Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The ouroboros of autoimmunity

Nature Immunology volume 25, pages 743–754 (2024)Cite this article

Subjects

Abstract

Human autoimmunity against elements conferring protective immunity can be symbolized by the ‘ouroboros’, a snake eating its own tail. Underlying infection is autoimmunity against three immunological targets: neutrophils, complement and cytokines. Autoantibodies against neutrophils can cause peripheral neutropenia underlying mild pyogenic bacterial infections. The pathogenic contribution of autoantibodies against molecules of the complement system is often unclear, but autoantibodies specific for C3 convertase can enhance its activity, lowering complement levels and underlying severe bacterial infections. Autoantibodies neutralizing granulocyte–macrophage colony-stimulating factor impair alveolar macrophages, thereby underlying pulmonary proteinosis and airborne infections, type I interferon viral diseases, type II interferon intra-macrophagic infections, interleukin-6 pyogenic bacterial diseases and interleukin-17A/F mucocutaneous candidiasis. Each of these five cytokine autoantibodies underlies a specific range of infectious diseases, phenocopying infections that occur in patients with the corresponding inborn errors. In this Review, we analyze this ouroboros of immunity against immunity and posit that it should be considered as a factor in patients with unexplained infection.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The ouroboros of autoimmunity to components conferring protective immunity.

Similar content being viewed by others

References

  1. Liblau, R. S., Wong, F. S., Mars, L. T. & Santamaria, P. Autoreactive CD8 T cells in organ-specific autoimmunity: emerging targets for therapeutic intervention. Immunity 17, 1–6 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Sciascia, S. et al. Autoantibodies testing in autoimmunity: diagnostic, prognostic and classification value. Autoimmun. Rev. 22, 103356 (2023).

    Article  CAS  PubMed  Google Scholar 

  3. Wang, L., Wang, F. S. & Gershwin, M. E. Human autoimmune diseases: a comprehensive update. J. Intern. Med. 278, 369–395 (2015).

    Article  CAS  PubMed  Google Scholar 

  4. Gershwin, M. E. & Tsokas, G. The Autoimmune Diseases (Academic Press, 2019).

  5. Price, J. V. et al. Protein microarray analysis reveals BAFF-binding autoantibodies in systemic lupus erythematosus. J. Clin. Invest. 123, 5135–5145 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ilonen, J., Lempainen, J. & Veijola, R. The heterogeneous pathogenesis of type 1 diabetes mellitus. Nat. Rev. Endocrinol. 15, 635–650 (2019).

    Article  CAS  PubMed  Google Scholar 

  7. Berentsen, S. & Barcellini, W. Autoimmune hemolytic anemias. N. Engl. J. Med. 385, 1407–1419 (2021).

    Article  CAS  PubMed  Google Scholar 

  8. Xiao, Y., Zhao, S. & Li, B. Aplastic anemia is related to alterations in T cell receptor signaling. Stem Cell Investig. 4, 85 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Wang, L. & Liu, H. Pathogenesis of aplastic anemia. Hematology 24, 559–566 (2019).

    Article  PubMed  Google Scholar 

  10. Casanova, J.-L. & Abel, L. From rare disorders of immunity to common determinants of infection: following the mechanistic thread. Cell 185, 3086–3103 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Casanova, J.-L. From second thoughts on the germ theory to a full-blown host theory. Proc. Natl Acad. Sci. USA 120, e2301186120 (2003).

    Article  Google Scholar 

  12. Fomsgaard, A., Svenson, M. & Bendtzen, K. Auto-antibodies to tumour necrosis factor alpha in healthy humans and patients with inflammatory diseases and gram-negative bacterial infections. Scand. J. Immunol. 30, 219–223 (1989).

    Article  CAS  PubMed  Google Scholar 

  13. Winfield, J. B. Anti-lymphocyte antibodies in systemic lupus erythematosus. Clin. Rheum. Dis. 11, 523–549 (1985).

    Article  CAS  PubMed  Google Scholar 

  14. Li, C. et al. Antilymphocyte antibodies in systemic lupus erythematosus: association with disease activity and lymphopenia. J. Immunol. Res. 2014, 672126 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Minota, S. & Winfield, J. B. IgG anti-lymphocyte antibodies in systemic lupus erythematosus react with surface molecules shared by peripheral T cells and a primitive T cell line. J. Immunol. 138, 1750–1756 (1987).

    Article  CAS  PubMed  Google Scholar 

  16. Young, N. S. Aplastic anemia. N. Engl. J. Med. 379, 1643–1656 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Boxer, L. A., Greenberg, M. S., Boxer, G. J. & Stossel, T. P. Autoimmune neutropenia. N. Engl. J. Med. 293, 748–753 (1975).

    Article  CAS  PubMed  Google Scholar 

  18. Lalezari, P., Jiang, A. F., Yegen, L. & Santorineou, M. Chronic autoimmune neutropenia due to anti-NA2 antibody. N. Engl. J. Med. 293, 744–747 (1975).

    Article  CAS  PubMed  Google Scholar 

  19. Bux, J., Behrens, G., Jaeger, G. & Welte, K. Diagnosis and clinical course of autoimmune neutropenia in infancy: analysis of 240 cases. Blood 91, 181–186 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Dresch, C., Flandrin, G. & Breton-Gorius, J. Phagocytosis of neutrophil polymorphonuclears by macrophages in human bone marrow: importance in granulopoiesis. J. Clin. Pathol. 33, 1110–1113 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Parmley, R. T. et al. Phagocytosis of neutrophils by marrow macrophages in childhood chronic benign neutropenia. J. Pediatr. 98, 207–212 (1981).

