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.

Treg-associated monogenic autoimmune disorders and gut microbial dysbiosis

Abstract

Primary immunodeficiency diseases (PIDs) caused by a single-gene defect generally are referred to as monogenic autoimmune disorders. For example, mutations in the transcription factor autoimmune regulator (AIRE) result in a condition called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; while mutations in forkhead box P3 lead to regulatory T cell (Treg)-deficiency-induced multiorgan inflammation, which in humans is called “immune dysregulation, polyendocrinopathy, enteropathy with X-linked inheritance” (or IPEX syndrome). Previous studies concluded that monogenic diseases are insensitive to commensal microbial regulation because they develop even in germ-free (GF) animals, a conclusion that has limited the number of studies determining the role of microbiota in monogenic PIDs. However, emerging evidence shows that although the onset of the disease is independent of the microbiota, several monogenic PIDs vary in severity in association with the microbiome. In this review, we focus on monogenic PIDs associated with Treg deficiency/dysfunction, summarizing the gut microbial dysbiosis that has been shown to be linked to these diseases. From limited studies, we have gleaned several mechanistic insights that may prove to be of therapeutic importance in the early stages of life.

Impact

  • This review paper serves to refute the concept that monogenic PIDs are not linked to the microbiome.

  • The onset of monogenic PIDs is independent of microbiota; single-gene mutations such as AIRE or Foxp3 that affect central or peripheral immune tolerance produce monogenic diseases even in a GF environment.

  • However, the severity and outcome of PIDs are markedly impacted by the microbial composition.

  • We suggest that future research for these conditions may focus on targeting the microbiome.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Clinical autoimmune manifestations of representative monogenic autoimmune diseases.
Fig. 2: Two main groups of autoimmune diseases are defined by innate-adaptive immunity and microbial environment.
Fig. 3: The mechanism of L. reuteri DSM 17938-associated protection against Treg deficiency autoimmunity in SF mice.

References

  1. 1.

    Anaya, J. M., Shoenfeld, Y., Rojas-Villarrage, A. & Cervera R. Autoimmunity. From Bench to Bedside (Rosario University Press, 2013).

  2. 2.

    Okada, Y. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376–381 (2014).

    CAS  PubMed  Article  Google Scholar 

  3. 3.

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

    PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Momozawa, Y. et al. IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes. Nat. Commun. 9, 2427 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  5. 5.

    Amaya-Uribe, L., Rojas, M., Azizi, G., Anaya, J. M. & Gershwin, M. E. Primary immunodeficiency and autoimmunity: a comprehensive review. J. Autoimmun. 99, 52–72 (2019).

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Castagnoli, R., Delmonte, O. M., Calzoni, E. & Notarangelo, L. D. Hematopoietic stem cell transplantation in primary immunodeficiency diseases: current status and future perspectives. Front. Pediatr. 7, 295 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Sonnenburg, E. D. & Sonnenburg, J. L. The ancestral and industrialized gut microbiota and implications for human health. Nat. Rev. Microbiol. 17, 383–390 (2019).

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Round, J. L. & Mazmanian, S. K. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 107, 12204–12209 (2010).

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Ruohtula, T. et al. Maturation of gut microbiota and circulating regulatory T cells and development of IgE sensitization in early life. Front. Immunol. 10, 2494 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Goodrich, J. K. et al. Human genetics shape the gut microbiome. Cell 159, 789–799 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Lukens, J. R. et al. Dietary modulation of the microbiome affects autoinflammatory disease. Nature 516, 246–249 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Lupp, C. et al. Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 2, 119–129 (2007).

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Kishikawa, T. et al. Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population. Ann. Rheum. Dis. 79, 103–111 (2020).

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Maeda, Y. & Takeda, K. Host-microbiota interactions in rheumatoid arthritis. Exp. Mol. Med. 51, 1–6 (2019).

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Durazzo, M., Ferro, A. & Gruden, G. Gastrointestinal microbiota and type 1 diabetes mellitus: the state of art. J. Clin. Med. 8, 1843 (2019).

