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  • Review Article
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Sequential immunotherapy: towards cures for autoimmunity

Abstract

Despite major progress in the treatment of autoimmune diseases in the past two decades, most therapies do not cure disease and can be associated with increased risk of infection through broad suppression of the immune system. However, advances in understanding the causes of autoimmune disease and clinical data from novel therapeutic modalities such as chimeric antigen receptor T cell therapies provide evidence that it may be possible to re-establish immune homeostasis and, potentially, prolong remission or even cure autoimmune diseases. Here, we propose a ‘sequential immunotherapy’ framework for immune system modulation to help achieve this ambitious goal. This framework encompasses three steps: controlling inflammation; resetting the immune system through elimination of pathogenic immune memory cells; and promoting and maintaining immune homeostasis via immune regulatory agents and tissue repair. We discuss existing drugs and those in development for each of the three steps. We also highlight the importance of causal human biology in identifying and prioritizing novel immunotherapeutic strategies as well as informing their application in specific patient subsets, enabling precision medicine approaches that have the potential to transform clinical care.

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Fig. 1: The sequential immunotherapy framework for immune modulation.
Fig. 2: CAR T cell approaches to resetting humoral immunity.
Fig. 3: Approaches to reset T cell memory and restore homeostasis.

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References

  1. Fugger, L., Jensen, L. T. & Rossjohn, J. Challenges, progress, and prospects of developing therapies to treat autoimmune diseases. Cell 181, 63–80 (2020).

    CAS  PubMed  Google Scholar 

  2. Melsheimer, R., Geldhof, A., Apaolaza, I. & Schaible, T. Remicade(®) (infliximab): 20 years of contributions to science and medicine. Biologics 13, 139–178 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Pisetsky, D. S. Pathogenesis of autoimmune disease. Nat. Rev. Nephrol. 19, 509–524 (2023).

    CAS  PubMed  Google Scholar 

  4. Confavreux, C., Hutchinson, M., Hours, M. M., Cortinovis-Tourniaire, P. & Moreau, T. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N. Engl. J. Med. 339, 285–291 (1998).

    CAS  PubMed  Google Scholar 

  5. Jethwa, H., Lam, S., Smith, C. & Giles, I. Does rheumatoid arthritis really improve during pregnancy? A systematic review and metaanalysis. J. Rheumatol. 46, 245–250 (2019).

    PubMed  Google Scholar 

  6. Siddiqui, S. et al. Paraneoplastic pemphigus as a presentation of acute myeloid leukemia: early diagnosis and remission. Hematol. Oncol. Stem Cell Ther. 10, 155–160 (2017).

    CAS  PubMed  Google Scholar 

  7. Siau, R. T., Morris, A. & Karoo, R. O. Surgery results in complete cure of Lambert–Eaton myasthenic syndrome in a patient with metastatic Merkel cell carcinoma. J. Plast. Reconstr. Aesthet. Surg. 67, e162–e164 (2014).

    PubMed  Google Scholar 

  8. Lin, C., Ying, Z. & Sijing, C. Spontaneous resolution of dermatomyositis associated with fallopian-tube carcinoma following staging surgery: a case report. Medicine 98, e14530 (2019).

    PubMed  PubMed Central  Google Scholar 

  9. Atkins, H. L. et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet 388, 576–585 (2016).

    PubMed  Google Scholar 

  10. Cohen, J. A. et al. Autologous hematopoietic cell transplantation for treatment-refractory relapsing multiple sclerosis: position statement from the American Society for Blood and Marrow Transplantation. Biol. Blood Marrow Transpl. 25, 845–854 (2019).

    Google Scholar 

  11. Sullivan, K. M. et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. N. Engl. J. Med. 378, 35–47 (2018).

    PubMed  PubMed Central  Google Scholar 

  12. Burt, R. K. et al. Nonmyeloablative hematopoietic stem cell transplantation for systemic lupus erythematosus. JAMA 295, 527–535 (2006).

    CAS  PubMed  Google Scholar 

  13. Goklemez, S. et al. Long-term follow-up after lymphodepleting autologous haematopoietic cell transplantation for treatment-resistant systemic lupus erythematosus. Rheumatology 61, 3317–3328 (2022).

    CAS  PubMed  Google Scholar 

  14. Snowden, J. A. et al. Autologous haematopoietic stem cell transplantation (aHSCT) for severe resistant autoimmune and inflammatory diseases—a guide for the generalist. Clin. Med. 18, 329–334 (2018).

    Google Scholar 

  15. Rickert, C. G. & Markmann, J. F. Current state of organ transplant tolerance. Curr. Opin. Organ. Transpl. 24, 441–450 (2019).

    CAS  Google Scholar 

  16. Benítez, C. et al. Prospective multicenter clinical trial of immunosuppressive drug withdrawal in stable adult liver transplant recipients. Hepatology 58, 1824–1835 (2013).

    PubMed  Google Scholar 

  17. Hillier, S. G. Diamonds are forever: the cortisone legacy. J. Endocrinol. 195, 1–6 (2007).

    CAS  PubMed  Google Scholar 

  18. Lai, Y. & Dong, C. Therapeutic antibodies that target inflammatory cytokines in autoimmune diseases. Int. Immunol. 28, 181–188 (2016).

    CAS  PubMed  Google Scholar 

  19. Lee, D. S. W., Rojas, O. L. & Gommerman, J. L. B cell depletion therapies in autoimmune disease: advances and mechanistic insights. Nat. Rev. Drug Discov. 20, 179–199 (2021).

    CAS  PubMed  Google Scholar 

  20. Wu, S., Xu, Y., Yang, L., Guo, L. & Jiang, X. Short-term risk and long-term incidence rate of infection and malignancy with IL-17 and IL-23 inhibitors in adult patients with psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Front. Immunol. 14, 1294416 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Gorman, J. A. et al. The TYK2-P1104A autoimmune protective variant limits coordinate signals required to generate specialized T cell subsets. Front. Immunol. 10, 44 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Minegishi, Y. et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 25, 745–755 (2006).

    CAS  PubMed  Google Scholar 

  23. Diogo, D. et al. TYK2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits. PLoS ONE 10, e0122271 (2015).

    PubMed  PubMed Central  Google Scholar 

  24. Dendrou, C. A. et al. Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity. Sci. Transl Med. 8, 363ra149 (2016).

    PubMed  PubMed Central  Google Scholar 

  25. Kerner, G. et al. Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry. Proc. Natl Acad. Sci. USA 116, 10430–10434 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Armstrong, A. W. et al. Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: efficacy and safety results from the 52-week, randomized, double-blinded, placebo-controlled phase 3 POETYK PSO-1 trial. J. Am. Acad. Dermatol. 88, 29–39 (2023).

    CAS  PubMed  Google Scholar 

  27. Strober, B. et al. Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: efficacy and safety results from the 52-week, randomized, double-blinded, phase 3 Program fOr Evaluation of TYK2 inhibitor psoriasis second trial. J. Am. Acad. Dermatol. 88, 40–51 (2023).

    CAS  PubMed  Google Scholar 

  28. Bristol-Myers Squibb. SOTYKTU (deucravacitinib). US Food and Drug Administration https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214958s000lbl.pdf (2022).

  29. Mease, P. J. et al. Efficacy and safety of selective TYK2 inhibitor, deucravacitinib, in a phase II trial in psoriatic arthritis. Ann. Rheum. Dis. 81, 815–822 (2022).

    CAS  PubMed  Google Scholar 

  30. Morand, E. et al. Deucravacitinib, a tyrosine kinase 2 inhibitor, in systemic lupus erythematosus: a phase II, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 75, 242–252 (2023).

    CAS  PubMed  Google Scholar 

  31. Elgueta, R. et al. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol. Rev. 229, 152–172 (2009).

    CAS  PubMed  Google Scholar 

  32. Marken, J., Muralidharan, S. & Giltiay, N. V. Anti-CD40 antibody KPL-404 inhibits T cell-mediated activation of B cells from healthy donors and autoimmune patients. Arthritis Res. Ther. 23, 5 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Raychaudhuri, S. et al. Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat. Genet. 40, 1216–1223 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Ishigaki, K. et al. Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases. Nat. Genet. 52, 669–679 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Boumpas, D. T. et al. A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum. 48, 719–727 (2003).

    CAS  PubMed  Google Scholar 

  37. Shock, A. et al. CDP7657, an anti-CD40L antibody lacking an Fc domain, inhibits CD40L-dependent immune responses without thrombotic complications: an in vivo study. Arthritis Res. Ther. 17, 234 (2015).

