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Tolerance and Autoimmunity in Primary Immunodeficiency Disease: a Comprehensive Review

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Abstract

The immune system has evolved to respond to pathogens (nonself) and unresponsive to self-antigens (tolerance). During the development of T and B cells in the thymus and bone marrow, respectively, self-reactive T and B cells are deleted by a process of apoptosis (both T and B cells) and become unresponsive to self-antigen by receptor editing (for B cells). However, few self-reactive T cells are leaked into the periphery. A number of mechanisms are responsible to ensure that self-reactive T and B cells remain unresponsive to self-antigens. In the central tolerance, major mechanisms include apoptosis (for T cells) and receptor editing (for B cells), and in the peripheral tolerance, a major mechanism appears to be regulated by Treg cells. In T cell central tolerance, one of the most important molecules is a transcription factor, autoimmune regulator, which is selectively expressed in medullary thymic epithelial cells (mTECs) and constitutively regulates the transcription of hundreds of self-antigens in mTECs, thereby inducing central tolerance, negative selection, and Treg differentiation from some self-reactive thymocytes. Primary immunodeficiency diseases are a group of monogenic diseases where mutations of certain genes have resulted in the loss of central and/or peripheral tolerance. As a result autoimmunity and autoimmune diseases are common among patients with primary immunodeficiency diseases. Here, we have provided a comprehensive review of the mechanisms of central and peripheral tolerance and autoimmune manifestations and mechanisms of autoimmunity in primary immunodeficiency diseases.

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References

  1. Nortarangelo LD, Gambineri E, Badolato R (2006) Immunodeficiencies with autoimmune consequences. Adv Immunol 89:321–370

    Article  Google Scholar 

  2. Westerberg LS, Klein C, Snapper SB (2008) Breakdown of T cell tolerance and autoimmunity in primary immunodeficiency—lessons learned from monogenic disorders in mice and men. Curr Opin Immunol 20:646–654

    Article  PubMed  CAS  Google Scholar 

  3. Ulmanen I, Halonen M, Ilmarinen T, Peltonen L (2005) Monogenic autoimmune diseases—lessons of self-tolerance. Curr Opin Immunol 17:609–615

    Article  PubMed  CAS  Google Scholar 

  4. Derbinski J, Schulte A, Kyewski B, Klein L (2001) Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2:1032–1039

    Article  PubMed  CAS  Google Scholar 

  5. Mathis D, Benoist C (2009) Aire. Ann Rev Immuno 27:287–312

    Article  CAS  Google Scholar 

  6. Hogquist KA, Baldwin TA, Jameson SC (2005) Central tolerance: learning self-control in the thymus. Nat Rev Immunol 5:772–782

    Article  PubMed  CAS  Google Scholar 

  7. Baba T, Nakamoto Y, Mukaida N (2009) Crucial contribution of thymic Sirp alpha + conventional dendritic cells to central tolerance against blood-borne antigens I a CCR2-dependent manner. J Immunol 183:3053–3063

    Article  PubMed  CAS  Google Scholar 

  8. Pillai S, Mattoo H, Cariappa A (2011) B cells and autoimmunity. Curr Opin Immunol 23:721–731

    Article  PubMed  CAS  Google Scholar 

  9. Mauri C, Bosma A (2012) Immune regulatory function of B cells. Ann Rev Immunol 30:221–241

    Article  CAS  Google Scholar 

  10. Sakaguchi S, Yamaguchi T, Nomura T, Ono R (2008) Regulatory T cells and immune tolerance. Cell 133:775–787

    Article  PubMed  CAS  Google Scholar 

  11. Moraes-Vasconcelos D, Costa-Carvalho BT, Torgerson TR, Ochs HD (2008) Primary immune deficiency disorders presenting as autoimmune diseases: IPEX and APECED. J Clin Immunol 28(Suppl 1):S11–S19

    Article  PubMed  CAS  Google Scholar 

  12. Brunkow ME, Jeffrey EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA et al (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27:68–73

    Article  PubMed  CAS  Google Scholar 

  13. Notarangelo JD (2010) Primary immunodeficiencies. J Allergy Clin Immunol 125:S182–S194

    Article  PubMed  Google Scholar 

  14. Finish-German APECED Consortium (1997) An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zing-finger domains. Nat Genet 17:399–403

    Article  Google Scholar 

  15. Villaseñor J, Benoist C, Mathis D (2005) AIRE and APECED: molecular insights into an autoimmune disease. Immunol Rev 204:156–164

    Article  PubMed  Google Scholar 

  16. Wildin RS, Smyk-Pearson S, Filipovich AH (2002) Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Gent 39:537–545

    Article  CAS  Google Scholar 

  17. Bosco JB, Gupta S (2008) Disorders of apoptosis: mechanisms for autoimmunity in primary immunodeficiency diseases. J Clin Immunol 28:S20–S28

    Article  Google Scholar 

  18. Poliani PL, Facchetti F, Ravanini M, Gennery AR, Villa A, Roifman CM et al (2009) Eraly defects in T cell development severely affect distribution and maturation of thymic stromal cells: possible implications for the pathophysiology of Omenn syndrome. Blood 114:105–108

    Article  PubMed  CAS  Google Scholar 

  19. Nadeau K, Hwa V, Rosenfeld RG (2011) STAT5b deficiency: an unsuspected cause of growth failure, immunodeficiency, and sever pulmonary disease. J Ped 158:701–708

    Article  CAS  Google Scholar 

  20. Cohen AC, Nadeau KC, Tu W, Hwa V, Dionis K, Dezrodnik I et al (2006) Decreased accumulation and regulatory function of CD4+ CD25 (high) T cells in human STAT5b deficiency. J Immunol 177:2770–2774