  19. 19.

    Thomas, R. M. & Jobin, C. Microbiota in pancreatic health and disease: the next frontier in microbiome research. Nat. Rev. Gastroenterol. Hepatol. 17, 53–64 (2020).

    PubMed  Article  Google Scholar 

  20. 20.

    Kim, J. W., Kwok, S. K., Choe, J. Y. & Park, S. H. Recent advances in our understanding of the link between the intestinal microbiota and systemic lupus erythematosus. Int. J. Mol. Sci. 20, 4871 (2019).

  21. 21.

    Brown, J., Quattrochi B., Everett, C., Hong, B. Y. & Cervantes, J. Gut commensals, dysbiosis, and immune response imbalance in the pathogenesis of multiple sclerosis. Mult. Scler. https://doi.org/10.1177/352458520928301 (2020).

  22. 22.

    He, B. et al. Lactobacillus reuteri reduces the severity of experimental autoimmune encephalomyelitis in mice by modulating gut microbiota. Front Immunol. 10, 385 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Kadowaki, A. & Quintana, F. J. The gut-CNS axis in multiple sclerosis. Trends Neurosci. 43, 622–634 (2020).

  24. 24.

    Balakrishnan, B. & Taneja, V. Microbial modulation of the gut microbiome for treating autoimmune diseases. Expert. Rev. Gastroenterol. Hepatol. 12, 985–996 (2018).

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Vangoitsenhoven, R. & Cresci, G. A. M. Role of microbiome and antibiotics in autoimmune diseases. Nutr. Clin. Pract. 35, 406–416 (2020).

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Schmidt, R. E., Grimbacher, B. & Witte, T. Autoimmunity and primary immunodeficiency: two sides of the same coin? Nat. Rev. Rheumatol. 14, 7–18 (2017).

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Ouyang, W. et al. Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells. Nat. Immunol. 11, 618–627 (2010).

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    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  Article  Google Scholar 

  29. 29.

    Bennett, C. L. & Ochs, H. D. IPEX is a unique X-linked syndrome characterized by immune dysfunction, polyendocrinopathy, enteropathy, and a variety of autoimmune phenomena. Curr. Opin. Pediatr. 13, 533–538 (2001).

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Halabi-Tawil, M. et al. Cutaneous manifestations of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Br. J. Dermatol. 160, 645–651 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Azizi, G. et al. Monogenic polyautoimmunity in primary immunodeficiency diseases. Autoimmun. Rev. 17, 1028–1039 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32.

    Albert, M. H. & Freeman, A. F. Wiskott-Aldrich syndrome (WAS) and dedicator of cytokinesis 8- (DOCK8) deficiency. Front. Pediatr. 7, 451 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Candotti, F. Clinical manifestations and pathophysiological mechanisms of the Wiskott-Aldrich syndrome. J. Clin. Immunol. 38, 13–27 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    El-Darouti, M. A. & Al-Ali, F. M. Alopecia, nail dystrophy, vitiligo, and hypoparathyroidism. Challenging Cases Dermatol. 2, 199–206 (2019).

    Article  Google Scholar 

  35. 35.

    Hsu, C., Lee, J. Y. Y. & Chao, S. C. Omenn syndrome: a case report and review of literature. Dermatol. Sin. 29, 50–54 (2011).

    Article  Google Scholar 

  36. 36.

    Roos, D. et al. Mutations in the X-linked and autosomal recessive forms of chronic granulomatous disease. Blood 87, 1663–1681 (1996).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Takeda, A. J. et al. Human PI3Kgamma deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology. Nat. Commun. 10, 4364 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. 38.

    Chervonsky, A. V. Microbiota and autoimmunity. Cold Spring Harb. Perspect. Biol. 5, a007294 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. 39.

