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Autoimmunity and organ damage in systemic lupus erythematosus

Nature Immunology volume 21, pages 605–614 (2020)Cite this article

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Abstract

Impressive progress has been made over the last several years toward understanding how almost every aspect of the immune system contributes to the expression of systemic autoimmunity. In parallel, studies have shed light on the mechanisms that contribute to organ inflammation and damage. New approaches that address the complicated interaction between genetic variants, epigenetic processes, sex and the environment promise to enlighten the multitude of pathways that lead to what is clinically defined as systemic lupus erythematosus. It is expected that each patient owns a unique ‘interactome’, which will dictate specific treatment.

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Fig. 1: The pathogenetic landscape of SLE.
Fig. 2: T cell early and late signaling aberrations in T cells from patients with SLE.

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References

  1. Durcan, L., O’Dwyer, T. & Petri, M. Management strategies and future directions for systemic lupus erythematosus in adults. Lancet 393, 2332–2343 (2019).

    Article  PubMed  Google Scholar 

  2. Dörner, T. & Furie, R. Novel paradigms in systemic lupus erythematosus. Lancet 393, 2344–2358 (2019).

    Article  PubMed  Google Scholar 

  3. Tsokos, G. C. Systemic lupus erythematosus. N. Engl. J. Med. 365, 2110–2121 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Theofilopoulos, A. N., Kono, D. H. & Baccala, R. The multiple pathways to autoimmunity. Nat. Immunol. 18, 716–724 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Deng, Y. & Tsao, B. P. Updates in lupus genetics. Curr. Rheumatol. Rep. 19, 68 (2017).

    Article  PubMed  CAS  Google Scholar 

  6. Langefeld, C. D. et al. Transancestral mapping and genetic load in systemic lupus erythematosus. Nat. Commun. 8, 16021 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tsokos, G. C., Lo, M. S., Costa Reis, P. & Sullivan, K. E. New insights into the immunopathogenesis of systemic lupus erythematosus. Nat. Rev. Rheumatol. 12, 716–730 (2016).

    Article  CAS  PubMed  Google Scholar 

  8. Teruel, M. & Alarcon-Riquelme, M. E. Genetics of systemic lupus erythematosus and Sjögren's syndrome: an update. Curr. Opin. Rheumatol. 28, 506–514 (2016).

    Article  CAS  PubMed  Google Scholar 

  9. Acosta-Herrera, M. et al. Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases. Ann. Rheum. Dis. 78, 311–319 (2019).

    Article  CAS  PubMed  Google Scholar 

  10. Deligianni, C. & Spilianakis, C. G. Long-range genomic interactions epigenetically regulate the expression of a cytokine receptor. EMBO Rep. 13, 819–826 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jhunjhunwala, S. et al. The 3D structure of the immunoglobulin heavy-chain locus: implications for long-range genomic interactions. Cell 133, 265–279 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hedrich, C. M., Mäbert, K., Rauen, T. & Tsokos, G. C. DNA methylation in systemic lupus erythematosus. Epigenomics 9, 505–525 (2017).

    Article  CAS  PubMed  Google Scholar 

  13. Li, H. et al. Precision DNA demethylation ameliorates disease in lupus-prone mice. JCI Insight 3, 120880 (2018).

    Article  PubMed  Google Scholar 

  14. Hedrich, C. M. et al. cAMP-responsive element modulator α (CREM α) trans-represses the transmembrane glycoprotein CD8 and contributes to the generation of CD3+CD4–CD8– T cells in health and disease. J. Biol. Chem. 288, 31880–31887 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hedrich, C. M., Rauen, T. & Tsokos, G. C. cAMP-responsive element modulator (CREM)α protein signaling mediates epigenetic remodeling of the human interleukin-2 gene: implications in systemic lupus erythematosus. J. Biol. Chem. 286, 43429–43436 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hedrich, C. M. et al. Stat3 promotes IL-10 expression in lupus T cells through trans-activation and chromatin remodeling. Proc. Natl Acad. Sci. USA 111, 13457–13462 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jin, F. et al. Serum microRNA profiles serve as novel biomarkers for autoimmune diseases. Front. Immunol. 9, 2381 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Coit, P. & Sawalha, A. H. The human microbiome in rheumatic autoimmune diseases: a comprehensive review. Clin. Immunol. 170, 70–79 (2016).