    Article  CAS  PubMed  Google Scholar 

  22. Lalezari, P. & Spaet, T. H. Studies on the genetics of leukocyte antigens. Blood 14, 748–758 (1959).

    Article  CAS  PubMed  Google Scholar 

  23. Lalezari, P., Nussbaum, M., Gelman, S. & Spaet, T. H. Neonatal neutropenia due to maternal isoimmunization. Blood 15, 236–243 (1960).

    Article  CAS  PubMed  Google Scholar 

  24. Kitching, A. R. et al. ANCA-associated vasculitis. Nat. Rev. Dis. Primers 6, 71 (2020).

    Article  PubMed  Google Scholar 

  25. Thieblemont, N., Wright, H. L., Edwards, S. W. & Witko-Sarsat, V. Human neutrophils in auto-immunity. Semin. Immunol. 28, 159–173 (2016).

    Article  CAS  PubMed  Google Scholar 

  26. Zuo, Y. et al. Anti-neutrophil extracellular trap antibodies and impaired neutrophil extracellular trap degradation in antiphospholipid syndrome. Arthritis Rheumatol. 72, 2130–2135 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Khandpur, R. et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci. Transl. Med. 5, 178ra140 (2013).

    Article  Google Scholar 

  28. Wright, H. L., Moots, R. J. & Edwards, S. W. The multifactorial role of neutrophils in rheumatoid arthritis. Nat. Rev. Rheumatol. 10, 593–601 (2014).

    Article  CAS  PubMed  Google Scholar 

  29. Zuo, Y. et al. Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.abd3876 (2020).

  30. Muschter, S., Berthold, T. & Greinacher, A. Developments in the definition and clinical impact of human neutrophil antigens. Curr. Opin. Hematol. 18, 452–460 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Elghetany, M. T. Surface antigen changes during normal neutrophilic development: a critical review. Blood Cells Mol. Dis. 28, 260–274 (2002).

    Article  PubMed  Google Scholar 

  32. Boggs, D. R. Granulocyte turnover in autoimmune neutropenia. N. Engl. J. Med. 294, 165 (1976).

    Article  CAS  PubMed  Google Scholar 

  33. Fioredda, F. et al. Late-onset and long-lasting autoimmune neutropenia: an analysis from the Italian Neutropenia Registry. Blood Adv. 4, 5644–5649 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Audia, S., Grienay, N., Mounier, M., Michel, M. & Bonnotte, B. Evans’ syndrome: from diagnosis to treatment. J. Clin. Med. https://doi.org/10.3390/jcm9123851 (2020).

  35. Defendi, F., Thielens, N. M., Clavarino, G., Cesbron, J. Y. & Dumestre-Perard, C. The immunopathology of complement proteins and innate immunity in autoimmune disease. Clin. Rev. Allergy Immunol. 58, 229–251 (2020).

    Article  CAS  PubMed  Google Scholar 

  36. Schroder-Braunstein, J. & Kirschfink, M. Complement deficiencies and dysregulation: pathophysiological consequences, modern analysis, and clinical management. Mol. Immunol. 114, 299–311 (2019).

    Article  PubMed  Google Scholar 

  37. Ram, S., Lewis, L. A. & Rice, P. A. Infections of people with complement deficiencies and patients who have undergone splenectomy. Clin. Microbiol. Rev. 23, 740–780 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lim, D. et al. Absence of the sixth component of complement in a patient with repeated episodes of meningococcal meningitis. J. Pediatr. 89, 42–47 (1976).

    Article  CAS  PubMed  Google Scholar 

  39. Wang, X. et al. Inherited human complement C5 deficiency. Nonsense mutations in exons 1 (Gln1 to Stop) and 36 (Arg1458 to Stop) and compound heterozygosity in three African-American families. J. Immunol. 154, 5464–5471 (1995).

    Article  CAS  PubMed  Google Scholar 

  40. Wurzner, R. et al. Molecular basis of subtotal complement C6 deficiency. A carboxy-terminally truncated but functionally active C6. J. Clin. Invest. 95, 1877–1883 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Nishizaka, H., Horiuchi, T., Zhu, Z. B., Fukumori, Y. & Volanakis, J. E. Genetic bases of human complement C7 deficiency. J. Immunol. 157, 4239–4243 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Kaufmann, T. et al. Genetic basis of human complement C8 beta deficiency. J. Immunol. 150, 4943–4947 (1993).

    Article  CAS  PubMed  Google Scholar 

  43. Austen, K. F. Inborn errors of the complement system of man. N. Engl. J. Med. 276, 1363–1368 (1967).

    Article  CAS  PubMed  Google Scholar 

  44. Rosain, J. et al. Complement deficiencies and human diseases. Ann. Biol. Clin. 72, 271–280 (2014).

    CAS  Google Scholar 

  45. Pettigrew, H. D., Teuber, S. S. & Gershwin, M. E. Clinical significance of complement deficiencies. Ann. N. Y. Acad. Sci. 1173, 108–123 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Fakhouri, F., Zuber, J., Fremeaux-Bacchi, V. & Loirat, C. Haemolytic uraemic syndrome. Lancet 390, 681–696 (2017).

    Article  PubMed  Google Scholar 

  47. Merle, N. S., Noe, R., Halbwachs-Mecarelli, L., Fremeaux-Bacchi, V. & Roumenina, L. T. Complement system part II: role in immunity. Front. Immunol. 6, 257 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Matola, A. T., Jozsi, M. & Uzonyi, B. Overview on the role of complement-specific autoantibodies in diseases. Mol. Immunol. 151, 52–60 (2022).

    Article  CAS  PubMed  Google Scholar 

  49. Siegert, C. E. et al. Predictive value of IgG autoantibodies against C1q for nephritis in systemic lupus erythematosus. Ann. Rheum. Dis. 52, 851–856 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Trendelenburg, M. et al. High prevalence of anti-C1q antibodies in biopsy-proven active lupus nephritis. Nephrol. Dial. Transpl. 21, 3115–3121 (2006).