    Mogensen, T. H. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin. Microbiol. Rev. 22, 240–273 (2009). Table.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Chervonsky, A. V. Influence of microbial environment on autoimmunity. Nat. Immunol. 11, 28–35 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Frank, D. N. et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl Acad. Sci. USA 104, 13780–13785 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Gevers, D. et al. The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe 15, 382–392 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Chassaing, B. et al. Crohn disease-associated adherent-invasive E. coli bacteria target mouse and human Peyer’s patches via long polar fimbriae. J. Clin. Invest. 121, 966–975 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Lamps, L. W. et al. Pathogenic Yersinia DNA is detected in bowel and mesenteric lymph nodes from patients with Crohn’s disease. Am. J. Surg. Pathol. 27, 220–227 (2003).

    PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    Leu, S. B. et al. Pathogenic Yersinia DNA in intestinal specimens of pediatric patients with Crohn’s disease. Fetal Pediatr. Pathol. 32, 367–370 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Navaneethan, U., Venkatesh, P. G. & Shen, B. Clostridium difficile infection and inflammatory bowel disease: understanding the evolving relationship. World J. Gastroenterol. 16, 4892–4904 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Gray, D. H., Gavanescu, I., Benoist, C. & Mathis, D. Danger-free autoimmune disease in Aire-deficient mice. Proc. Natl Acad. Sci. USA 104, 18193–18198 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48.

    Chinen, T., Volchkov, P. Y., Chervonsky, A. V. & Rudensky, A. Y. A critical role for regulatory T cell-mediated control of inflammation in the absence of commensal microbiota. J. Exp. Med. 207, 2323–2330 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    He, B. et al. Resetting microbiota by Lactobacillus reuteri inhibits T reg deficiency-induced autoimmunity via adenosine A2A receptors. J. Exp. Med. 214, 107–123 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Kawamoto, S. et al. Foxp3(+) T cells regulate immunoglobulin a selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity 41, 152–165 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. 51.

    Dobes, J. et al. Gastrointestinal autoimmunity associated with loss of central tolerance to enteric alpha-defensins. Gastroenterology 149, 139–150 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Hetemaki, I. et al. Anticommensal responses are associated with regulatory T cell defect in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients. J. Immunol. 196, 2955–2964 (2016).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  53. 53.

    Zhang, H., Sparks, J. B., Karyala, S. V., Settlage, R. & Luo, X. M. Host adaptive immunity alters gut microbiota. ISME J. 9, 770–781 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Rigoni, R. et al. Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic RAG defects. J. Exp. Med. 213, 355–375 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Zhang, L., Li, Y. Y., Tang, X. & Zhao, X. Faecal microbial dysbiosis in children with Wiskott-Aldrich syndrome. Scand. J. Immunol. 91, e12805 (2020).

    PubMed  PubMed Central  Google Scholar 

  56. 56.

    Ohya, T. et al. Childhood-onset inflammatory bowel diseases associated with mutation of Wiskott-Aldrich syndrome protein gene. World J. Gastroenterol. 23, 8544–8552 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Packey, C. D. & Sartor, R. B. Commensal bacteria, traditional and opportunistic pathogens, dysbiosis and bacterial killing in inflammatory bowel diseases. Curr. Opin. Infect. Dis. 22, 292–301 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Oh, J. et al. The altered landscape of the human skin microbiome in patients with primary immunodeficiencies. Genome Res. 23, 2103–2114 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Kelsen, J. R., Baldassano, R. N., Artis, D. & Sonnenberg, G. F. Maintaining intestinal health: the genetics and immunology of very early onset inflammatory bowel disease. Cell Mol. Gastroenterol. Hepatol. 1, 462–476 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Serra, E. G. et al. Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease. Nat. Commun. 11, 995 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Dominguez-Bello, M. G. et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl Acad. Sci. USA 107, 11971–11975 (2010).

    PubMed  Article  Google Scholar 

  62. 62.