    Article  CAS  PubMed  Google Scholar 

  19. Greiling, T. M. et al. Commensal orthologs of the human autoantigen Ro60 as triggers of autoimmunity in lupus. Sci. Transl. Med. 10, eaan2306 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Teng, F. et al. Gut microbiota drive autoimmune arthritis by promoting differentiation and migration of Peyer's patch T follicular helper cells. Immunity 44, 875–888 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Turer, E. E. et al. Homeostatic MyD88-dependent signals cause lethal inflammation in the absence of A20. J. Exp. Med. 205, 451–464 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zegarra-Ruiz, D. F. et al. A diet-sensitive commensal Lactobacillus strain mediates TLR7-dependent systemic autoimmunity. Cell Host Microbe 25, 113–127.e6 (2019).

    Article  CAS  PubMed  Google Scholar 

  24. Manfredo Vieira, S. et al. Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science 359, 1156–1161 (2018).

    Article  CAS  PubMed  Google Scholar 

  25. Odhams, C. A. et al. Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus. Nat. Commun. 10, 2164 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Moulton, V. R. & Tsokos, G. C. Why do women get lupus? Clin. Immunol. 144, 53–56 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Liang, Y. et al. A gene network regulated by the transcription factor VGLL3 as a promoter of sex-biased autoimmune diseases. Nat. Immunol. 18, 152–160 (2017).

    Article  CAS  PubMed  Google Scholar 

  28. Garcia-Romo, G. S. et al. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci. Transl. Med. 3, 73ra20 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Frangou, E. et al. REDD1/autophagy pathway promotes thromboinflammation and fibrosis in human systemic lupus erythematosus (SLE) through NETs decorated with tissue factor (TF) and interleukin-17A (IL-17A). Ann. Rheum. Dis. 78, 238–248 (2019).

    Article  CAS  PubMed  Google Scholar 

  30. Puga, I. et al. B cell–helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat. Immunol. 13, 170–180 (2012).

    Article  CAS  Google Scholar 

  31. Blanco, P., Palucka, A. K., Gill, M., Pascual, V. & Banchereau, J. Induction of dendritic cell differentiation by IFN-α in systemic lupus erythematosus. Science 294, 1540–1543 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Jacquemin, C. et al. OX40 ligand contributes to human lupus pathogenesis by promoting T follicular helper response. Immunity 42, 1159–1170 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jacquemin, C. et al. OX40L/OX40 axis impairs follicular and natural Treg function in human SLE. JCI Insight 3, e122167 (2018).

    Article  PubMed Central  Google Scholar 

  34. Joo, H. et al. Serum from patients with SLE instructs monocytes to promote IgG and IgA plasmablast differentiation. J. Exp. Med. 209, 1335–1348 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Barrat, F. J. et al. Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J. Exp. Med. 202, 1131–1139 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pisitkun, P. et al. Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 312, 1669–1672 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Rowland, S. L. et al. Early, transient depletion of plasmacytoid dendritic cells ameliorates autoimmunity in a lupus model. J. Exp. Med. 211, 1977–1991 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Furie, R. et al. Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus. J. Clin. Invest. 129, 1359–1371 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Guiducci, C. et al. TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus. Nature 465, 937–941 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Li, H. et al. Interferon-induced mechanosensing defects impede apoptotic cell clearance in lupus. J. Clin. Invest. 125, 2877–2890 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Ramirez-Ortiz, Z. G. et al. The receptor TREML4 amplifies TLR7-mediated signaling during antiviral responses and autoimmunity. Nat. Immunol. 16, 495–504 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Park, S. H. et al. Type I interferons and the cytokine TNF cooperatively reprogram the macrophage epigenome to promote inflammatory activation. Nat. Immunol. 18, 1104–1116 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Banchereau, R. et al. Personalized immunomonitoring uncovers molecular networks that stratify lupus patients. Cell 165, 551–565 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Barrat, F. J., Crow, M. K. & Ivashkiv, L. B. Interferon target-gene expression and epigenomic signatures in health and disease. Nat. Immunol. 20, 1574–1583 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhuang, H., Szeto, C., Han, S., Yang, L. & Reeves, W. H. Animal models of interferon signature positive lupus. Front. Immunol. 6, 291 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Schwarting, A. et al. Interferon-β: a therapeutic for autoimmune lupus in MRL-Fas lpr mice. J. Am. Soc. Nephrol. 16, 3264–3272 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Shinde, R. et al. Apoptotic cell-induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans. Nat. Immunol. 19, 571–582 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lood, C. et al. Platelet transcriptional profile and protein expression in patients with systemic lupus erythematosus: up-regulation of the type I interferon system is strongly associated with vascular disease. Blood 116, 1951–1957 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Duffau, P. et al. Platelet CD154 potentiates interferon-α secretion by plasmacytoid dendritic cells in systemic lupus erythematosus. Sci. Transl. Med. Sci. Transl. Med. 2, 47ra63 (2010).