    Article  CAS  Google Scholar 

  51. Marto, N., Bertolaccini, M. L., Calabuig, E., Hughes, G. R. & Khamashta, M. A. Anti-C1q antibodies in nephritis: correlation between titres and renal disease activity and positive predictive value in systemic lupus erythematosus. Ann. Rheum. Dis. 64, 444–448 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Edwards, K. M., Alford, R., Gewurz, H. & Mold, C. Recurrent bacterial infections associated with C3 nephritic factor and hypocomplementemia. N. Engl. J. Med. 308, 1138–1141 (1983).

    Article  CAS  PubMed  Google Scholar 

  53. Thompson, R. A., Yap, P. L., Brettle, R. B., Dunmow, R. E. & Chapel, H. Meningococcal meningitis associated with persistent hypocomplementaemia due to circulating C3 nephritic factor. Clin. Exp. Immunol. 52, 153–156 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Teisner, B. et al. C3 nephritic factor in a patient with recurrent Neisseria meningitidis infections. Acta Pathol. Microbiol. Immunol. Scand. C. 92, 341–349 (1984).

    CAS  PubMed  Google Scholar 

  55. Davis, A. E. 3rd, Ziegler, J. B., Gelfand, E. W., Rosen, F. S. & Alper, C. A. Heterogeneity of nephritic factor and its identification as an immunoglobulin. Proc. Natl Acad. Sci. USA 74, 3980–3983 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Daha, M. R., Fearon, D. T. & Austen, K. F. C3 nephritic factor (C3NeF): stabilization of fluid phase and cell-bound alternative pathway convertase. J. Immunol. 116, 1–7 (1976).

    Article  CAS  PubMed  Google Scholar 

  57. Kaartinen, K., Safa, A., Kotha, S., Ratti, G. & Meri, S. Complement dysregulation in glomerulonephritis. Semin. Immunol. 45, 101331 (2019).

    Article  CAS  PubMed  Google Scholar 

  58. Noris, M., Donadelli, R. & Remuzzi, G. Autoimmune abnormalities of the alternative complement pathway in membranoproliferative glomerulonephritis and C3 glomerulopathy. Pediatr. Nephrol. 34, 1311–1323 (2019).

    Article  PubMed  Google Scholar 

  59. Lazear, H. M., Schoggins, J. W. & Diamond, M. S. Shared and distinct functions of type I and type III Interferons. Immunity 50, 907–923 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mogensen, K. E., Daubas, P., Gresser, I., Sereni, D. & Varet, B. Patient with circulating antibodies to alpha-interferon. Lancet 2, 1227–1228 (1981).

    Article  CAS  PubMed  Google Scholar 

  61. Pozzetto, B., Mogensen, K. E., Tovey, M. G. & Gresser, I. Characteristics of autoantibodies to human interferon in a patient with varicella-zoster disease. J. Infect. Dis. 150, 707–713 (1984).

    Article  CAS  PubMed  Google Scholar 

  62. Casanova, J. L. & Anderson, M. S. Unlocking life-threatening COVID-19 through two types of inborn errors of type I IFNs. J. Clin. Invest. https://doi.org/10.1172/JCI166283 (2023).

  63. Bastard, P. et al. Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths. Sci. Immunol. https://doi.org/10.1126/sciimmunol.abl4340 (2021).

  64. Manry, J. et al. The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies. Proc. Natl Acad. Sci. USA 119, e2200413119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bastard, P. et al. Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs. Sci. Immunol. https://doi.org/10.1126/sciimmunol.abp8966 (2022).

  66. Sokal, A. et al. Human type I IFN deficiency does not impair B cell response to SARS-CoV-2 mRNA vaccination. J. Exp. Med. https://doi.org/10.1084/jem.20220258 (2023).

  67. Bastard, P. et al. Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine. J. Exp. Med. https://doi.org/10.1084/jem.20202486 (2021).

  68. Zhang, Q. et al. Autoantibodies against type I IFNs in patients with critical influenza pneumonia. J. Exp. Med. https://doi.org/10.1084/jem.20220514 (2022).

  69. Alotaibi, F. et al. Type I interferon autoantibodies in hospitalized patients with Middle East respiratory syndrome and association with outcomes and treatment effect of interferon beta-1b in MIRACLE clinical trial. Influenza Other Respir. Viruses 17, e13116 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Gervais, A. et al. Autoantibodies neutralizing type I IFNs underlie West Nile virus encephalitis in approximately 40% of patients. J. Exp. Med. https://doi.org/10.1084/jem.20230661 (2023).

  71. Nagafuchi, S. et al. Recurrent herpes simplex virus infection in a patient with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy associated with L29P and IVS9-1G>C compound heterozygous autoimmune regulator gene mutations. J. Intern. Med. 261, 605–610 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Mathian, A. et al. Lower disease activity but higher risk of severe COVID-19 and herpes zoster in patients with systemic lupus erythematosus with pre-existing autoantibodies neutralising IFN-α. Ann. Rheum. Dis. 81, 1695–1703 (2022).

    Article  CAS  PubMed  Google Scholar 

  73. Hetemäki, I. et al. Patients with autoimmune polyendocrine syndrome type 1 have an increased susceptibility to severe herpesvirus infections. Clin. Immunol. 231, 108851 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Busnadiego, I. et al. Critically ill COVID-19 patients with neutralizing autoantibodies against type I interferons have increased risk of herpesvirus disease. PLoS Biol. 20, e3001709 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Batra, A. et al. Varicella recurrence complicated by pneumonia after liver transplantation for APECED. J. Pediatr. Gastroenterol. Nutr. 44, 637–639 (2007).