    Charbit-Henrion, F. et al. Diagnostic yield of next-generation sequencing in very early-onset inflammatory bowel diseases: a multicentre study. J. Crohns Colitis 12, 1104–1112 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Kraaij, M. D. et al. Induction of regulatory T cells by macrophages is dependent on production of reactive oxygen species. Proc. Natl Acad. Sci. USA 107, 17686–17691 (2010).

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Schwerd, T. et al. NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease. Mucosal Immunol. 11, 562–574 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. 65.

    Sokol, H. et al. Intestinal dysbiosis in inflammatory bowel disease associated with primary immunodeficiency. J. Allergy Clin. Immunol. 143, 775–778 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  66. 66.

    Clarke, E. L. et al. T cell dynamics and response of the microbiota after gene therapy to treat X-linked severe combined immunodeficiency. Genome Med. 10, 70 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Aagaard, K. et al. The placenta harbors a unique microbiome. Sci. Transl. Med. 6, 237ra65 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  68. 68.

    Vieira, A. T., Fukumori, C. & Ferreira, C. M. New insights into therapeutic strategies for gut microbiota modulation in inflammatory diseases. Clin. Transl. Immunol. 5, e87 (2016).

    Article  CAS  Google Scholar 

  69. 69.

    Lozupone, C. A., Stombaugh, J. I., Gordon, J. I., Jansson, J. K. & Knight, R. Diversity, stability and resilience of the human gut microbiota. Nature 489, 220–230 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Walker, A. W. et al. Dominant and diet-responsive groups of bacteria within the human colonic microbiota. ISME J. 5, 220–230 (2011).

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Hill, C. et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat. Rev. Gastroenterol. Hepatol. 11, 506–514 (2014).

    PubMed  Article  Google Scholar 

  72. 72.

    Liu, Y., Tran, D. Q. & Rhoads, J. M. Probiotics in disease prevention and treatment. J. Clin. Pharm. 58(Suppl. 10), S164–S179 (2018).

    CAS  Article  Google Scholar 

  73. 73.

    Liu, Y., Alookaran, J. J. & Rhoads, J. M. Probiotics in autoimmune and inflammatory disorders. Nutrients 10, 1537 (2018).

  74. 74.

    Strisciuglio, C. et al. Bifidobacteria enhance antigen sampling and processing by dendritic cells in pediatric inflammatory bowel disease. Inflamm. Bowel. Dis. 21, 1491–1498 (2015).

    PubMed  Article  Google Scholar 

  75. 75.

    Serena, G. & Fasano, A. Use of probiotics to prevent celiac disease and IBD in pediatrics. Adv. Exp. Med. Biol. 1125, 69–81 (2019).

    PubMed  Article  Google Scholar 

  76. 76.

    Miele, E. et al. Nutrition in pediatric inflammatory bowel disease: A Position Paper on Behalf of the Porto Inflammatory Bowel Disease Group of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition. J. Pediatr. Gastroenterol. Nutr. 66, 687–708 (2018).

    PubMed  Article  Google Scholar 

  77. 77.

    Savino, F. et al. Lactobacillus reuteri DSM 17938 in infantile colic: a Randomized, Double-Blind, Placebo-Controlled Trial. Pediatrics 126, e526–e533 (2010).

    PubMed  Article  Google Scholar 

  78. 78.

    Dinleyici, E. C. et al. Lactobacillus reuteri DSM 17938 shortens acute infectious diarrhea in a pediatric outpatient setting. J. Pediatr. 91, 392–396 (2015).

    Article  Google Scholar 

  79. 79.

    Fatheree, N. Y. et al. Lactobacillus reuteri for infants with colic: a Double-Blind, Placebo-Controlled, Randomized Clinical Trial. J. Pediatr. 191, 170–178 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Ohta, A. & Sitkovsky, M. Extracellular adenosine-mediated modulation of regulatory T cells. Front. Immunol. 5, 304 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  81. 81.

    Romio, M. et al. Extracellular purine metabolism and signaling of CD73-derived adenosine in murine Treg and Teff cells. Am. J. Physiol. Cell Physiol. 301, C530–C539 (2011).

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Liu, Y. et al. Lactobacillus reuteri DSM 17938 feeding of healthy newborn mice regulates immune responses while modulating gut microbiota and boosting beneficial metabolites. Am. J. Physiol. Gastrointest. Liver Physiol. 317, G824–G838 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Antonioli, L., Pacher, P., Vizi, E. S. & Hasko, G. CD39 and CD73 in immunity and inflammation. Trends Mol. Med. 19, 355–367 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    He, B., Hoang, T. K., Tran, D. Q., Rhoads, J. M. & Liu, Y. Adenosine A2A receptor deletion blocks the beneficial effects of Lactobacillus reuteri in regulatory T-deficient scurfy mice. Front. Immunol. 8, 1680 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  85. 85.

    Santoni de Sio, F. R. et al. Role of human forkhead box P3 in early thymic maturation and peripheral T-cell homeostasis. J. Allergy Clin. Immunol. 142, 1909–1921 (2018).

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Goodwin, M. et al. CRISPR-based gene editing enables FOXP3 gene repair in IPEX patient cells. Sci. Adv. 6, eaaz0571 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Bacchetta, R. et al. Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J. Clin. Invest. 116, 1713–1722 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Bacchetta, R., Barzaghi, F. & Roncarolo, M. G. From IPEX syndrome to FOXP3 mutation: a lesson on immune dysregulation. Ann. NY Acad. Sci. 1417, 5–22 (2018).

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Blair, P. J. et al. CD4+CD8- T cells are the effector cells in disease pathogenesis in the scurfy (sf) mouse. J. Immunol. 153, 3764–3774 (1994).

    CAS  PubMed  Google Scholar 

  90. 90.

    Suscovich, T. J., Perdue, N. R. & Campbell, D. J. Type-1 immunity drives early lethality in scurfy mice. Eur. J. Immunol. 42, 2305–2310 (2012).

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Caudy, A. A., Reddy, S. T., Chatila, T., Atkinson, J. P. & Verbsky, J. W. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J. Allergy Clin. Immunol. 119, 482–487 (2007).

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Garg, G. et al. Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminished CD4+CD25+ regulatory T cell function. J. Immunol. 188, 4644–4653 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Goudy, K. et al. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clin. Immunol. 146, 248–261 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    d’Azzo, A., Bongiovanni, A. & Nastasi, T. E3 ubiquitin ligases as regulators of membrane protein trafficking and degradation. Traffic 6, 429–441 (2005).

    PubMed  Article  CAS  Google Scholar 

  95. 95.

    Liu, Y. C. The E3 ubiquitin ligase Itch in T cell activation, differentiation, and tolerance. Semin. Immunol. 19, 197–205 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Roychoudhuri, R. et al. BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis. Nature 498, 506–510 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97.

    Buchbinder, E. I. & Desai, A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am. J. Clin. Oncol. 39, 98–106 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Charbonnier, L. M. et al. Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA. J. Allergy Clin. Immunol. 135, 217–227 (2015).

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Alroqi, F. J. et al. DOCK8 deficiency presenting as an IPEX-like disorder. J. Clin. Immunol. 37, 811–819 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    Biggs, C. M., Keles, S. & Chatila, T. A. DOCK8 deficiency: insights into pathophysiology, clinical features and management. Clin. Immunol. 181, 75–82 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Charbit-Henrion, F. et al. Deficiency in mucosa-associated lymphoid tissue lymphoma translocation 1: a novel cause of IPEX-like syndrome. J. Pediatr. Gastroenterol. Nutr. 64, 378–384 (2017).

    PubMed  Article  CAS  Google Scholar 

  102. 102.

    Brustle, A. et al. MALT1 is an intrinsic regulator of regulatory T cells. Cell Death Differ. 24, 1214–1223 (2017).

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Liu, L. et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J. Exp. Med. 208, 1635–1648 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Uzel, G. et al. Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome. J. Allergy Clin. Immunol. 131, 1611–1623 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. 105.

    Weinacht, K. G. et al. Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation. J. Allergy Clin. Immunol. 139, 1629–1640 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Haapaniemi, E. M. et al. Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3. Blood 125, 639–648 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. 107.

    Harris, T. J. et al. Cutting edge: an in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity. J. Immunol. 179, 4313–4317 (2007).

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    Milner, J. D. et al. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood 125, 591–599 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. 109.

    Jenks, J. A. et al. Differentiating the roles of STAT5B and STAT5A in human CD4+ T cells. Clin. Immunol. 148, 227–236 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. 110.

    Kanai, T., Jenks, J. & Nadeau, K. C. The STAT5b pathway defect and autoimmunity. Front. Immunol. 3, 234 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Anderson, M. S. et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 298, 1395–1401 (2002).

    CAS  PubMed  Article  Google Scholar 

  112. 112.

    Guo, C. J., Leung, P. S. C., Zhang, W., Ma, X. & Gershwin, M. E. The immunobiology and clinical features of type 1 autoimmune polyglandular syndrome (APS-1). Autoimmun. Rev. 17, 78–85 (2018).

    CAS  PubMed  Article  Google Scholar 

  113. 113.

    Laakso, S. M. et al. Regulatory T cell defect in APECED patients is associated with loss of naive FOXP3(+) precursors and impaired activated population. J. Autoimmun. 35, 351–357 (2010).

    CAS  PubMed  Article  Google Scholar 

  114. 114.

    Cassani, B. et al. Defect of regulatory T cells in patients with Omenn syndrome. J. Allergy Clin. Immunol. 125, 209–216 (2010).

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Lee, Y. N. et al. Characterization of T and B cell repertoire diversity in patients with RAG deficiency. Sci. Immunol. 1, eaah6109 (2016).

  116. 116.

    de la Chapelle, A., Herva, R., Koivisto, M. & Aula, P. A deletion in chromosome 22 can cause DiGeorge syndrome. Hum. Genet. 57, 253–256 (1981).

    PubMed  Article  Google Scholar 

  117. 117.

    McDonald-McGinn, D. M. et al. Phenotype of the 22q11.2 deletion in individuals identified through an affected relative: cast a wide FISHing net! Genet. Med. 3, 23–29 (2001).

    CAS  PubMed  Article  Google Scholar 

  118. 118.

    Sullivan, K. E., McDonald-McGinn, D. & Zackai, E. H. CD4(+) CD25(+) T-cell production in healthy humans and in patients with thymic hypoplasia. Clin. Diagn. Lab. Immunol. 9, 1129–1131 (2002).

    PubMed  PubMed Central  Google Scholar 

  119. 119.

    Adriani, M. et al. Impaired in vitro regulatory T cell function associated with Wiskott-Aldrich syndrome. Clin. Immunol. 124, 41–48 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Marangoni, F. et al. WASP regulates suppressor activity of human and murine CD4(+)CD25(+)FOXP3(+) natural regulatory T cells. J. Exp. Med. 204, 369–380 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

The study was supported by NIH/NCCIH R01AT007083 and NIH/NIAID R03AI117442. The probiotic Lactobacillus reuteri DSM 17938 was obtained as a gift from BioGaia AB.

Author information

Affiliations

Authors

Contributions

Y.L. has contributed to the conception and the structure. J.F. and S.A.A. have contributed to the acquisition and summarization of literature. Y.L. drafted the article. D.QT. and J.M.R. revised it critically for important intellectual content. All authors have reviewed and edited the article and approved the final version to be published.

Corresponding author

Correspondence to Yuying Liu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Liu, Y., Freeborn, J., Armbrister, S.A. et al. Treg-associated monogenic autoimmune disorders and gut microbial dysbiosis. Pediatr Res (2021). https://doi.org/10.1038/s41390-021-01445-2

Download citation

Search

Quick links