    Article  PubMed  CAS  Google Scholar 

  50. Charles, N., Hardwick, D., Daugas, E., Illei, G. G. & Rivera, J. Basophils and the T helper 2 environment can promote the development of lupus nephritis. Nat. Med. 16, 701–707 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Dörner, T. & Lipsky, P. E. Beyond pan-B-cell-directed therapy — new avenues and insights into the pathogenesis of SLE. Nat. Rev. Rheumatol. 12, 645–657 (2016).

    Article  PubMed  CAS  Google Scholar 

  52. Tipton, C. M., Hom, J. R., Fucile, C. F., Rosenberg, A. F. & Sanz, I. Understanding B-cell activation and autoantibody repertoire selection in systemic lupus erythematosus: a B-cell immunomics approach. Immunol. Rev. 284, 120–131 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Dörner, T., Giesecke, C. & Lipsky, P. E. Mechanisms of B cell autoimmunity in SLE. Arthritis Res. Ther. 13, 243 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Yurasov, S. et al. Defective B cell tolerance checkpoints in systemic lupus erythematosus. J. Exp. Med. 201, 703–711 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Suurmond, J. et al. Loss of an IgG plasma cell checkpoint in patients with lupus. J. Allergy Clin. Immunol. 143, 1586–1597 (2019).

    Article  CAS  PubMed  Google Scholar 

  56. Manni, M. et al. Regulation of age-associated B cells by IRF5 in systemic autoimmunity. Nat. Immunol. 19, 407–419 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sun, C. et al. High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry. Nat. Genet. 48, 323–330 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Scharer, C. D. et al. Epigenetic programming underpins B cell dysfunction in human SLE. Nat. Immunol. 20, 1071–1082 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zumaquero, E. et al. IFNγ induces epigenetic programming of human T-bethi B cells and promotes TLR7/8 and IL-21 induced differentiation. Elife 8, e41641 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Jenks, S. A. et al. Distinct effector B cells induced by unregulated Toll-like receptor 7 contribute to pathogenic responses in systemic lupus erythematosus. Immunity 49, 725–739.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tipton, C. M. et al. Diversity, cellular origin and autoreactivity of antibody-secreting cell population expansions in acute systemic lupus erythematosus. Nat. Immunol. 16, 755–765 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Henault, J. et al. Self-reactive IgE exacerbates interferon responses associated with autoimmunity. Nat. Immunol. 17, 196–203 (2016).

    Article  CAS  PubMed  Google Scholar 

  63. Mohan, C., Adams, S., Stanik, V. & Datta, S. K. Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus. J. Exp. Med. 177, 1367–1381 (1993).

    Article  CAS  PubMed  Google Scholar 

  64. Christophersen, A. et al. Distinct phenotype of CD4+ T cells driving celiac disease identified in multiple autoimmune conditions. Nat. Med. 25, 734–737 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kim, S. J., Lee, K. & Diamond, B. Follicular helper T cells in systemic lupus erythematosus. Front. Immunol. 9, 1793 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Odegard, J. M. et al. ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. J. Exp. Med. 205, 2873–2886 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Faliti, C. E. et al. P2X7 receptor restrains pathogenic Tfh cell generation in systemic lupus erythematosus. J. Exp. Med. 216, 317–336 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Caielli, S. et al. A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate. Nat. Med. 25, 75–81 (2019).