    Article  PubMed  Google Scholar 

  76. Walter, J. E. et al. Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency. J. Clin. Invest. 125, 4135–4148 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Bastard, P., Zhang, Q., Zhang, S. Y., Jouanguy, E. & Casanova, J. L. Type I interferons and SARS-CoV-2: from cells to organisms. Curr. Opin. Immunol. 74, 172–182 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Chauvineau-Grenier, A. et al. Autoantibodies neutralizing type I interferons in 20% of COVID-19 deaths in a French hospital. J. Clin. Immunol. 42, 459–470 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Bastard, P. et al. Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children. J. Exp. Med. 221, e20231353 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Vallbracht, A., Treuner, J., Flehmig, B., Joester, K. E. & Niethammer, D. Interferon-neutralizing antibodies in a patient treated with human fibroblast interferon. Nature 289, 496–497 (1981).

    Article  CAS  PubMed  Google Scholar 

  81. Itri, L. M. et al. Incidence and clinical significance of neutralizing antibodies in patients receiving recombinant interferon alfa-2a by intramuscular injection. Cancer 59, 668–674 (1987).

    Article  CAS  PubMed  Google Scholar 

  82. Fierlbeck, G. & Schreiner, T. Incidence and clinical significance of therapy-induced neutralizing antibodies against interferon-beta. J. Interferon Res. 14, 205–206 (1994).

    Article  CAS  PubMed  Google Scholar 

  83. Shiono, H. et al. Spontaneous production of anti-IFN-alpha and anti-IL-12 autoantibodies by thymoma cells from myasthenia gravis patients suggests autoimmunization in the tumor. Int. Immunol. 15, 903–913 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Meager, A., Vincent, A., Newsom-Davis, J. & Willcox, N. Spontaneous neutralising antibodies to interferon–alpha and interleukin-12 in thymoma-associated autoimmune disease. Lancet 350, 1596–1597 (1997).

    Article  CAS  PubMed  Google Scholar 

  85. Panem, S., Check, I. J., Henriksen, D. & Vilcek, J. Antibodies to alpha-interferon in a patient with systemic lupus erythematosus. J. Immunol. 129, 1–3 (1982).

    Article  CAS  PubMed  Google Scholar 

  86. Meager, A. et al. Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med. 3, e289 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Bastard, P. et al. Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1. J. Exp. Med. 218, e20210554 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Husebye, E. S., Anderson, M. S. & Kämpe, O. Autoimmune polyendocrine syndromes. N. Engl. J. Med. 378, 1132–1141 (2018).

  89. Oftedal, B. E., Sjøgren, T. & Wolff, A. S. B. Interferon autoantibodies as signals of a sick thymus. Front. Immunol. https://doi.org/10.3389/fimmu.2024.1327784 (2024).

  90. Le Voyer, T. et al. Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency. Nature 623, 803–813 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Wolff, A. S. et al. Clinical and serologic parallels to APS-I in patients with thymomas and autoantigen transcripts in their tumors. J. Immunol. 193, 3880–3890 (2014).

    Article  CAS  PubMed  Google Scholar 

  92. Strobel, P. et al. Deficiency of the autoimmune regulator AIRE in thymomas is insufficient to elicit autoimmune polyendocrinopathy syndrome type 1 (APS-1). J. Pathol. 211, 563–571 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Cheng, M. H. et al. Acquired autoimmune polyglandular syndrome, thymoma, and an AIRE defect. N. Engl. J. Med. 362, 764–766 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Rosenberg, J. M. et al. Neutralizing anti-cytokine autoantibodies against interferon-alpha in immunodysregulation polyendocrinopathy enteropathy X-linked. Front. Immunol. 9, 544 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Chen, K. et al. Autoimmunity due to RAG deficiency and estimated disease incidence in RAG1/2 mutations. J. Allergy Clin. Immunol. 133, 880–882 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Rosain, J. Thymic dysplasia underlies anti-type I IFN autoantibody production and viral diseases in women with incontinentia pigmenti. J. Exp. Med. Under review (2023).

  97. Hetemaki, I. et al. Loss-of-function mutation in IKZF2 leads to immunodeficiency with dysregulated germinal center reactions and reduction of MAIT cells. Sci. Immunol. 6, eabe3454 (2021).

    Article  CAS  PubMed  Google Scholar 

  98. Materna, M. et al. The immunopathological landscape of human pre-TCRa deficiency: from rare to common variants. Science 383, eadh4059 (2024).

  99. Nathan, C. F., Murray, H. W., Wiebe, M. E. & Rubin, B. Y. Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J. Exp. Med. 158, 670–689 (1983).

    Article  CAS  PubMed  Google Scholar 

  100. Schroder, K., Hertzog, P. J., Ravasi, T. & Hume, D. A. Interferon-gamma: an overview of signals, mechanisms and functions. J. Leukoc. Biol. 75, 163–189 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Ogishi, M. et al. Inborn errors of human transcription factors governing IFN-gamma antimycobacterial immunity. Curr. Opin. Immunol. 81, 102296 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Boisson-Dupuis, S. & Bustamante, J. Mycobacterial diseases in patients with inborn errors of immunity. Curr. Opin. Immunol. 72, 262–271 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Bustamante, J., Boisson-Dupuis, S., Abel, L. & Casanova, J. L. Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-gamma immunity. Semin. Immunol. 26, 454–470 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Kerner, G. et al. Inherited human IFN-gamma deficiency underlies mycobacterial disease. J. Clin. Invest. 130, 3158–3171 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ku, C. L., Chi, C. Y., von Bernuth, H. & Doffinger, R. Autoantibodies against cytokines: phenocopies of primary immunodeficiencies? Hum. Genet 139, 783–794 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Shih, H. P., Ding, J. Y., Yeh, C. F., Chi, C. Y. & Ku, C. L. Anti-interferon-gamma autoantibody-associated immunodeficiency. Curr. Opin. Immunol. 72, 206–214 (2021).