    PubMed  CAS  Google Scholar 

  21. Willerford DM, Chen J, Ferry JA, Davidson L, Ma A, Alt FW (1995) Interleukin 2 receptor alpha chain regulate the size and content of the peripheral lymphoid compartment. Immunity 3:521–530

    Article  PubMed  CAS  Google Scholar 

  22. Sharfe N, Dadi HK, Shahar M, Roifman CM (1997) Human immune disorder arising from mutation of the α chain of the interleukin-2 receptor. Proc Natl Acad Sci (USA) 94:3168–3171

    Article  CAS  Google Scholar 

  23. Roifman CM (2000) Human IL-2 receptor alpha chain deficiency. Pediatr Res 48:6–11

    Article  PubMed  CAS  Google Scholar 

  24. Feske S, Picard C, Fischer A (2010) Immunodeficiency due to mutations in ORAI1 and STIM1. Clin Immunol 135:162–182

    Article  Google Scholar 

  25. Picard C, McCarl CA, Papolos A, Khalil S, Luthy K, Hivroz C, LeDeist F et al (2009) STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity. N Eng J Med 360:1971–1980

    Article  CAS  Google Scholar 

  26. Jesus AA, Duarte AJ, Oliveira JB (2008) Autoimmunity in hyper-IgM syndrome. J Clin Immunol 28(Suppl 1):S62–S66

    Article  PubMed  CAS  Google Scholar 

  27. Notarangelo LD, Miao CH, Ochs HD (2008) Wiskott–Aldrich syndrome. Curr Opin Hematol 15:30–36

    Article  PubMed  CAS  Google Scholar 

  28. Freeman AF, Holland SH (2008) The hyper-IgE syndromes. Immunol Allergy Clin North Am 28:277–291

    Article  PubMed  Google Scholar 

  29. De Ravin SS, Naumann N, Cowen EW et al (2008) Chronic granulomatous disease as a risk for autoimmune disease. J Allergy Clin Immunol 122:1097–1103

    Article  PubMed  Google Scholar 

  30. Kraaij MD, Savageb NDL, van der Kooija SW, Koekkoeka K, Wangc J, van den Bergd JM et al (2010) Induction of regulatory T cells by macrophages is dependent on production of reactive oxygen species. Proc Natl Acad Sci (USA) 107:17686–17691

    Article  CAS  Google Scholar 

  31. Collin M, Bigley V, Haniffa M, Hambleton S (2011) Human dendritic cell deficiency: the missing ID? Nature Rev Immunol 11:575–583

    Article  CAS  Google Scholar 

  32. Barilla-LaBarca MI, Atkinson JP (2003) Rheumatic syndromes associated with complement deficiency. Curr Opin Rheumatol 15:55–60

    Article  PubMed  CAS  Google Scholar 

  33. Unsworth DJ (2008) Complement deficiency and disease. J Clin Pathol 61:1013–1017

    Article  PubMed  CAS  Google Scholar 

  34. Knight AK, Cunningham-Rundles C (2006) Inflammatory and autoimmune complications of common variable immune deficiency. Autoimmune Rev 5:156–159

    Article  CAS  Google Scholar 

  35. Baccheli C, Buckridge S, Thrasher AJ, Gasper HB (2007) Molecular defects in common variable immunodeficiency. J Exp Immunol 149:401–409

    Article  Google Scholar 

  36. Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, Drager R et al (2003) Homozygous loss of ICOS is associated with adult onset common variable immunodeficiency. Nat Immunol 4:261–268

    Article  PubMed  CAS  Google Scholar 

  37. Van Zelm MC, Reisli I, van der Burg M, Castano D, van Noesel CJ, van Tol MJ et al (2006) An antibody deficiency syndrome due to mutation in the CD19 gene. N Eng J Med 354:1901–1912

    Article  Google Scholar 

  38. Castigli E, Wilson SA, Garibyan I, Rachid R, Bonilla F, Schneider L et al (2005) TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Gen 37:829–834

    Article  CAS  Google Scholar 

  39. Losi CG, Silini A, Fiorini C, Soresina A, Meini A, Meini A, Ferrari S et al (2005) Mutational analysis of human BAFF receptor TNFRSF13C (BAFF-R) in patients with common variable immunodeficiency. J Clin Immunol 25:496–502

    Article  PubMed  CAS  Google Scholar 

  40. Yu GP, Chiang D, Song SJ, Hoyte EG, Huang J, Vanisharn C et al (2009) Regulator T cell dysfunction in subjects with common variable immunodeficiency complicated by autoimmune disease. Clin Immunol 131:240–253

    Article  PubMed  CAS  Google Scholar 

  41. Yel L (2010) Selective IgA deficiency. J Clin Immunol 30:10–16

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Programs in Primary Immunodeficiency and Aging and Jeffrey Modell Diagnostic Center for Primary Immunodeficiencies, Division of Basic and Clinical Immunology, Medical sciences I, C-240, University of California at Irvine, Irvine, CA, 92697, USA

    Sudhir Gupta & Ankmalika Gupta Louis

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  1. Sudhir Gupta
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  2. Ankmalika Gupta Louis
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Correspondence to Sudhir Gupta.

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Gupta, S., Louis, A.G. Tolerance and Autoimmunity in Primary Immunodeficiency Disease: a Comprehensive Review. Clinic Rev Allerg Immunol 45, 162–169 (2013). https://doi.org/10.1007/s12016-012-8345-8

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  • DOI: https://doi.org/10.1007/s12016-012-8345-8

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