    Article  CAS  PubMed  Google Scholar 

  69. Katsuyama, E. et al. The CD38/NAD/SIRTUIN1/EZH2 axis mitigates cytotoxic CD8 T cell function and identifies patients with SLE prone to infections. Cell Rep. 30, 112–123.e4 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Tarrago, M. G. et al. A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD+ decline. Cell Metab. 27, 1081–1095.e10 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. McKinney, E. F., Lee, J. C., Jayne, D. R., Lyons, P. A. & Smith, K. G. T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature 523, 612–616 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Sharabi, A. et al. Regulatory T cells in the treatment of disease. Nat. Rev. Drug Discov. 17, 823–844 (2018).

    Article  CAS  PubMed  Google Scholar 

  73. Mizui, M. et al. IL-2 protects lupus-prone mice from multiple end-organ damage by limiting CD4–CD8– IL-17–producing T cells. J. Immunol. 193, 2168–2177 (2014).

    Article  CAS  PubMed  Google Scholar 

  74. Crispin, J. C. et al. Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J. Immunol. 181, 8761–8766 (2008).

    Article  CAS  PubMed  Google Scholar 

  75. He, J. et al. Low-dose interleukin-2 treatment selectively modulates CD4+ T cell subsets in patients with systemic lupus erythematosus. Nat. Med. 22, 991–993 (2016).

    Article  CAS  PubMed  Google Scholar 

  76. Comte, D. et al. Brief report: CD4+ T cells from patients with systemic lupus erythematosus respond poorly to exogenous interleukin-2. Arthritis Rheumatol. 69, 808–813 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Moulton, V. R. et al. Pathogenesis of human systemic lupus erythematosus: a cellular perspective. Trends Mol. Med. 23, 615–635 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Burzyn, D. et al. A special population of regulatory T cells potentiates muscle repair. Cell 155, 1282–1295 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Afeltra, A. et al. The involvement of T regulatory lymphocytes in a cohort of lupus nephritis patients: a pilot study. Intern. Emerg. Med. 10, 677–683 (2015).

    Article  PubMed  Google Scholar 

  80. Crispin, J. C., Hedrich, C. M., Suárez-Fueyo, A., Comte, D. & Tsokos, G. C. SLE-associated defects promote altered T cell function. Crit. Rev. Immunol. 37, 39–58 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Moulton, V. R. & Tsokos, G. C. T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity. J. Clin. Invest. 125, 2220–2227 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Sharabi, A. & Tsokos, G. C. T cell metabolism: new insights in systemic lupus erythematosus pathogenesis and therapy. Nat. Rev. Rheumatol. 16, 100–112 (2020).

    Article  CAS  PubMed  Google Scholar 

  83. Flores-Mendoza, G., Sansón, S. P., Rodriguez-Castro, S., Crispin, J. C. & Rosetti, F. Mechanisms of tissue injury in lupus nephritis. Trends Mol. Med. 24, 364–378 (2018).

    Article  CAS  PubMed  Google Scholar 

  84. Maeda, K. et al. CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease. J. Clin. Invest. 128, 3445–3459 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Steinmetz, O. M. et al. CXCR3 mediates renal Th1 and Th17 immune response in murine lupus nephritis. J. Immunol. 183, 4693–4704 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Peng, S. L. et al. Murine lupus in the absence of alpha beta T cells. J. Immunol. 156, 4041–4049 (1996).

    CAS  PubMed  Google Scholar 

  87. Tilstra, J. S. et al. Kidney-infiltrating T cells in murine lupus nephritis are metabolically and functionally exhausted. J. Clin. Invest. 128, 4884–4897 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Winchester, R. et al. Immunologic characteristics of intrarenal T cells: trafficking of expanded CD8+ T cell β-chain clonotypes in progressive lupus nephritis. Arthritis Rheum. 64, 1589–1600 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Amarilyo, G., Lourenço, E. V., Shi, F. D. & La Cava, A. IL-17 promotes murine lupus. J. Immunol. 193, 540–543 (2014).

    Article  CAS  PubMed  Google Scholar 

  90. Liarski, V. M. et al. Cell distance mapping identifies functional T follicular helper cells in inflamed human renal tissue. Sci. Transl. Med. 6, 230ra246 (2014).