    Article  CAS  PubMed  Google Scholar 

  107. Doffinger, R. et al. Autoantibodies to interferon-gamma in a patient with selective susceptibility to mycobacterial infection and organ-specific autoimmunity. Clin. Infect. Dis. 38, e10–e14 (2004).

    Article  PubMed  Google Scholar 

  108. Hoflich, C. et al. Naturally occurring anti-IFN-gamma autoantibody and severe infections with Mycobacterium cheloneae and Burkholderia cocovenenans. Blood 103, 673–675 (2004).

    Article  PubMed  Google Scholar 

  109. Puel, A., Bastard, P., Bustamante, J. & Casanova, J. L. Human autoantibodies underlying infectious diseases. J. Exp. Med. https://doi.org/10.1084/jem.20211387 (2022).

  110. Qiu, Y. et al. Pathogen spectrum and immunotherapy in patients with anti-IFN-gamma autoantibodies: a multicenter retrospective study and systematic review. Front. Immunol. 13, 1051673 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Browne, S. K. et al. Adult-onset immunodeficiency in Thailand and Taiwan. N. Engl. J. Med. 367, 725–734 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Kampitak, T., Suwanpimolkul, G., Browne, S. & Suankratay, C. Anti-interferon-gamma autoantibody and opportunistic infections: case series and review of the literature. Infection 39, 65–71 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. Wongkulab, P., Wipasa, J., Chaiwarith, R. & Supparatpinyo, K. Autoantibody to interferon-gamma associated with adult-onset immunodeficiency in non-HIV individuals in northern Thailand. PLoS ONE 8, e76371 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Tang, B. S. et al. Disseminated penicilliosis, recurrent bacteremic nontyphoidal salmonellosis, and burkholderiosis associated with acquired immunodeficiency due to autoantibody against gamma interferon. Clin. Vaccin. Immunol. 17, 1132–1138 (2010).

    Article  CAS  Google Scholar 

  115. Guo, J. et al. Anti-IFN-gamma autoantibodies underlie disseminated Talaromyces marneffei infections. J. Exp. Med. https://doi.org/10.1084/jem.20190502 (2020).

  116. Zeng, W. et al. Characterization of anti-interferon-gamma antibodies in HIV-negative patients infected with disseminated Talaromyces marneffei and Cryptococcosis. Open Forum Infect. Dis. 6, ofz208 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Chi, C. Y. et al. Anti-IFN-gamma autoantibodies in adults with disseminated nontuberculous mycobacterial infections are associated with HLA-DRB1*16:02 and HLA-DQB1*05:02 and the reactivation of latent varicella-zoster virus infection. Blood 121, 1357–1366 (2013).

    Article  CAS  PubMed  Google Scholar 

  118. Pithukpakorn, M. et al. HLA-DRB1 and HLA-DQB1 are associated with adult-onset immunodeficiency with acquired anti-interferon-gamma autoantibodies. PLoS ONE 10, e0128481 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Chi, C. Y. et al. Clinical manifestations, course, and outcome of patients with neutralizing anti-interferon-gamma autoantibodies and disseminated nontuberculous mycobacterial infections. Medicine 95, e3927 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Patel, S. Y. et al. Anti-IFN-gamma autoantibodies in disseminated nontuberculous mycobacterial infections. J. Immunol. 175, 4769–4776 (2005).

    Article  CAS  PubMed  Google Scholar 

  121. Hong, G. H. et al. Natural history and evolution of Anti-Interferon-gamma autoantibody-associated immunodeficiency syndrome in Thailand and the United States. Clin. Infect. Dis. 71, 53–62 (2020).

    Article  CAS  PubMed  Google Scholar 

  122. Ku, C. L. et al. Anti-IFN-gamma autoantibodies are strongly associated with HLA-DR*15:02/16:02 and HLA-DQ*05:01/05:02 across Southeast Asia. J. Allergy Clin. Immunol. 137, 945–948 (2016).

    Article  CAS  PubMed  Google Scholar 

  123. Shih, H. P. et al. Pathogenic autoantibodies to IFN-gamma act through the impedance of receptor assembly and Fc-mediated response. J. Exp. Med. https://doi.org/10.1084/jem.20212126 (2022).

  124. Lin, C. H. et al. Identification of a major epitope by anti-interferon-gamma autoantibodies in patients with mycobacterial disease. Nat. Med. 22, 994–1001 (2016).

    Article  CAS  PubMed  Google Scholar 

  125. Rosain, J. et al. Mendelian susceptibility to mycobacterial disease: 2014–2018 update. Immunol. Cell Biol. 97, 360–367 (2019).

    Article  PubMed  Google Scholar 

  126. Ratnatunga, C. N. et al. The rise of non-tuberculosis mycobacterial lung disease. Front Immunol. 11, 303 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Turano, A. & Caruso, A. The role of human autoantibodies against gamma-interferon. J. Antimicrob. Chemother. 32, 99–105 (1993).

    Article  PubMed  Google Scholar 

  128. Caruso, A. & Turano, A. Natural antibodies to interferon-gamma. Biotherapy 10, 29–37 (1997).

    Article  CAS  PubMed  Google Scholar 

  129. Caruso, A. et al. Natural antibodies to IFN-gamma in man and their increase during viral infection. J. Immunol. 144, 685–690 (1990).

    Article  CAS  PubMed  Google Scholar 

  130. Turano, A. et al. Natural human antibodies to gamma interferon interfere with the immunomodulating activity of the lymphokine. Proc. Natl Acad. Sci. USA 89, 4447–4451 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ferre, E. M. et al. Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. JCI Insight 1, e88782 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Gaffen, S. L. Structure and signalling in the IL-17 receptor family. Nat. Rev. Immunol. 9, 556–567 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Cua, D. J. & Tato, C. M. Innate IL-17-producing cells: the sentinels of the immune system. Nat. Rev. Immunol. 10, 479–489 (2010).