    PubMed  PubMed Central  Google Scholar 

  38. Furie, R. A. et al. Phase 2, randomized, placebo-controlled trial of dapirolizumab pegol in patients with moderate-to-severe active systemic lupus erythematosus. Rheumatology 60, 5397–5407 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Fisher, B. A. et al. Assessment of the anti-CD40 antibody iscalimab in patients with primary Sjögren’s syndrome: a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study. Lancet Rheumatol. 2, e142–e152 (2020).

    PubMed  Google Scholar 

  40. Kahaly, G. J. et al. A novel anti-CD40 monoclonal antibody, iscalimab, for control of Graves hyperthyroidism—a proof-of-concept trial. J. Clin. Endocrinol. Metab. 105, dgz013 (2020).

    PubMed  Google Scholar 

  41. Magnotti, F. et al. Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients. EMBO Mol. Med. 11, e10547 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Canna, S. W. et al. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat. Genet. 46, 1140–1146 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Romberg, N. et al. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat. Genet. 46, 1135–1139 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Canna, S. W. et al. Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition. J. Allergy Clin. Immunol. 139, 1698–1701 (2017).

    CAS  PubMed  Google Scholar 

  45. Mokry, L. E. et al. Interleukin-18 as a drug repositioning opportunity for inflammatory bowel disease: a Mendelian randomization study. Sci. Rep. 9, 9386 (2019).

    PubMed  PubMed Central  Google Scholar 

  46. Beck, D. B., Werner, A., Kastner, D. L. & Aksentijevich, I. Disorders of ubiquitylation: unchained inflammation. Nat. Rev. Rheumatol. 18, 435–447 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Yu, M. P., Xu, X. S., Zhou, Q., Deuitch, N. & Lu, M. P. Haploinsufficiency of A20 (HA20): updates on the genetics, phenotype, pathogenesis and treatment. World J. Pediatr. 16, 575–584 (2020).

    PubMed  Google Scholar 

  48. Ramos, P. S. et al. A comprehensive analysis of shared loci between systemic lupus erythematosus (SLE) and sixteen autoimmune diseases reveals limited genetic overlap. PLoS Genet. 7, e1002406 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Catrysse, L., Vereecke, L., Beyaert, R. & van Loo, G. A20 in inflammation and autoimmunity. Trends Immunol. 35, 22–31 (2014).

    CAS  PubMed  Google Scholar 

  50. Zhou, Q. et al. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat. Genet. 48, 67–73 (2016).

    CAS  PubMed  Google Scholar 

  51. Nititham, J. et al. Meta-analysis of the TNFAIP3 region in psoriasis reveals a risk haplotype that is distinct from other autoimmune diseases. Genes. Immun. 16, 120–126 (2015).

    CAS  PubMed  Google Scholar 

  52. Ovejero-Benito, M. C. et al. Polymorphisms associated with anti-TNF drugs response in patients with psoriasis and psoriatic arthritis. J. Eur. Acad. Dermatol. Venereol. 33, e175–e177 (2019).

    CAS  PubMed  Google Scholar 

  53. Tejasvi, T. et al. TNFAIP3 gene polymorphisms are associated with response to TNF blockade in psoriasis. J. Invest. Dermatol. 132, 593–600 (2012).

    CAS  PubMed  Google Scholar 

  54. Beck, D. B. et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N. Engl. J. Med. 383, 2628–2638 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Mastellos, D. C., Hajishengallis, G. & Lambris, J. D. A guide to complement biology, pathology and therapeutic opportunity. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-023-00926-1 (2023).

    Article  PubMed  Google Scholar 

  56. Apellis Pharmaceuticals. EMPAVELI (pegcetacoplan). US Food and Drug Administration https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215014s002lbl.pdf (2021).

  57. Apellis Pharmaceuticals. SOLIRIS (eculizumab). US Food and Drug Administration https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125166s431lbl.pdf (2007).

  58. Monach, P. A. Complement. Arthritis Rheumatol. https://doi.org/10.1002/art.42671 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Jang, J. H. et al. Iptacopan monotherapy in patients with paroxysmal nocturnal hemoglobinuria: a 2-cohort open-label proof-of-concept study. Blood Adv. 6, 4450–4460 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Schubart, A. et al. Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proc. Natl Acad. Sci. USA 116, 7926–7931 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Novartis. FABHALTA (iptacopan). US Food and Drug Administration https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/218276s000lbl.pdf (2023).

  62. Fahnoe, K. C. et al. Development and optimization of bifunctional fusion proteins to locally modulate complement activation in diseased tissue. Front. Immunol. 13, 869725 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Bafadhel, M. et al. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am. J. Respir. Crit. Care Med. 184, 662–671 (2011).

    PubMed  Google Scholar 

  64. Vogelmeier, C. F. et al. Goals of COPD treatment: focus on symptoms and exacerbations. Respir. Med. 166, 105938 (2020).

    PubMed  Google Scholar 

  65. Woodruff, P. G. et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am. J. Respir. Crit. Care Med. 180, 388–395 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Oishi, K., Matsunaga, K., Shirai, T., Hirai, K. & Gon, Y. Role of type 2 inflammatory biomarkers in chronic obstructive pulmonary disease. J. Clin. Med. 9, 2760 (2020).

    Google Scholar 

  67. Bhatt, S. P. et al. Dupilumab for COPD with type 2 inflammation indicated by eosinophil counts. N. Engl. J. Med. 389, 205–214 (2023).

    CAS  PubMed  Google Scholar 

  68. Regeneron Pharmaceuticals, Sanofi Aventis. DUPIXENT (dupilumab). US Food and Drug Administration https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761055s046lbl.pdf (2017).

  69. Sanofi. Press Release: Dupixent® sBLA accepted for FDA Priority Review for treatment of COPD with type 2 inflammation. sanofi https://www.sanofi.com/en/media-room/press-releases/2024/2024-02-23-06-00-00-2834219 (2024).

  70. Wenzel, S. et al. Dupilumab in persistent asthma with elevated eosinophil levels. N. Engl. J. Med. 368, 2455–2466 (2013).

    CAS  PubMed  Google Scholar 

  71. Feagan, B. G. et al. DOP87 The anti-TL1A antibody PRA023 demonstrated proof-of-concept in Crohn’s disease: phase 2a APOLLO-CD study results. J. Crohn’s Colitis 17, i162–i164 (2023).

    Google Scholar 

  72. Sands, B. et al. OP40 PRA023 demonstrated efficacy and favorable safety as induction therapy for moderately to severely active UC: phase 2 artemis-UC study results. J. Crohn’s Colitis 17, i56–i59 (2023).

    Google Scholar 

  73. Faustino, L. C. et al. Precision medicine in Graves’ disease: CD40 gene variants predict clinical response to an anti-CD40 monoclonal antibody. Front. Endocrinol. 12, 691781 (2021).

    Google Scholar 

  74. Kato, Y. et al. Apoptosis-derived membrane vesicles drive the cGAS–STING pathway and enhance type I IFN production in systemic lupus erythematosus. Ann. Rheum. Dis. 77, 1507–1515 (2018).

    CAS  PubMed  Google Scholar 

  75. An, J. et al. Expression of cyclic GMP-AMP synthase in patients with systemic lupus erythematosus. Arthritis Rheumatol. 69, 800–807 (2017).

    CAS  PubMed  Google Scholar 

  76. Perrigoue, J. et al. P328 In silico evaluation and pre-clinical efficacy of anti-TNF and anti-IL-23 combination therapy in inflammatory bowel disease. J. Crohn’s Colitis 16, i348 (2022).

    Google Scholar 

  77. Feagan, B. G. et al. Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trial. Lancet Gastroenterol. Hepatol. 8, 307–320 (2023).

    PubMed  Google Scholar 

  78. Plenge, R. M. Disciplined approach to drug discovery and early development. Sci. Transl Med. 8, 349ps315 (2016).

    Google Scholar 

  79. van Gisbergen, K., Zens, K. D. & Münz, C. T-cell memory in tissues. Eur. J. Immunol. 51, 1310–1324 (2021).

    PubMed  Google Scholar 

  80. Maschmeyer, P. et al. Immunological memory in rheumatic inflammation—a roadblock to tolerance induction. Nat. Rev. Rheumatol. 17, 291–305 (2021).

    CAS  PubMed  Google Scholar 

  81. Jokinen, S., Osterlund, P., Julkunen, I. & Davidkin, I. Cellular immunity to mumps virus in young adults 21 years after measles–mumps–rubella vaccination. J. Infect. Dis. 196, 861–867 (2007).

    CAS  PubMed  Google Scholar 

  82. Casado, J. L. et al. Progressive and parallel decline of humoral and T-cell immunity in convalescent healthcare workers with asymptomatic or mild-to-moderate severe ecute respiratory syndrome coronavirus 2 infection. J. Infect. Dis. 224, 241–245 (2021).