    Article  CAS  Google Scholar 

  91. Kinloch, A. J. et al. Vimentin is a dominant target of in situ humoral immunity in human lupus tubulointerstitial nephritis. Arthritis Rheumatol. 66, 3359–3370 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Liarski, V. M. et al. Quantifying in situ adaptive immune cell cognate interactions in humans. Nat. Immunol. 20, 503–513 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Davidson, A., Aranow, C. & Mackay, M. Lupus nephritis: challenges and progress. Curr. Opin. Rheumatol. 31, 682–688 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Sahu, R., Bethunaickan, R., Singh, S. & Davidson, A. Structure and function of renal macrophages and dendritic cells from lupus-prone mice. Arthritis Rheumatol. 66, 1596–1607 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Iwata, Y. et al. Aberrant macrophages mediate defective kidney repair that triggers nephritis in lupus-susceptible mice. J. Immunol. 188, 4568–4580 (2012).

    Article  CAS  PubMed  Google Scholar 

  96. Berthier, C. C. et al. Cross-species transcriptional network analysis defines shared inflammatory responses in murine and human lupus nephritis. J. Immunol. 189, 988–1001 (2012).

    Article  CAS  PubMed  Google Scholar 

  97. Finsterbusch, M. et al. Patrolling monocytes promote intravascular neutrophil activation and glomerular injury in the acutely inflamed glomerulus. Proc. Natl Acad. Sci. USA 113, E5172–E5181 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kuriakose, J. et al. Patrolling monocytes promote the pathogenesis of early lupus-like glomerulonephritis. J. Clin. Invest. 129, 2251–2265 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Der, E. et al. Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways. Nat. Immunol. 20, 915–927 (2019); erratum 20, 1556 (2019)..

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Arazi, A. et al. The immune cell landscape in kidneys of patients with lupus nephritis. Nat. Immunol. 20, 902–914 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ge, Y. et al. Cgnz1 allele confers kidney resistance to damage preventing progression of immune complex-mediated acute lupus glomerulonephritis. J. Exp. Med. 210, 2387–2401 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Schwartz, N., Stock, A. D. & Putterman, C. Neuropsychiatric lupus: new mechanistic insights and future treatment directions. Nat. Rev. Rheumatol. 15, 137–152 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  103. DeGiorgio, L. A. et al. A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat. Med. 7, 1189–1193 (2001).

    Article  CAS  PubMed  Google Scholar 

  104. Kowal, C. et al. Human lupus autoantibodies against NMDA receptors mediate cognitive impairment. Proc. Natl Acad. Sci. USA 103, 19854–19859 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Kowal, C. et al. Cognition and immunity; antibody impairs memory. Immunity 21, 179–188 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Stock, A. D. et al. Tertiary lymphoid structures in the choroid plexus in neuropsychiatric lupus. JCI Insight 4, 124203 (2019).

    Article  PubMed  Google Scholar 

  107. DiStasio, M. M., Nagakura, I., Nadler, M. J. & Anderson, M. P. T lymphocytes and cytotoxic astrocyte blebs correlate across autism brains. Ann. Neurol. 86, 885–898 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Heneka, M. T. An immune-cell signature marks the brain in Alzheimer's disease. Nature 577, 322–323 (2020).

    Article  CAS  PubMed  Google Scholar 

  109. Menke, J. et al. Sunlight triggers cutaneous lupus through a CSF-1-dependent mechanism in MRL-Fas lpr mice. J. Immunol. 181, 7367–7379 (2008).

    Article  CAS  PubMed  Google Scholar 

  110. Martens, H. A. et al. Analysis of C1q polymorphisms suggests association with systemic lupus erythematosus, serum C1q and CH50 levels and disease severity. Ann. Rheum. Dis. 68, 715–720 (2009).