    Article  CAS  PubMed  Google Scholar 

  134. Chang, S. H. & Dong, C. A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses. Cell Res. 17, 435–440 (2007).

    Article  PubMed  Google Scholar 

  135. Mills, K. H. G. IL-17 and IL-17-producing cells in protection versus pathology. Nat. Rev. Immunol. 23, 38–54 (2023).

    Article  CAS  PubMed  Google Scholar 

  136. Wright, J. F. et al. The human IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex. J. Immunol. 181, 2799–2805 (2008).

    Article  CAS  PubMed  Google Scholar 

  137. Puel, A. et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 332, 65–68 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Ling, Y. et al. Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis. J. Exp. Med. 212, 619–631 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Tangye, S. G. & Puel, A. The Th17/IL-17 axis and host defense against fungal infections. J. Allergy Clin. Immunol. Pract. 11, 1624–1634 (2023).

    Article  CAS  PubMed  Google Scholar 

  140. Chang, S. H. & Dong, C. Signaling of interleukin-17 family cytokines in immunity and inflammation. Cell. Signal. 23, 1069–1075 (2011).

    Article  CAS  PubMed  Google Scholar 

  141. Ely, L. K., Fischer, S. & Garcia, K. C. Structural basis of receptor sharing by interleukin 17 cytokines. Nat. Immunol. 10, 1245–1251 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Su, Y. et al. Interleukin-17 receptor D constitutes an alternative receptor for interleukin-17A important in psoriasis-like skin inflammation. Sci. Immunol. 4, eaau9657 (2019).

    Article  CAS  PubMed  Google Scholar 

  143. Kisand, K. et al. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J. Exp. Med. 207, 299–308 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Puel, A. et al. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J. Exp. Med. 207, 291–297 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Puel, A. & Casanova, J. L. Comment on ‘aberrant type 1 immunity drives susceptibility to mucosal fungal infections. Science 373, eabi5459 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Puel, A. et al. Inborn errors of mucocutaneous immunity to Candida albicans in humans: a role for IL-17 cytokines? Curr. Opin. Immunol. 22, 467–474 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Kisand, K. et al. Mucocutaneous candidiasis and autoimmunity against cytokines in APECED and thymoma patients: clinical and pathogenetic implications. Eur. J. Immunol. 41, 1517–1527 (2011).

    Article  CAS  PubMed  Google Scholar 

  148. Kisand, K., Meager, A., Hayday, A. & Willcox, N. Comment on “Aberrant type 1 immunity drives susceptibility to mucosal fungal infections”. Science 373, eabi6235 (2021).

    Article  PubMed  Google Scholar 

  149. Sharifinejad, N. et al. The clinical, molecular, and therapeutic features of patients with IL10/IL10R deficiency: a systematic review. Clin. Exp. Immunol. 208, 281–291 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Yamazaki, Y. et al. Two novel gain-of-function mutations of STAT1 responsible for chronic mucocutaneous candidiasis disease: impaired production of IL-17A and IL-22, and the presence of anti-IL-17F autoantibody. J. Immunol. 193, 4880–4887 (2014).

    Article  CAS  PubMed  Google Scholar 

  151. Tanaka, T., Narazaki, M. & Kishimoto, T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb. Perspect. Biol. 6, a016295 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Hirano, T. IL-6 in inflammation, autoimmunity and cancer. Int. Immunol. 33, 127–148 (2021).

    Article  CAS  PubMed  Google Scholar 

  153. Choy, E. H. et al. Translating IL-6 biology into effective treatments. Nat. Rev. Rheumatol. 16, 335–345 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Rose-John, S., Jenkins, B. J., Garbers, C., Moll, J. M. & Scheller, J. Targeting IL-6 trans-signalling: past present and future prospects. Nat. Rev. Immunol. 23, 666–681 (2023).

  155. Spencer, S. et al. Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses. J. Exp. Med. 216, 1986–1998 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Nahum, A. et al. Defining the biological responses of IL-6 by the study of a novel IL-6 receptor chain immunodeficiency. J. Allergy Clin. Immunol. 145, 1011–1015 (2020).

    Article  CAS  PubMed  Google Scholar 

  157. Chen, Y. H., Spencer, S., Laurence, A., Thaventhiran, J. E. & Uhlig, H. H. Inborn errors of IL-6 family cytokine responses. Curr. Opin. Immunol. 72, 135–145 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Puel, A. & Casanova, J. L. The nature of human IL-6. J. Exp. Med. 216, 1969–1971 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Beziat, V. et al. Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome. J. Exp. Med. https://doi.org/10.1084/jem.20191804 (2020).

  160. Chen, Y. H. et al. Functional and structural analysis of cytokine-selective IL6ST defects that cause recessive hyper-IgE syndrome. J. Allergy Clin. Immunol. 148, 585–598 (2021).

    Article  CAS  PubMed  Google Scholar 

  161. Arlabosse, T. et al. New dominant-negative IL6ST variants expand the immunological and clinical spectrum of GP130-Dependent Hyper-IgE syndrome. J. Clin. Immunol. 43, 1566–1580 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Puel, A. et al. Recurrent staphylococcal cellulitis and subcutaneous abscesses in a child with autoantibodies against IL-6. J. Immunol. 180, 647–654 (2008).

    Article  CAS  PubMed  Google Scholar 

  163. Bloomfield, M. et al. Anti-IL6 autoantibodies in an infant with CRP-less septic shock. Front. Immunol. 10, 2629 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Nanki, T. et al. Suppression of elevations in serum C reactive protein levels by anti-IL-6 autoantibodies in two patients with severe bacterial infections. Ann. Rheum. Dis. 72, 1100–1102 (2013).