    CAS  PubMed  Google Scholar 

  83. Lee, W. S. & Amengual, O. B cells targeting therapy in the management of systemic lupus erythematosus. Immunol. Med. 43, 16–35 (2020).

    PubMed  Google Scholar 

  84. Genentech. RITUXAN (rituximab). US Food and Drug Administration https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103705s5367s5388lbl.pdf (1997).

  85. Sans-Pola, C. et al. Off-label use of rituximab in patients with systemic lupus erythematosus with extrarenal disease activity: a retrospective study and literature review. Front. Med. 10, 1159794 (2023).

    Google Scholar 

  86. Genentech. OCREVUS (ocrelizumab). US Food and Drug Administration https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761053s012lbl.pdf (2017).

  87. Novartis. KESIMPTA (ofatumumab). US Food and Drug Administration https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125326s080lbl.pdf (2009).

  88. Mysler, E. F. et al. Efficacy and safety of ocrelizumab in active proliferative lupus nephritis: results from a randomized, double-blind, phase III study. Arthritis Rheum. 65, 2368–2379 (2013).

    CAS  PubMed  Google Scholar 

  89. Merrill, J. T. et al. Obexelimab in systemic lupus erythematosus with exploration of response based on gene pathway co-expression patterns: a double-blind, randomized, placebo-controlled, phase 2 trial. Arthritis Rheumatol.  75, 2185–2194 (2023).

    CAS  PubMed  Google Scholar 

  90. Clowse, M. E. et al. Efficacy and safety of epratuzumab in moderately to severely active systemic lupus erythematosus: results from two phase III randomized, double-blind, placebo-controlled trials. Arthritis Rheumatol. 69, 362–375 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Ramwadhdoebe, T. H. et al. Effect of rituximab treatment on T and B cell subsets in lymph node biopsies of patients with rheumatoid arthritis. Rheumatology 58, 1075–1085 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Kamburova, E. G. et al. A single dose of rituximab does not deplete B cells in secondary lymphoid organs but alters phenotype and function. Am. J. Transpl. 13, 1503–1511 (2013).

    CAS  Google Scholar 

  93. Mougiakakos, D. et al. CD19-targeted CAR T cells in refractory systemic lupus erythematosus. N. Engl. J. Med. 385, 567–569 (2021).

    PubMed  Google Scholar 

  94. Mackensen, A. et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat. Med. 28, 2124–2132 (2022).

    CAS  PubMed  Google Scholar 

  95. Pecher, A. C. et al. CD19-targeting CAR T cells for myositis and interstitial lung disease associated with antisynthetase syndrome. JAMA 329, 2154–2162 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Schett, G., Mackensen, A. & Mougiakakos, D. CAR T-cell therapy in autoimmune diseases. Lancet 402, 2034–2044 (2023).

    CAS  PubMed  Google Scholar 

  97. Müller, F. et al. CD19 CAR T-cell therapy in autoimmune disease—a case series with follow-up. N. Engl. J. Med. 390, 687–700 (2024).

    PubMed  Google Scholar 

  98. Haghikia, A. et al. Anti-CD19 CAR T cells for refractory myasthenia gravis. Lancet Neurol. 22, 1104–1105 (2023).

    CAS  PubMed  Google Scholar 

  99. Golay, J., Andrea, A. E. & Cattaneo, I. Role of Fc core fucosylation in the effector function of IgG1 antibodies. Front. Immunol. 13, 929895 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Tapia-Galisteo, A., Álvarez-Vallina, L. & Sanz, L. Bi- and trispecific immune cell engagers for immunotherapy of hematological malignancies. J. Hematol. Oncol. 16, 83 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT06041568 (2024).

  102. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT06087406 (2024).

  103. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05155345 (2024).

  104. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05198557 (2023).

  105. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04524273 (2024).

  106. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT06193889 (2024).

  107. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT06152172 (2024).

  108. GlaxoSmithKline. BENLYSTA (belimumab). US Food and Drug Administration https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125370s082,761043s028lbl.pdf (2011).

  109. Davidson, A. The rationale for BAFF inhibition in systemic lupus erythematosus. Curr. Rheumatol. Rep. 14, 295–302 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Levy, R. A. et al. 10 years of belimumab experience: what have we learnt? Lupus 30, 1705–1721 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Bowman, S. J. et al. Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with primary Sjögren’s syndrome: a randomised, double-blind, placebo-controlled, phase 2b dose-finding trial. Lancet 399, 161–171 (2022).

    CAS  PubMed  Google Scholar 

  112. Shen, N. et al. Phase 2 safety and efficacy of subcutaneous (s.c.) dose ianalumab (VAY736; anti-BAFFR mAb) administered monthly over 28 weeks in patients with systemic lupus erythematosus (SLE) of moderate-to-severe activity [abstract]. Arthritis Rheumatol. 75 (Suppl. 9), 2487 (2023).

    Google Scholar 

  113. Ringheim, G. E., Wampole, M. & Oberoi, K. Bruton’s tyrosine kinase (BTK) inhibitors and autoimmune diseases: making sense of BTK inhibitor specificity profiles and recent clinical trial successes and failures. Front. Immunol. 12, 662223 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Wu, D. et al. Telitacicept in patients with active systemic lupus erythematosus: results of a phase 2b, randomised, double-blind, placebo-controlled trial. Ann. Rheum. Dis. https://doi.org/10.1136/ard-2023-224854 (2023).

    Article  PubMed  Google Scholar 

  115. Cheng, Q. et al. CXCR4–CXCL12 interaction is important for plasma cell homing and survival in NZB/W mice. Eur. J. Immunol. 48, 1020–1029 (2018).

    CAS  PubMed  Google Scholar 

  116. Takeda Pharmaceuticals. VELCADE (bortezomib). US Food and Drug Administration https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021602s046lbl.pdf (2003).

  117. Obeng, E. A. et al. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 107, 4907–4916 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Pasquale, R., Giannotta, J. A., Barcellini, W. & Fattizzo, B. Bortezomib in autoimmune hemolytic anemia and beyond. Ther. Adv. Hematol. 12, 20406207211046428 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Ostendorf, L. et al. Targeting CD38 with daratumumab in refractory systemic lupus erythematosus. N. Engl. J. Med. 383, 1149–1155 (2020).

    CAS  PubMed  Google Scholar 

  120. Pleguezuelo, D. E. et al. Case report: Resetting the humoral immune response by targeting plasma cells with daratumumab in anti-phospholipid syndrome. Front. Immunol. 12, 667515 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Janssen Biotech. DARZALEX (daratumumab). US Food and Drug Administration https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761145s002lbl.pdf (2020).

  122. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT04146051 (2024).

  123. Zhang, W. et al. Treatment of systemic lupus erythematosus using BCMA–CD19 compound CAR. Stem Cell Rev. Rep. 17, 2120–2123 (2021).

    PubMed  PubMed Central  Google Scholar 

  124. Ellebrecht, C. T. et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 353, 179–184 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Chang, D. J. et al. A phase 1 trial of targeted DSG3-CAART cell therapy in mucosal-dominant pemphigus vulgaris (mPV) patients: early cohort data. Mol. Ther. 30, 373 (2022).

    Google Scholar 

  126. Oh, S. et al. Precision targeting of autoantigen-specific B cells in muscle-specific tyrosine kinase myasthenia gravis with chimeric autoantibody receptor T cells. Nat. Biotechnol. 41, 1229–1238 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Reincke, S. M. et al. Chimeric autoantibody receptor T cells deplete NMDA receptor-specific B cells. Cell 186, 5084–5097 (2023).

    CAS  PubMed  Google Scholar 

  128. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT05451212 (2023).

  129. Pickens, C. J. et al. Antigen–drug conjugates as a novel therapeutic class for the treatment of antigen-specific autoimmune disorders. Mol. Pharm. 16, 2452–2461 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Cavalié, M. et al. Maintenance therapy of adult vitiligo with 0.1% tacrolimus ointment: a randomized, double blind, placebo-controlled study. J. Invest. Dermatol. 135, 970–974 (2015).

    PubMed  Google Scholar 

  131. Harris, J. E. et al. Rapid skin repigmentation on oral ruxolitinib in a patient with coexistent vitiligo and alopecia areata (AA). J. Am. Acad. Dermatol. 74, 370–371 (2016).

    PubMed  Google Scholar 

  132. Azzolino, V. et al. Jak inhibitors reverse vitiligo in mice but do not deplete skin resident memory T cells. J. Invest. Dermatol. 141, 182–184 (2021).

    CAS  PubMed  Google Scholar 

  133. Cheuk, S. et al. Epidermal TH22 and Tc17 cells form a localized disease memory in clinically healed psoriasis. J. Immunol. 192, 3111–3120 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Zundler, S. et al. Hobit- and blimp-1-driven CD4+ tissue-resident memory T cells control chronic intestinal inflammation. Nat. Immunol. 20, 288–300 (2019).

    CAS  PubMed  Google Scholar 

  135. Richmond, J. M. et al. Resident memory and recirculating memory T cells cooperate to maintain disease in a mouse model of vitiligo. J. Invest. Dermatol. 139, 769–778 (2019).

    CAS  PubMed  Google Scholar 

  136. Astellas Pharma US, Inc. AMEVIVE (alefacept). US Food and Drug Administration https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125036s0144lbl.pdf (2003).

  137. Ellis, C. N. & Krueger, G. G. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N. Engl. J. Med. 345, 248–255 (2001).

    CAS  PubMed  Google Scholar 

  138. Chamian, F. et al. Alefacept (anti-CD2) causes a selective reduction in circulating effector memory T cells (TEM) and relative preservation of central memory T cells (TCM) in psoriasis. J. Transl Med. 5, 27 (2007).

    PubMed  PubMed Central  Google Scholar 

  139. Rigby, M. R. et al. Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Diabetes Endocrinol. 1, 284–294 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Maeda, Y. et al. Depletion of central memory CD8+ T cells might impede the antitumor therapeutic effect of mogamulizumab. Nat. Commun. 12, 7280 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Cepek, K. L. et al. Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the αEβ7 integrin. Nature 372, 190–193 (1994).

    CAS  PubMed  Google Scholar 

  142. Hadley, G. A., Bartlett, S. T., Via, C. S., Rostapshova, E. A. & Moainie, S. The epithelial cell-specific integrin, CD103 (αE integrin), defines a novel subset of alloreactive CD8+ CTL. J. Immunol. 159, 3748–3756 (1997).

    CAS  PubMed  Google Scholar 

  143. Zhang, L. et al. An anti-CD103 immunotoxin promotes long-term survival of pancreatic islet allografts. Am. J. Transpl. 9, 2012–2023 (2009).

    CAS  Google Scholar 

  144. Xue, D., Liu, P., Chen, W., Zhang, C. & Zhang, L. An anti-CD103 antibody–drug conjugate prolongs the survival of pancreatic islet allografts in mice. Cell Death Dis. 10, 735 (2019).

    PubMed  PubMed Central  Google Scholar 

  145. Schluns, K. S. & Lefrançois, L. Cytokine control of memory T-cell development and survival. Nat. Rev. Immunol. 3, 269–279 (2003).

    CAS  PubMed  Google Scholar 

  146. Herold, K. C. et al. Immunomodulatory activity of humanized anti-IL-7R monoclonal antibody RN168 in subjects with type 1 diabetes. JCI Insight 4, e126054 (2019).

    PubMed  PubMed Central  Google Scholar 

  147. Ryan, G. E., Harris, J. E. & Richmond, J. M. Resident memory T cells in autoimmune skin diseases. Front. Immunol. 12, 652191 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Richmond, J. M. et al. Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo. Sci Transl Med 10, eaam7710 (2018).

    PubMed  PubMed Central  Google Scholar 

  149. Cellier, C. et al. Safety and efficacy of AMG 714 in patients with type 2 refractory coeliac disease: a phase 2a, randomised, double-blind, placebo-controlled, parallel-group study. Lancet Gastroenterol. Hepatol. 4, 960–970 (2019).

    PubMed  Google Scholar 

  150. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04338581 (2024).

  151. Mackay, L. K. et al. Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes. Science 352, 459–463 (2016).

    CAS  PubMed  Google Scholar 

  152. Laidlaw, B. J., Gray, E. E., Zhang, Y., Ramírez-Valle, F. & Cyster, J. G. Sphingosine-1-phosphate receptor 2 restrains egress of γδ T cells from the skin. J. Exp. Med. 216, 1487–1496 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Cyster, J. G. & Allen, C. D. C. B cell responses: cell interaction dynamics and decisions. Cell 177, 524–540 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Vincent, B. G. et al. Toxin-coupled MHC class I tetramers can specifically ablate autoreactive CD8+ T cells and delay diabetes in nonobese diabetic mice. J. Immunol. 184, 4196–4204 (2010).

    CAS  PubMed  Google Scholar 

  155. Goldberg, S. D. et al. A strategy for selective deletion of autoimmunity-related T cells by pMHC-targeted delivery. Pharmaceutics 13, 1669 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Fishman, S. et al. Adoptive transfer of mRNA-transfected T cells redirected against diabetogenic CD8 T cells can prevent diabetes. Mol. Ther. 25, 456–464 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Britanova, O. V. et al. Targeted depletion of TRBV9+ T cells as immunotherapy in a patient with ankylosing spondylitis. Nat. Med. https://doi.org/10.1038/s41591-023-02613-z (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Komech, E. A. et al. CD8+ T cells with characteristic T cell receptor β motif are detected in blood and expanded in synovial fluid of ankylosing spondylitis patients. Rheumatology 57, 1097–1104 (2018).

    CAS  PubMed  Google Scholar 

  159. Faham, M. et al. Discovery of T cell receptor β motifs specific to HLA-B27-positive ankylosing spondylitis by deep repertoire sequence analysis. Arthritis Rheumatol. 69, 774–784 (2017).

    CAS  PubMed  Google Scholar 

  160. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05445076 (2023).

  161. Bouneaud, C., Kourilsky, P. & Bousso, P. Impact of negative selection on the T cell repertoire reactive to a self-peptide: a large fraction of T cell clones escapes clonal deletion. Immunity 13, 829–840 (2000).

    CAS  PubMed  Google Scholar 

  162. Danke, N. A., Koelle, D. M., Yee, C., Beheray, S. & Kwok, W. W. Autoreactive T cells in healthy individuals. J. Immunol. 172, 5967–5972 (2004).

    CAS  PubMed  Google Scholar 

  163. Przybyla, A. et al. Natural T cell autoreactivity to melanoma antigens: clonally expanded melanoma-antigen specific CD8+ memory T cells can be detected in healthy humans. Cancer Immunol. Immunother. 68, 709–720 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Gorelik, L. & Flavell, R. A. Abrogation of TGFβ signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12, 171–181 (2000).

    CAS  PubMed  Google Scholar 

  165. ElTanbouly, M. A. et al. VISTA is a checkpoint regulator for naïve T cell quiescence and peripheral tolerance. Science 367, eaay0524 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Appleman, L. J. & Boussiotis, V. A. T cell anergy and costimulation. Immunol. Rev. 192, 161–180 (2003).

    CAS  PubMed  Google Scholar 

  167. Vanhove, B. et al. Antagonist anti-CD28 therapeutics for the treatment of autoimmune disorders. Antibodies (Basel) 6, 19 (2017).

    PubMed  Google Scholar 

  168. Gimmi, C. D., Freeman, G. J., Gribben, J. G., Gray, G. & Nadler, L. M. Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation. Proc. Natl Acad. Sci. USA 90, 6586–6590 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Linsley, P. S. et al. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science 257, 792–795 (1992).

    CAS  PubMed  Google Scholar 

  170. Bristol Myers Squibb. ORENCIA (abatacept). US Food and Drug Administration https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125118s249lbl.pdf (2005).

  171. Bristol Myers Squibb. NULOJIX (belatacept). US Food and Drug Administration https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125554s128lbl.pdf (2014).

  172. Rochman, Y., Yukawa, M., Kartashov, A. V. & Barski, A. Functional characterization of human T cell hyporesponsiveness induced by CTLA4-Ig. PLoS ONE 10, e0122198 (2015).

    PubMed  PubMed Central  Google Scholar 

  173. Judge, T. A. et al. The in vivo mechanism of action of CTLA4Ig. J. Immunol. 156, 2294–2299 (1996).

    CAS  PubMed  Google Scholar 

  174. Guinan, E. C. et al. Transplantation of anergic histoincompatible bone marrow allografts. N. Engl. J. Med. 340, 1704–1714 (1999).

    CAS  PubMed  Google Scholar 

  175. Cope, A. P. et al. Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial. Lancet 403, 838–849 (2024).

    CAS  PubMed  Google Scholar 

  176. Rech, J. et al. Abatacept inhibits inflammation and onset of rheumatoid arthritis in individuals at high risk (ARIAA): a randomised, international, multicentre, double-blind, placebo-controlled trial. Lancet 403, 850–859 (2024).

    CAS  PubMed  Google Scholar 

  177. Moskophidis, D., Lechner, F., Pircher, H. & Zinkernagel, R. M. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 362, 758–761 (1993).

    CAS  PubMed  Google Scholar 

  178. Budimir, N., Thomas, G. D., Dolina, J. S. & Salek-Ardakani, S. Reversing T-cell exhaustion in cancer: lessons learned from PD-1/PD-L1 immune checkpoint blockade. Cancer Immunol. Res. 10, 146–153 (2022).

    CAS  PubMed  Google Scholar 

  179. Zhang, Z. et al. T cell dysfunction and exhaustion in cancer. Front. Cell Dev. Biol. 8, 17 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Wiedeman, A. E. et al. Autoreactive CD8+ T cell exhaustion distinguishes subjects with slow type 1 diabetes progression. J. Clin. Invest. 130, 480–490 (2020).

    CAS  PubMed  Google Scholar 

  182. Sims, E. K. et al. Teplizumab improves and stabilizes β cell function in antibody-positive high-risk individuals. Sci Transl Med 13, eabc8980 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Tuttle, J. et al. A phase 2 trial of peresolimab for adults with rheumatoid arthritis. N. Engl. J. Med. 388, 1853–1862 (2023).

    CAS  PubMed  Google Scholar 

  184. Angin, M., Brignone, C. & Triebel, F. A LAG-3-specific agonist antibody for the treatment of T cell-induced autoimmune diseases. J. Immunol. 204, 810–818 (2020).

    CAS  PubMed  Google Scholar 

  185. Ehst, B. et al. 89 A phase 2b, randomized, double-blind, placebo-controlled, global study to evaluate the efficacy and safety of ANB032 in the treatment of moderate-to-severe atopic dermatitis. J. Invest. Dermatol. https://doi.org/10.1016/j.jid.2023.09.097 (2023).

  186. Michelson, D. A., Hase, K., Kaisho, T., Benoist, C. & Mathis, D. Thymic epithelial cells co-opt lineage-defining transcription factors to eliminate autoreactive T cells. Cell 185, 2542–2558 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Xu, X. et al. Splenic stroma-educated regulatory dendritic cells induce apoptosis of activated CD4 T cells via Fas ligand-enhanced IFN-γ and nitric oxide. J. Immunol. 188, 1168–1177 (2012).

    CAS  PubMed  Google Scholar 

  188. Iberg, C. A. & Hawiger, D. Natural and induced tolerogenic dendritic cells. J. Immunol. 204, 733–744 (2020).

    CAS  PubMed  Google Scholar 

  189. Cifuentes-Rius, A., Desai, A., Yuen, D., Johnston, A. P. R. & Voelcker, N. H. Inducing immune tolerance with dendritic cell-targeting nanomedicines. Nat. Nanotechnol. 16, 37–46 (2021).

    CAS  PubMed  Google Scholar 

  190. Akagbosu, B. et al. Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota. Nature 610, 752–760 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Kedmi, R. et al. A RORγt+ cell instructs gut microbiota-specific Treg cell differentiation. Nature 610, 737–743 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Lyu, M. et al. ILC3s select microbiota-specific regulatory T cells to establish tolerance in the gut. Nature 610, 744–751 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Krienke, C. et al. A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis. Science 371, 145–153 (2021).

    CAS  PubMed  Google Scholar 

  194. Tremain, A. C. et al. Synthetically glycosylated antigens for the antigen-specific suppression of established immune responses. Nat. Biomed. Eng. 7, 1142–1155 (2023).

    CAS  PubMed  Google Scholar 

  195. Benne, N., Ter Braake, D., Stoppelenburg, A. J. & Broere, F. Nanoparticles for inducing antigen-specific T cell tolerance in autoimmune diseases. Front. Immunol. 13, 864403 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Kelly, C. P. et al. TAK-101 nanoparticles induce gluten-specific tolerance in celiac disease: a randomized, double-blind, placebo-controlled study. Gastroenterology 161, 66–80.e8 (2021).

    CAS  PubMed  Google Scholar 

  197. Murray, J. A. et al. Safety and tolerability of KAN-101, a liver-targeted immune tolerance therapy, in patients with coeliac disease (ACeD): a phase 1 trial. Lancet Gastroenterol. Hepatol. 8, 735–747 (2023).

    PubMed  Google Scholar 

  198. Kenison, J. E. et al. Tolerogenic nanoparticles suppress central nervous system inflammation. Proc. Natl Acad. Sci. USA 117, 32017–32028 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Sands, E. et al. Tolerogenic nanoparticles mitigate the formation of anti-drug antibodies against pegylated uricase in patients with hyperuricemia. Nat. Commun. 13, 272 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Arend, W. P. & Firestein, G. S. Pre-rheumatoid arthritis: predisposition and transition to clinical synovitis. Nat. Rev. Rheumatol. 8, 573–586 (2012).

    CAS  PubMed  Google Scholar 

  201. Curran, A. M., Naik, P., Giles, J. T. & Darrah, E. PAD enzymes in rheumatoid arthritis: pathogenic effectors and autoimmune targets. Nat. Rev. Rheumatol. 16, 301–315 (2020).

    CAS  PubMed  Google Scholar 

  202. Darrah, E. et al. Erosive rheumatoid arthritis is associated with antibodies that activate PAD4 by increasing calcium sensitivity. Sci. Transl Med. 5, 186ra165 (2013).

    Google Scholar 

  203. Volkov, M. et al. Evolution of anti-modified protein antibody responses can be driven by consecutive exposure to different post-translational modifications. Arthritis Res. Ther. 23, 298 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Willis, V. C. et al. N-α-Benzoyl-N5-(2-chloro-1-iminoethyl)-l-ornithine amide, a protein arginine deiminase inhibitor, reduces the severity of murine collagen-induced arthritis. J. Immunol. 186, 4396–4404 (2011).

    CAS  PubMed  Google Scholar 

  205. Willis, V. C. et al. Protein arginine deiminase 4 inhibition is sufficient for the amelioration of collagen-induced arthritis. Clin. Exp. Immunol. 188, 263–274 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Monahan, R. C. et al. Autoantibodies against specific post-translationally modified proteins are present in patients with lupus and associate with major neuropsychiatric manifestations. RMD Open 8, e002079 (2022).

    PubMed  PubMed Central  Google Scholar 

  207. James, E. A., Mallone, R., Kent, S. C. & DiLorenzo, T. P. T-cell epitopes and neo-epitopes in type 1 diabetes: a comprehensive update and reappraisal. Diabetes 69, 1311–1335 (2020).

    PubMed  PubMed Central  Google Scholar 

  208. Leffler, J. et al. A subset of patients with systemic lupus erythematosus fails to degrade DNA from multiple clinically relevant sources. Arthritis Res. Ther. 17, 205 (2015).

    PubMed  PubMed Central  Google Scholar 

  209. Omarjee, O. et al. Monogenic lupus: dissecting heterogeneity. Autoimmun. Rev. 18, 102361 (2019).

    CAS  PubMed  Google Scholar 

  210. Hartl, J. et al. Autoantibody-mediated impairment of DNASE1L3 activity in sporadic systemic lupus erythematosus. J. Exp. Med. 218, e20201138 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Papayannopoulos, V. Neutrophil extracellular traps in immunity and disease. Nat. Rev. Immunol. 18, 134–147 (2018).

    CAS  PubMed  Google Scholar 

  212. Wildin, R. S. et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 27, 18–20 (2001).

    CAS  PubMed  Google Scholar 

  213. Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20–21 (2001).

    CAS  PubMed  Google Scholar 

  214. Sakaguchi, S. et al. Regulatory T cells and human disease. Annu. Rev. Immunol. 38, 541–566 (2020).

    CAS  PubMed  Google Scholar 

  215. Bittner, S., Hehlgans, T. & Feuerer, M. Engineered Treg cells as putative therapeutics against inflammatory diseases and beyond. Trends Immunol. 44, 468–483 (2023).

    CAS  PubMed  Google Scholar 

  216. Whangbo, J. S., Antin, J. H. & Koreth, J. The role of regulatory T cells in graft-versus-host disease management. Expert. Rev. Hematol. 13, 141–154 (2020).

    CAS  PubMed  Google Scholar 

  217. Clinigen, Inc. PROLEUKIN (aldesleukin). US Food and Drug Administration https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/103293s51,54lbl.pdf (1992).

  218. Graßhoff, H. et al. Low-dose IL-2 therapy in autoimmune and rheumatic diseases. Front. Immunol. 12, 648408 (2021).

    PubMed  PubMed Central  Google Scholar 

  219. Lotze, M. T., Frana, L. W., Sharrow, S. O., Robb, R. J. & Rosenberg, S. A. In vivo administration of purified human interleukin 2. I. Half-life and immunologic effects of the Jurkat cell line-derived interleukin 2. J. Immunol. 134, 157–166 (1985).

    CAS  PubMed  Google Scholar 

  220. Dixit, N. et al. NKTR-358: a novel regulatory T-cell stimulator that selectively stimulates expansion and suppressive function of regulatory T cells for the treatment of autoimmune and inflammatory diseases. J. Transl Autoimmun. 4, 100103 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Khoryati, L. et al. An IL-2 mutein engineered to promote expansion of regulatory T cells arrests ongoing autoimmunity in mice. Sci. Immunol. 5, eaba5264 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Peterson, L. B. et al. A long-lived IL-2 mutein that selectively activates and expands regulatory T cells as a therapy for autoimmune disease. J. Autoimmun. 95, 1–14 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Fanton, C. et al. Selective expansion of regulatory T cells by NKTR-358 in healthy volunteers and patients with systemic lupus erythematosus. J. Transl Autoimmun. 5, 100152 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Raeber, M. E., Sahin, D., Karakus, U. & Boyman, O. A systematic review of interleukin-2-based immunotherapies in clinical trials for cancer and autoimmune diseases. EBioMedicine 90, 104539 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Lykhopiy, V., Malviya, V., Humblet-Baron, S. & Schlenner, S. M. IL-2 immunotherapy for targeting regulatory T cells in autoimmunity. Genes. Immun. 24, 248–262 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Ward, N. C. et al. Persistent IL-2 receptor signaling by IL-2/CD25 fusion protein controls diabetes in NOD mice by multiple mechanisms. Diabetes 69, 2400–2413 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. Xie, J. H. et al. Mouse IL-2/CD25 fusion protein induces regulatory T cell expansion and immune suppression in preclinical models of systemic lupus erythematosus. J. Immunol. 207, 34–43 (2021).

    CAS  PubMed  Google Scholar 

  228. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT04736134 (2024).

  229. McQuaid, S. L. et al. Low-dose IL-2 induces CD56bright NK regulation of T cells via NKp44 and NKp46. Clin. Exp. Immunol. 200, 228–241 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Amgen. Amgen reports first quarter financial results. AMGEN https://www.amgen.com/newsroom/press-releases/2023/04/amgen-reports-first-quarter-financial-results (2023).

  231. Skartsis, N., Ferreira, L. M. R. & Tang, Q. The dichotomous outcomes of TNFα signaling in CD4+ T cells. Front. Immunol. 13, 1042622 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Chopra, M. et al. Exogenous TNFR2 activation protects from acute GvHD via host Treg cell expansion. J. Exp. Med. 213, 1881–1900 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  233. Fischer, R. et al. Selective activation of tumor necrosis factor receptor II induces antiinflammatory responses and alleviates experimental arthritis. Arthritis Rheumatol. 70, 722–735 (2018).

    CAS  PubMed  Google Scholar 

  234. Torrey, H. et al. A novel TNFR2 agonist antibody expands highly potent regulatory T cells. Sci. Signal. 13, eaba9600 (2020).

    CAS  PubMed  Google Scholar 

  235. Zhao, X. et al. TNF signaling drives myeloid-derived suppressor cell accumulation. J. Clin. Invest. 122, 4094–4104 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Delacher, M. et al. Genome-wide DNA-methylation landscape defines specialization of regulatory T cells in tissues. Nat. Immunol. 18, 1160–1172 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. Schiering, C. et al. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature 513, 564–568 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. Vasanthakumar, A. et al. The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells. Nat. Immunol. 16, 276–285 (2015).

    CAS  PubMed  Google Scholar 

  239. Son, J. et al. Tumor-infiltrating regulatory T-cell accumulation in the tumor microenvironment is mediated by IL33/ST2 signaling. Cancer Immunol. Res. 8, 1393–1406 (2020).

    CAS  PubMed  Google Scholar 

  240. Bluestone, J. A. et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci. Transl Med. 7, 315ra189 (2015).

    PubMed  PubMed Central  Google Scholar 

  241. Tang, Q. et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J. Exp. Med. 199, 1455–1465 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  242. Huter, E. N., Stummvoll, G. H., DiPaolo, R. J., Glass, D. D. & Shevach, E. M. Cutting edge: antigen-specific TGFβ-induced regulatory T cells suppress TH17-mediated autoimmune disease. J. Immunol. 181, 8209–8213 (2008).

    CAS  PubMed  Google Scholar 

  243. Honaker, Y. et al. Gene editing to induce FOXP3 expression in human CD4+ T cells leads to a stable regulatory phenotype and function. Sci. Transl Med. 12, eaay6422 (2020).

    CAS  PubMed  Google Scholar 

  244. Boardman, D. A. et al. Expression of a chimeric antigen receptor specific for donor HLA class I enhances the potency of human regulatory T cells in preventing human skin transplant rejection. Am. J. Transpl. 17, 931–943 (2017).

    CAS  Google Scholar 

  245. Wagner, J. C., Ronin, E., Ho, P., Peng, Y. & Tang, Q. Anti-HLA-A2-CAR Tregs prolong vascularized mouse heterotopic heart allograft survival. Am. J. Transpl. 22, 2237–2245 (2022).

    CAS  Google Scholar 

  246. Muller, Y. D. et al. Precision engineering of an anti-HLA-A2 chimeric antigen receptor in regulatory T cells for transplant immune tolerance. Front. Immunol. 12, 686439 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  247. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT04817774 (2024).

  248. Kim, Y. C. et al. Engineered MBP-specific human Tregs ameliorate MOG-induced EAE through IL-2-triggered inhibition of effector T cells. J. Autoimmun. 92, 77–86 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  249. Spanier, J. A. et al. Tregs with an MHC class II peptide-specific chimeric antigen receptor prevent autoimmune diabetes in mice. J. Clin. Invest. 133, e168601 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  250. Uenishi, G. I. et al. GNTI-122: an autologous antigen-specific engineered Treg cell therapy for type 1 diabetes. JCI Insight 9, e171844 (2024).

    PubMed  PubMed Central  Google Scholar 

  251. Cook, P. J. et al. A chemically inducible IL-2 receptor signaling complex allows for effective in vitro and in vivo selection of engineered CD4+ T cells. Mol. Ther. 31, 2472–2488 (2023).

    CAS  PubMed  Google Scholar 

  252. Irvine, A. D., McLean, W. H. & Leung, D. Y. Filaggrin mutations associated with skin and allergic diseases. N. Engl. J. Med. 365, 1315–1327 (2011).

    CAS  PubMed  Google Scholar 

  253. Chavanas, S. et al. Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat. Genet. 25, 141–142 (2000).

    CAS  PubMed  Google Scholar 

  254. Liu, C. Y., Cham, C. M. & Chang, E. B. Epithelial wound healing in inflammatory bowel diseases: the next therapeutic frontier. Transl Res. 236, 35–51 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  255. Sanchez-Solares, J. et al. Celiac disease causes epithelial disruption and regulatory T cell recruitment in the oral mucosa. Front. Immunol. 12, 623805 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  256. Friščić, J. & Hoffmann, M. H. Stromal cell regulation of inflammatory responses. Curr. Opin. Immunol. 74, 92–99 (2022).

    PubMed  Google Scholar 

  257. Rieder, F., Fiocchi, C. & Rogler, G. Mechanisms, management, and treatment of fibrosis in patients with inflammatory bowel diseases. Gastroenterology 152, 340–350 (2017).

    PubMed  Google Scholar 

  258. Santacroce, G., Lenti, M. V. & Di Sabatino, A. Therapeutic targeting of intestinal fibrosis in Crohn’s disease. Cells 11, 429 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  259. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05843578 (2024).

  260. Ge, Y., Huang, M. & Yao, Y. M. Efferocytosis and its role in inflammatory disorders. Front. Cell Dev. Biol. 10, 839248 (2022).

    PubMed  PubMed Central  Google Scholar 

  261. Negreiros-Lima, G. L. et al. Cyclic AMP regulates key features of macrophages via PKA: recruitment, reprogramming and efferocytosis. Cells 9, 128 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  262. Kourtzelis, I. et al. DEL-1 promotes macrophage efferocytosis and clearance of inflammation. Nat. Immunol. 20, 40–49 (2019).

    CAS  PubMed  Google Scholar 

  263. Proto, J. D. et al. Regulatory T cells promote macrophage efferocytosis during inflammation resolution. Immunity 49, 666–677 (2018).

    CAS  PubMed  Google Scholar 

  264. Ye, K., Chen, Z. & Xu, Y. The double-edged functions of necroptosis. Cell Death Dis. 14, 163 (2023).

    PubMed  PubMed Central  Google Scholar 

  265. Dannappel, M. et al. RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 513, 90–94 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  266. Xu, J. et al. Epithelial Gab1 calibrates RIPK3-dependent necroptosis to prevent intestinal inflammation. JCI Insight 8, e162701 (2023).

    PubMed  PubMed Central  Google Scholar 

  267. Weisel, K. et al. A randomized, placebo-controlled experimental medicine study of RIPK1 inhibitor GSK2982772 in patients with moderate to severe rheumatoid arthritis. Arthritis Res. Ther. 23, 85 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  268. Weisel, K. et al. Response to inhibition of receptor-interacting protein kinase 1 (RIPK1) in active plaque psoriasis: a randomized placebo-controlled study. Clin. Pharmacol. Ther. 108, 808–816 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  269. Chang, E. H., Carnevale, D. & Chavan, S. S. Editorial: Understanding and targeting neuro-immune interactions within disease and inflammation. Front. Immunol. 14, 1201669 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  270. Oetjen, L. K. et al. Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Cell 171, 217–228 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  271. Kim, B. et al. Neuroimmune interplay during type 2 inflammation: symptoms, mechanisms and therapeutic targets in atopic diseases. J. Allergy Clin. Immunol. https://doi.org/10.1016/j.jaci.2023.08.017 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  272. Schneider, K. M. et al. The enteric nervous system relays psychological stress to intestinal inflammation. Cell 186, 2823–2838 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  273. Chu, C., Artis, D. & Chiu, I. M. Neuro-immune interactions in the tissues. Immunity 52, 464–474 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  274. Seillet, C. et al. The neuropeptide VIP confers anticipatory mucosal immunity by regulating ILC3 activity. Nat. Immunol. 21, 168–177 (2020).

    CAS  PubMed  Google Scholar 

  275. Picard, C. et al. International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee report on inborn errors of immunity. J. Clin. Immunol. 38, 96–128 (2018).

    PubMed  Google Scholar 

  276. Ouahed, J. et al. Very early onset inflammatory bowel disease: a clinical approach with a focus on the role of genetics and underlying immune deficiencies. Inflamm. Bowel Dis. 26, 820–842 (2020).

    PubMed  Google Scholar 

  277. Caliskan, M., Brown, C. D. & Maranville, J. C. A catalog of GWAS fine-mapping efforts in autoimmune disease. Am. J. Hum. Genet. 108, 549–563 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  278. Zheng, J. et al. Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases. Nat. Genet. 52, 1122–1131 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  279. Zhao, J. H. et al. Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets. Nat. Immunol. 24, 1540–1551 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  280. Sun, B. B. et al. Genomic atlas of the human plasma proteome. Nature 558, 73–79 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  281. Sun, B. B. et al. Plasma proteomic associations with genetics and health in the UK Biobank. Nature 622, 329–338 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  282. Rood, J. E., Maartens, A., Hupalowska, A., Teichmann, S. A. & Regev, A. Impact of the Human Cell Atlas on medicine. Nat. Med. 28, 2486–2496 (2022).

    CAS  PubMed  Google Scholar 

  283. Orrù, V. et al. Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. Nat. Genet. 52, 1036–1045 (2020).

    PubMed  PubMed Central  Google Scholar 

  284. Soskic, B. et al. Chromatin activity at GWAS loci identifies T cell states driving complex immune diseases. Nat. Genet. 51, 1486–1493 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  285. Jagadeesh, K. A. et al. Identifying disease-critical cell types and cellular processes by integrating single-cell RNA-sequencing and human genetics. Nat. Genet. 54, 1479–1492 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  286. Korsunsky, I. et al. Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases. Med 3, 481–518 (2022).

    CAS  PubMed  Google Scholar 

  287. Friedrich, M. et al. IL-1-driven stromal–neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies. Nat. Med. 27, 1970–1981 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  288. Cortez, J. T. et al. CRISPR screen in regulatory T cells reveals modulators of Foxp3. Nature 582, 416–420 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  289. Smits, J. P. H. et al. Investigations into the FLG null phenotype: showcasing the methodology for CRISPR/Cas9 editing of human keratinocytes. J. Invest. Dermatol. 143, 1520–1528 (2023).

    CAS  PubMed  Google Scholar 

  290. Han, B., Salituro, F. G. & Blanco, M. J. Impact of allosteric modulation in drug discovery: innovation in emerging chemical modalities. ACS Med. Chem. Lett. 11, 1810–1819 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  291. Depil, S., Duchateau, P., Grupp, S. A., Mufti, G. & Poirot, L. ‘Off-the-shelf’ allogeneic CAR T cells: development and challenges. Nat. Rev. Drug Discov. 19, 185–199 (2020).

    CAS  PubMed  Google Scholar 

  292. Aghajanian, H., Rurik, J. G. & Epstein, J. A. CAR-based therapies: opportunities for immuno-medicine beyond cancer. Nat. Metab. 4, 163–169 (2022).

    PubMed  PubMed Central  Google Scholar 

  293. Xin, T. et al. In-vivo induced CAR-T cell for the potential breakthrough to overcome the barriers of current CAR-T cell therapy. Front. Oncol. 12, 809754 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  294. Michels, A., Ho, N. & Buchholz, C. J. Precision medicine: in vivo CAR therapy as a showcase for receptor-targeted vector platforms. Mol. Ther. 30, 2401–2415 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  295. Műzes, G. & Sipos, F. CAR-based therapy for autoimmune diseases: a novel powerful option. Cells 12, 1534 (2023).

    PubMed  PubMed Central  Google Scholar 

  296. Rurik, J. G. et al. CAR T cells produced in vivo to treat cardiac injury. Science 375, 91–96 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  297. Takamura, S. Niches for the long-term maintenance of tissue-resident memory T cells. Front. Immunol. 9, 1214 (2018).

    PubMed  PubMed Central  Google Scholar 

  298. Yi, J. et al. Antigen-specific depletion of CD4+ T cells by CAR T cells reveals distinct roles of higher- and lower-affinity TCRs during autoimmunity. Sci. Immunol. 7, eabo0777 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  299. Rana, J. & Biswas, M. Regulatory T cell therapy: current and future design perspectives. Cell Immunol. 356, 104193 (2020).

    CAS  PubMed  Google Scholar 

  300. Riedhammer, C. & Weissert, R. Antigen presentation, autoantigens, and immune regulation in multiple sclerosis and other autoimmune diseases. Front. Immunol. 6, 322 (2015).

    PubMed  PubMed Central  Google Scholar 

  301. Herrada, A. A. et al. Innate immune cells’ contribution to systemic lupus erythematosus. Front. Immunol. 10, 772 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  302. Geremia, A., Biancheri, P., Allan, P., Corazza, G. R. & Di Sabatino, A. Innate and adaptive immunity in inflammatory bowel disease. Autoimmun. Rev. 13, 3–10 (2014).

    CAS  PubMed  Google Scholar 

  303. Liao, X., Reihl, A. M. & Luo, X. M. Breakdown of immune tolerance in systemic lupus erythematosus by dendritic cells. J. Immunol. Res. 2016, 6269157 (2016).

    PubMed  PubMed Central  Google Scholar 

  304. Al-Mayouf, S. M. et al. Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus. Nat. Genet. 43, 1186–1188 (2011).

    CAS  PubMed  Google Scholar 

  305. Namjou, B. et al. Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes. Immun. 12, 270–279 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  306. Van Eyck, L. et al. Brief Report: IFIH1 mutation causes systemic lupus erythematosus with selective IgA deficiency. Arthritis Rheumatol. 67, 1592–1597 (2015).

    PubMed  Google Scholar 

  307. Zhang, C., Wang, W., Zhang, H., Wei, L. & Guo, S. Association of FCGR2A rs1801274 polymorphism with susceptibility to autoimmune diseases: a meta-analysis. Oncotarget 7, 39436–39443 (2016).

    PubMed  PubMed Central  Google Scholar 

  308. Willcocks, L. C. et al. A defunctioning polymorphism in FCGR2B is associated with protection against malaria but susceptibility to systemic lupus erythematosus. Proc. Natl Acad. Sci. USA 107, 7881–7885 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  309. Graham, R. R. et al. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat. Genet. 40, 1059–1061 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  310. Sigurdsson, S. et al. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am. J. Hum. Genet. 76, 528–537 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  311. Fukata, M. & Arditi, M. The role of pattern recognition receptors in intestinal inflammation. Mucosal Immunol. 6, 451–463 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  312. Shimizu, M., Takei, S., Mori, M. & Yachie, A. Pathogenic roles and diagnostic utility of interleukin-18 in autoinflammatory diseases. Front. Immunol. 13, 951535 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  313. 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).

    PubMed  PubMed Central  Google Scholar 

  314. Yap, H. Y. et al. Pathogenic role of immune cells in rheumatoid arthritis: implications in clinical treatment and biomarker development. Cells 7, 161 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  315. Riding, R. L. & Harris, J. E. The role of memory CD8+ T cells in vitiligo. J. Immunol. 203, 11–19 (2019).

    CAS  PubMed  Google Scholar 

  316. Terziroli Beretta-Piccoli, B., Mieli-Vergani, G. & Vergani, D. Autoimmmune hepatitis. Cell Mol. Immunol. 19, 158–176 (2022).

    CAS  PubMed  Google Scholar 

  317. Bentham, J. et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat. Genet. 47, 1457–1464 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  318. Carr, E. J. et al. Contrasting genetic association of IL2RA with SLE and ANCA-associated vasculitis. BMC Med. Genet. 10, 22 (2009).

    PubMed  PubMed Central  Google Scholar 

  319. Humrich, J. Y. et al. Low-dose interleukin-2 therapy in active systemic lupus erythematosus (LUPIL-2): a multicentre, double-blind, randomised and placebo-controlled phase II trial. Ann. Rheum. Dis. 81, 1685–1694 (2022).

    CAS  PubMed  Google Scholar 

  320. Verstockt, B. et al. IL-12 and IL-23 pathway inhibition in inflammatory bowel disease. Nat. Rev. Gastroenterol. Hepatol. 20, 433–446 (2023).

    CAS  PubMed  Google Scholar 

  321. Dema, B. & Charles, N. Autoantibodies in SLE: specificities, isotypes and receptors. Antibodies (Basel) 5, 2 (2016).

    PubMed  Google Scholar 

  322. Wu, F. et al. B cells in rheumatoid arthritis: pathogenic mechanisms and treatment prospects. Front Immunol 12, 750753 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  323. Hofmann, K., Clauder, A. K. & Manz, R. A. Targeting B cells and plasma cells in autoimmune diseases. Front. Immunol. 9, 835 (2018).

    PubMed  PubMed Central  Google Scholar 

  324. Dam, E. M. et al. The BANK1 SLE-risk variants are associated with alterations in peripheral B cell signaling and development in humans. Clin. Immunol. 173, 171–180 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  325. Jiang, S. H. et al. Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus. Nat. Commun. 10, 2201 (2019).

    PubMed  PubMed Central  Google Scholar 

  326. Ciesielski, O. et al. Citrullination in the pathology of inflammatory and autoimmune disorders: recent advances and future perspectives. Cell Mol. Life Sci. 79, 94 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  327. Jonsson, M. K. et al. Peptidylarginine deiminase 4 (PAD4) activity in early rheumatoid arthritis. Scand. J. Rheumatol. 49, 87–95 (2020).

    CAS  PubMed  Google Scholar 

  328. Demoruelle, M. K. et al. Anti-peptidylarginine deiminase-4 antibodies at mucosal sites can activate peptidylarginine deiminase-4 enzyme activity in rheumatoid arthritis. Arthritis Res. Ther. 23, 163 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  329. Forsthuber, T. G., Cimbora, D. M., Ratchford, J. N., Katz, E. & Stüve, O. B cell-based therapies in CNS autoimmunity: differentiating CD19 and CD20 as therapeutic targets. Ther. Adv. Neurol. Disord. 11, 1756286418761697 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  330. Crickx, E., Weill, J. C., Reynaud, C. A. & Mahévas, M. Anti-CD20-mediated B-cell depletion in autoimmune diseases: successes, failures and future perspectives. Kidney Int. 97, 885–893 (2020).

    CAS  PubMed  Google Scholar 

  331. Klein, L., Kyewski, B., Allen, P. M. & Hogquist, K. A. Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see). Nat. Rev. Immunol. 14, 377–391 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  332. Knapp, B., van der Merwe, P. A., Dushek, O. & Deane, C. M. MHC binding affects the dynamics of different T-cell receptors in different ways. PLoS Comput. Biol. 15, e1007338 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  333. Waldman, A. D., Fritz, J. M. & Lenardo, M. J. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat. Rev. Immunol. 20, 651–668 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  334. Chung, H. K., McDonald, B. & Kaech, S. M. The architectural design of CD8+ T cell responses in acute and chronic infection: parallel structures with divergent fates. J. Exp. Med. 218, e20201730 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  335. Fowell, D. J. & Kim, M. The spatio-temporal control of effector T cell migration. Nat. Rev. Immunol. 21, 582–596 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  336. Liu, Q., Sun, Z. & Chen, L. Memory T cells: strategies for optimizing tumor immunotherapy. Protein Cell 11, 549–564 (2020).

    PubMed  PubMed Central  Google Scholar 

  337. Steinbach, K., Vincenti, I. & Merkler, D. Resident-memory T cells in tissue-restricted immune responses: for better or worse? Front. Immunol. 9, 2827 (2018).

    PubMed  PubMed Central  Google Scholar 

  338. Rao, D. A. et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 542, 110–114 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  339. Bocharnikov, A. V. et al. PD-1hiCXCR5 T peripheral helper cells promote B cell responses in lupus via MAF and IL-21. JCI Insight 4, e130062 (2019).

    PubMed  PubMed Central  Google Scholar 

  340. Huang, Y. et al. T peripheral helper cells in autoimmune diseases: what do we know? Front. Immunol. 14, 1145573 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  341. Marks, K. E. & Rao, D. A. T peripheral helper cells in autoimmune diseases. Immunol. Rev. 307, 191–202 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  342. Matos, T. R. et al. Clinically resolved psoriatic lesions contain psoriasis-specific IL-17-producing αβ T cell clones. J. Clin. Invest. 127, 4031–4041 (2017).

    PubMed  PubMed Central  Google Scholar 

  343. Chang, M. H. et al. Arthritis flares mediated by tissue-resident memory T cells in the joint. Cell Rep. 37, 109902 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  344. Grover, P., Goel, P. N. & Greene, M. I. Regulatory T cells: regulation of identity and function. Front. Immunol. 12, 750542 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  345. Xing, Y. & Hogquist, K. A. T-cell tolerance: central and peripheral. Cold Spring Harb. Perspect. Biol. 4, a006957 (2012).

    PubMed  PubMed Central  Google Scholar 

  346. Karim, M., Feng, G., Wood, K. J. & Bushell, A. R. CD25+CD4+ regulatory T cells generated by exposure to a model protein antigen prevent allograft rejection: antigen-specific reactivation in vivo is critical for bystander regulation. Blood 105, 4871–4877 (2005).

    CAS  PubMed  Google Scholar 

  347. Arpaia, N. et al. A distinct function of regulatory T cells in tissue protection. Cell 162, 1078–1089 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  348. Somineni, H. K. et al. Blood-derived DNA methylation signatures of Crohn’s disease and severity of intestinal inflammation. Gastroenterology 156, 2254–2265 (2019).

    CAS  PubMed  Google Scholar 

  349. Davies, N. M., Holmes, M. V. & Davey Smith, G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ 362, k601 (2018).

    PubMed  PubMed Central  Google Scholar 

  350. Nelson, M. R. et al. The support of human genetic evidence for approved drug indications. Nat. Genet. 47, 856–860 (2015).

    CAS  PubMed  Google Scholar 

  351. King, E. A., Davis, J. W. & Degner, J. F. Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval. PLoS Genet. 15, e1008489 (2019).

    PubMed  PubMed Central  Google Scholar 

  352. Plenge, R. M., Scolnick, E. M. & Altshuler, D. Validating therapeutic targets through human genetics. Nat. Rev. Drug Discov. 12, 581–594 (2013).

    CAS  PubMed  Google Scholar 

  353. Backman, J. D. et al. Exome sequencing and analysis of 454,787 UK Biobank participants. Nature 599, 628–634 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  354. Szustakowski, J. D. et al. Advancing human genetics research and drug discovery through exome sequencing of the UK Biobank. Nat. Genet. 53, 942–948 (2021).

    CAS  PubMed  Google Scholar 

  355. Minikel, E. V. et al. Evaluating drug targets through human loss-of-function genetic variation. Nature 581, 459–464 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  356. Bjornevik, K. et al. Longitudinal analysis reveals high prevalence of Epstein–Barr virus associated with multiple sclerosis. Science 375, 296–301 (2022).

    CAS  PubMed  Google Scholar 

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Ramírez-Valle, F., Maranville, J.C., Roy, S. et al. Sequential immunotherapy: towards cures for autoimmunity. Nat Rev Drug Discov 23, 501–524 (2024). https://doi.org/10.1038/s41573-024-00959-8

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