    Article  CAS  PubMed  Google Scholar 

  111. Ramirez-Ortiz, Z. G. et al. The scavenger receptor SCARF1 mediates the clearance of apoptotic cells and prevents autoimmunity. Nat. Immunol. 14, 917–926 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Oh, S. H. et al. Expression of interleukin-17 is correlated with interferon-α expression in cutaneous lesions of lupus erythematosus. Clin. Exp. Dermatol. 36, 512–520 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. Guiducci, C. et al. Autoimmune skin inflammation is dependent on plasmacytoid dendritic cell activation by nucleic acids via TLR7 and TLR9. J. Exp. Med. 207, 2931–2942 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Mande, P. et al. Fas ligand promotes an inducible TLR-dependent model of cutaneous lupus-like inflammation. J. Clin. Invest. 128, 2966–2978 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Deng, G. M. & Tsokos, G. C. Pathogenesis and targeted treatment of skin injury in SLE. Nat. Rev. Rheumatol. 11, 663–669 (2015).

    Article  CAS  PubMed  Google Scholar 

  116. Liu, Y. & Kaplan, M. J. Cardiovascular disease in systemic lupus erythematosus: an update. Curr. Opin. Rheumatol. 30, 441–448 (2018).

    Article  PubMed  Google Scholar 

  117. Buie, J. J., Renaud, L. L., Muise-Helmericks, R. & Oates, J. C. IFN-α negatively regulates the expression of endothelial nitric oxide synthase and nitric oxide production: implications for systemic lupus erythematosus. J. Immunol. 199, 1979–1988 (2017).

    Article  CAS  PubMed  Google Scholar 

  118. Carlucci, P. M. et al. Neutrophil subsets and their gene signature associate with vascular inflammation and coronary atherosclerosis in lupus. JCI Insight 3, 99276 (2018).

    Article  PubMed  Google Scholar 

  119. Li, J. et al. CCR5+T-bet+FoxP3+ effector CD4 T cells drive atherosclerosis. Circ. Res. 118, 1540–1552 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Smith, E. et al. Cross-talk between iNKT cells and monocytes triggers an atheroprotective immune response in SLE patients with asymptomatic plaque. Sci. Immunol. 1, eaah4081 (2016).

    Article  PubMed  Google Scholar 

  121. Lim, H. et al. Proatherogenic conditions promote autoimmune T helper 17 cell responses in vivo. Immunity 40, 153–165 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Choi, J. Y. et al. Circulating follicular helper-like T cells in systemic lupus erythematosus: association with disease activity. Arthritis Rheumatol. 67, 988–999 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Ryu, H. et al. Atherogenic dyslipidemia promotes autoimmune follicular helper T cell responses via IL-27. Nat. Immunol. 19, 583–593 (2018); erratum 19, 1036 (2018).

    Article  CAS  PubMed  Google Scholar 

  124. Hedrich, C. M. & Tsokos, G. SNPs talk to genes using landlines: long-range chromatin interactions link genetic risk with epigenetic patterns in Takayasu arteritis. Ann. Rheum. Dis. 78, 1293–1295 (2019).

    Article  CAS  PubMed  Google Scholar 

  125. Libert, C., Dejager, L. & Pinheiro, I. The X chromosome in immune functions: when a chromosome makes the difference. Nat. Rev. Immunol. 10, 594–604 (2010).

    Article  CAS  PubMed  Google Scholar 

  126. Kottyan, L. C. et al. The IRF5–TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share. Hum. Mol. Genet. 24, 582–596 (2015).

    Article  CAS  PubMed  Google Scholar 

  127. Lee, M. N. et al. Common genetic variants modulate pathogen-sensing responses in human dendritic cells. Science 343, 1246980 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Pelikan, R. C. et al. Enhancer histone-QTLs are enriched on autoimmune risk haplotypes and influence gene expression within chromatin networks. Nat. Commun. 9, 2905 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Lu, X. et al. Lupus risk variant increases pSTAT1 binding and decreases ETS1 expression. Am. J. Hum. Genet. 96, 731–739 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Westra, H. J. et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat. Genet. 45, 1238–1243 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Mayadas, T. N., Tsokos, G. C. & Tsuboi, N. Mechanisms of immune complex–mediated neutrophil recruitment and tissue injury. Circulation 120, 2012–2024 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Liszewski, M. K., Java, A., Schramm, E. C. & Atkinson, J. P. Complement dysregulation and disease: insights from contemporary genetics. Annu. Rev. Pathol. 12, 25–52 (2017).