    Article  CAS  PubMed  Google Scholar 

  165. Galle, P., Svenson, M., Bendtzen, K. & Hansen, M. B. High levels of neutralizing IL-6 autoantibodies in 0.1% of apparently healthy blood donors. Eur. J. Immunol. 34, 3267–3275 (2004).

    Article  CAS  PubMed  Google Scholar 

  166. Karner, J. et al. IL-6-specific autoantibodies among APECED and thymoma patients. Immun. Inflamm. Dis. 4, 235–243 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Hansen, M. B., Svenson, M., Diamant, M. & Bendtzen, K. Anti-interleukin-6 antibodies in normal human serum. Scand. J. Immunol. 33, 777–781 (1991).

    Article  CAS  PubMed  Google Scholar 

  168. Hansen, M. B., Svenson, M., Diamant, M. & Bendtzen, K. High-affinity IgG autoantibodies to IL-6 in sera of normal individuals are competitive inhibitors of IL-6 in vitro. Cytokine 5, 72–80 (1993).

    Article  CAS  PubMed  Google Scholar 

  169. Svenson, M., Hansen, M. B. & Bendtzen, K. Binding of cytokines to pharmaceutically prepared human immunoglobulin. J. Clin. Invest. 92, 2533–2539 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Bhattacharya, P. et al. GM-CSF: an immune modulatory cytokine that can suppress autoimmunity. Cytokine 75, 261–271 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Gearing, D. P., King, J. A., Gough, N. M. & Nicola, N. A. Expression cloning of a receptor for human granulocyte-macrophage colony-stimulating factor. EMBO J. 8, 3667–3676 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Hayashida, K. et al. Molecular cloning of a second subunit of the receptor for human granulocyte-macrophage colony-stimulating factor (GM-CSF): reconstitution of a high-affinity GM-CSF receptor. Proc. Natl Acad. Sci. USA 87, 9655–9659 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Dirksen, U. et al. Human pulmonary alveolar proteinosis associated with a defect in GM-CSF/IL-3/IL-5 receptor common beta chain expression. J. Clin. Invest. 100, 2211–2217 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Rosen, S. H., Castleman, B. & Liebow, A. A. Pulmonary alveolar proteinosis. N. Engl. J. Med. 258, 1123–1142 (1958).

    Article  CAS  PubMed  Google Scholar 

  175. Trapnell, B. C. et al. Pulmonary alveolar proteinosis. Nat. Rev. Dis. Primers 5, 16 (2019).

    Article  PubMed  Google Scholar 

  176. Kitamura, T. et al. Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor. J. Exp. Med. 190, 875–880 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Rosen, L. B. et al. Anti-GM-CSF autoantibodies in patients with cryptococcal meningitis. J. Immunol. 190, 3959–3966 (2013).

    Article  CAS  PubMed  Google Scholar 

  178. Perrineau, S., Guery, R., Monnier, D., Puel, A. & Lanternier, F. Anti-GM-CSF autoantibodies and Cryptococcus neoformans var. grubii CNS vasculitis. J. Clin. Immunol. 40, 767–769 (2020).

    Article  PubMed  Google Scholar 

  179. Kuo, C. Y. et al. Disseminated cryptococcosis due to anti-granulocyte-macrophage colony-stimulating factor autoantibodies in the absence of pulmonary alveolar proteinosis. J. Clin. Immunol. 37, 143–152 (2017).

    Article  CAS  PubMed  Google Scholar 

  180. Saijo, T. et al. Anti-granulocyte-macrophage colony-stimulating factor autoantibodies are a risk factor for central nervous system infection by Cryptococcus gattii in otherwise immunocompetent patients. mBio 5, e00912–e00914 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Huynh, J. et al. Unusual presentation of severe endobronchial obstruction caused by Cryptococcus gattii in a child. J. Pediatr. Infect. Dis. Soc. 9, 67–70 (2020).

    Article  Google Scholar 

  182. Applen Clancey, S. et al. Cryptococcus deuterogattii VGIIa infection associated with travel to the pacific northwest outbreak region in an anti-granulocyte-macrophage colony-stimulating factor autoantibody-positive patient in the United States. mBio https://doi.org/10.1128/mBio.02733-18 (2019).

  183. Stevenson, B. et al. The significance of anti-granulocyte-macrophage colony-stimulating factor antibodies in cryptococcal infection: case series and review of antibody testing. Intern. Med. J. 49, 1446–1450 (2019).

    Article  PubMed  Google Scholar 

  184. Viola, G. M. et al. Disseminated cryptococcosis and anti-granulocyte-macrophage colony-stimulating factor autoantibodies: an underappreciated association. Mycoses 64, 576–582 (2021).

    Article  CAS  PubMed  Google Scholar 

  185. Panackal, A. A. et al. Susceptibility to Cryptococcal Meningoencephalitis associated with idiopathic CD4+ lymphopenia and secondary germline or acquired defects. Open Forum Infect. Dis. 4, ofx082 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  186. Crum-Cianflone, N. F., Lam, P. V., Ross-Walker, S., Rosen, L. B. & Holland, S. M. Autoantibodies to granulocyte-macrophage colony-stimulating factor associated with severe and unusual manifestations of Cryptococcus gattii infections. Open Forum Infect. Dis. 4, ofx211 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  187. Demir, S., Chebib, N., Thivolet-Bejui, F. & Cottin, V. Pulmonary alveolar proteinosis following cryptococcal meningitis: a possible cause? BMJ Case Rep. https://doi.org/10.1136/bcr-2017-222940 (2018).

  188. Mabo, A. et al. Infections in autoimmune pulmonary alveolar proteinosis: a large retrospective cohort. Thorax https://doi.org/10.1136/thorax-2023-220040 (2023).

