celrep.2019.04.111. [DOI] [PubMed] [Google Scholar]
  325. Zhang W, Xu W, Xiong S. Blockade of Notch1 signaling alleviates murine lupus via blunting macrophage activation and M2b polarization. J Immunol. 2010;184:6465–6478. doi: 10.4049/jimmunol.0904016. [DOI] [PubMed] [Google Scholar]
  326. Zhang XH, Dowling JP, Zhang JK. RIPK1 can mediate apoptosis in addition to necroptosis during embryonic development. Cell Death Dis. 2019;10:245. doi: 10.1038/s41419-019-1490-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  327. Zhang XX, Zhang HW, Xu CX, Li XM, Li M, Wu XX, Pu WJ, Zhou B, Wang HK, Li DL, et al. Ubiquitination of RIPK1 suppresses programmed cell death by regulating RIPK1 kinase activation during embryogenesis. Nat Commun. 2019;10:4158. doi: 10.1038/s41467-019-11839-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
  328. Zhao Z, Xiao X, Saw PE, Wu W, Huang H, Chen J, Nie Y. Chimeric antigen receptor T cells in solid tumors: a war against the tumor microenvironment. Sci China Life Sci. 2020;63:180–205. doi: 10.1007/s11427-019-9665-8. [DOI] [PubMed] [Google Scholar]
  329. Zhernakova A, Stahl EA, Trynka G, Raychaudhuri S, Festen EA, Franke L, Westra HJ, Fehrmann RSN, Kurreeman FAS, Thomson B, et al. Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci. PLoS Genet. 2011;7:e1002004. doi: 10.1371/journal.pgen.1002004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  330. Zhou Q, Wang H, Schwartz DM, Stoffels M, Park YH, Zhang Y, Yang D, Demirkaya E, Takeuchi M, Tsai WL, et al. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat Genet. 2016;48:67–73. doi: 10.1038/ng.3459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  331. Zhou Q, Yu X, Demirkaya E, Deuitch N, Stone D, Tsai WL, Kuehn HS, Wang H, Yang D, Park YH, et al. Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease. Proc Natl Acad Sci USA. 2016;113:10127–10132. doi: 10.1073/pnas.1612594113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  332. Zuercher AW, Spirig R, Baz Morelli A, Rowe T, Käsermann F. Next-generation Fc receptor-targeting biologics for autoimmune diseases. Autoimmun Rev. 2019;18:102366. doi: 10.1016/j.autrev.2019.102366. [DOI] [PubMed] [Google Scholar]
  333. Zundler S, Becker E, Spocinska M, Slawik M, Parga-Vidal L, Stark R, Wiendl M, Atreya R, Rath T, Leppkes M, et al. Hobit- and Blimp-1-driven CD4+ tissue-resident memory T cells control chronic intestinal inflammation. Nat Immunol. 2019;20:288–300. doi: 10.1038/s41590-018-0298-5. [DOI] [PubMed] [Google Scholar]

Articles from Science China. Life Sciences are provided here courtesy of Nature Publishing Group

RESOURCES