    Article  CAS  PubMed  Google Scholar 

  133. Yang, Y. et al. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am. J. Hum. Genet. 80, 1037–1054 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Deng, Y. & Tsao, B. P. Advances in lupus genetics and epigenetics. Curr. Opin. Rheumatol. 26, 482–492 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Zhao, J. et al. A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases. Nat. Genet. 49, 433–437 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Kim, K. et al. Variation in the ICAM1–ICAM4–ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries. Ann. Rheum. Dis. 71, 1809–1814 (2012).

    Article  CAS  PubMed  Google Scholar 

  137. Levine, B. & Kroemer, G. Biological functions of autophagy genes: a disease perspective. Cell 176, 11–42 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Wang, S., Wen, F., Wiley, G. B., Kinter, M. T. & Gaffney, P. M. An enhancer element harboring variants associated with systemic lupus erythematosus engages the TNFAIP3 promoter to influence A20 expression. PLoS Genet. 9, e1003750 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Vereecke, L., Beyaert, R. & van Loo, G. Genetic relationships between A20/TNFAIP3, chronic inflammation and autoimmune disease. Biochem. Soc. Trans. 39, 1086–1091 (2011).

    Article  CAS  PubMed  Google Scholar 

  140. Salmond, R. J., Brownlie, R. J., Morrison, V. L. & Zamoyska, R. The tyrosine phosphatase PTPN22 discriminates weak self peptides from strong agonist TCR signals. Nat. Immunol. 15, 875–883 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Molineros, J. E. et al. Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians. PLoS Genet. 15, e1008092 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Castillejo-López, C. et al. Genetic and physical interaction of the B-cell systemic lupus erythematosus-associated genes BANK1 and BLK. Ann. Rheum. Dis. 71, 136–142 (2012).

    Article  PubMed  CAS  Google Scholar 

  143. Chen, X. et al. An autoimmune disease variant of IgG1 modulates B cell activation and differentiation. Science 362, 700–705 (2018).

    Article  CAS  PubMed  Google Scholar 

  144. Freedman, B. I. et al. End-stage renal disease in African Americans with lupus nephritis is associated with APOL1. Arthritis Rheumatol. 66, 390–396 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Tang, Y. et al. MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins. Arthritis Rheum. 60, 1065–1075 (2009).

    Article  CAS  PubMed  Google Scholar 

  146. Zhao, X. et al. MicroRNA-125a contributes to elevated inflammatory chemokine RANTES levels via targeting KLF13 in systemic lupus erythematosus. Arthritis Rheum. 62, 3425–3435 (2010).

    Article  CAS  PubMed  Google Scholar 

  147. Thai, T. H. et al. Deletion of microRNA-155 reduces autoantibody responses and alleviates lupus-like disease in the Fas lpr mouse. Proc. Natl Acad. Sci. USA 110, 20194–20199 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Gonzalez-Martin, A. et al. The microRNA miR-148a functions as a critical regulator of B cell tolerance and autoimmunity. Nat. Immunol. 17, 433–440 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Zhu, S. et al. The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB2, TAB3 and IKK-α. Nat. Med. 18, 1077–1086 (2012).

    Article  CAS  PubMed  Google Scholar 

  150. Baumjohann, D. et al. The microRNA cluster miR-17~92 promotes TFH cell differentiation and represses subset-inappropriate gene expression. Nat. Immunol. 14, 840–848 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Kim, S. J., Gregersen, P. K. & Diamond, B. Regulation of dendritic cell activation by microRNA let-7c and BLIMP1. J. Clin. Invest. 123, 823–833 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Zhou, H. et al. miR-150 promotes renal fibrosis in lupus nephritis by downregulating SOCS1. J. Am. Soc. Nephrol. 24, 1073–1087 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

I thank my colleagues current and past who have helped me acquire a better understanding of this formidable disease known as lupus. I want to thank M. Tsokos for her support and feedback during the preparation of this report and N. Plummer for helping with the assembly of references. The work in my laboratory has been supported by the NIH.

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  1. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA

    George C. Tsokos

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Tsokos, G.C. Autoimmunity and organ damage in systemic lupus erythematosus. Nat Immunol 21, 605–614 (2020). https://doi.org/10.1038/s41590-020-0677-6

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