    Article  PubMed  Google Scholar 

  189. Arai, T., Inoue, Y., Akira, M., Nakata, K. & Kitaichi, M. Autoimmune pulmonary alveolar proteinosis following pulmonary aspergillosis. Intern. Med. 54, 3177–3180 (2015).

    Article  CAS  PubMed  Google Scholar 

  190. Ataya, A. et al. The Role of GM-CSF autoantibodies in infection and autoimmune pulmonary alveolar proteinosis: a concise review. Front. Immunol. 12, 752856 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Uchida, K. et al. GM-CSF autoantibodies and neutrophil dysfunction in pulmonary alveolar proteinosis. N. Engl. J. Med. 356, 567–579 (2007).

    Article  CAS  PubMed  Google Scholar 

  192. Shibata, Y. et al. GM-CSF regulates alveolar macrophage differentiation and innate immunity in the lung through PU.1. Immunity 15, 557–567 (2001).

    Article  CAS  PubMed  Google Scholar 

  193. Trapnell, B. C. & Whitsett, J. A. Gm-CSF regulates pulmonary surfactant homeostasis and alveolar macrophage-mediated innate host defense. Annu. Rev. Physiol. 64, 775–802 (2002).

    Article  CAS  PubMed  Google Scholar 

  194. Uchida, K. et al. Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects. Blood 113, 2547–2556 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Sakaue, S. et al. Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis. Nat. Commun. 12, 1032 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Anderson, K. et al. Pulmonary alveolar proteinosis: an autoimmune disease lacking an HLA association. PLoS ONE 14, e0213179 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Martin, E. et al. Role of IL-27 in Epstein–Barr virus infection revealed by IL-27RA deficiency. Nature https://doi.org/10.1038/s41586-024-07213-6 (2024).

  198. Wang, E. Y. et al. Diverse functional autoantibodies in patients with COVID-19. Nature 595, 283–288 (2021).

    Article  CAS  PubMed  Google Scholar 

  199. Jaycox, J. R., Dai, Y. & Ring, A. M. Decoding the autoantibody reactome. Science 383, 705–707 (2024).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the patients and their families for placing their trust in us and anticipating in our studies. We warmly thank the members of both branches of the Laboratory of Human Genetics of Infectious Diseases. We warmly thank J. Rosain, A. Gervais and T. Le Voyer for helpful discussions and suggestions. We warmly thank Y. Nemirovskaya, M. Woollett, D. Liu, S. Boucherit, M. Chrabieh and L. Lorenzo for administrative assistance. We also thank A. Geraldo and L. Bizien for experimental assistance. The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH; R01AI088364, R01AI163029, R01AI127564 and R21AI160576), the National Center for Advancing Translational Sciences (NCATS), the NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JPB Foundation, the Stavros Niarchos Foundation (SNF) as part of its grant to the SNF Institute for Global Infectious Disease Research at the Rockefeller University, the ‘Investissement d’Avenir’ program launched by the French Government and implemented by the Agence Nationale de la Recherche (ANR) (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM; EQU201903007798), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), ANR AI2D (ANR-22-CE15-0046) and ANR AAILC (ANR-21-LIBA-0002) projects, the European Union’s Horizon 2020 research and innovation program under grant agreement no. 824110 (EASI-genomics), the HORIZON-HLTH-2021-DISEASE-04 program under grant agreement 101057100 (UNDINE), the ANR-RHU COVIFERON Program (ANR-21-RHUS-08), the Square Foundation, Grandir - Fonds de solidarité pour l’enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, Battersea & Bowery Advisory Group, The French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM, Paris Cité University, Imagine Institute and William E. Ford, General Atlantic’s Chairman and Chief Executive Officer, Gabriel Caillaux, General Atlantic’s Co-President, Managing Director and Head of Business in EMEA and the General Atlantic Foundation. A.-L.N. was supported by the Imagine Institute international PhD program (with the support of the Fondation Bettencourt-Schueller) and the FRM (FDT202204015102). P.B. was supported by the FRM (EA20170638020), the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller) and a ‘Poste CCA-INSERM-Bettencourt’ (with the support of the Fondation Bettencourt-Schueller).

Author information

Authors and Affiliations

  1. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, New York, NY, USA

    Jean-Laurent Casanova, Jessica Peel, Anne Puel & Paul Bastard

  2. Howard Hughes Medical Institute, New York, NY, USA

    Jean-Laurent Casanova

  3. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children, Paris, France

    Jean-Laurent Casanova, Anna-Lena Neehus, Anne Puel & Paul Bastard

  4. Paris Cité University, Imagine Institute, Paris, France

    Jean-Laurent Casanova, Anna-Lena Neehus, Anne Puel & Paul Bastard

  5. Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France

    Jean-Laurent Casanova & Paul Bastard

  6. Trousseau Hospital for Sick Children, Centre de référence des neutropénies chroniques, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France

    Jean Donadieu

Authors
  1. Jean-Laurent Casanova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jessica Peel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jean Donadieu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna-Lena Neehus
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anne Puel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paul Bastard
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.-L.C., J.P., J.D., A.-L.N., A.P. and P.B. wrote the manuscript, and drafted the tables and figures.

Corresponding author

Correspondence to Jean-Laurent Casanova.

Ethics declarations

Competing interests

J.-L.C. declares being an inventor on a patent application PCT/US2021/042741, filed on 22 July 2021, submitted by The Rockefeller University, which covers the diagnosis of, susceptibility to and treatment of viral disease and viral vaccines, including COVID-19 and vaccine-associated diseases. The other authors declare no competing interests.

Peer review

Peer review information

Nature Immunology thanks Paul Utz and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Nick Bernard, in collaboration with the Nature Immunology team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Casanova, JL., Peel, J., Donadieu, J. et al. The ouroboros of autoimmunity. Nat Immunol 25, 743–754 (2024). https://doi.org/10.1038/s41590-024-01815-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41590-024-01815-y

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing