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Immunodeficiency and Autoimmunity

  • T. Prescott Atkinson
Chapter

Abstract

Immunodeficiencies are inherited and acquired defects in immune function that produce increased susceptibility to infection and, often, increased reactivity to self (autoimmunity) and environmental antigens (allergy/hypersensitivity). The primary immunodeficiency diseases are an ever-widening group of genetic disorders with defects in innate or adaptive immunity or both. Increasingly, it is becoming recognized that primary immune deficiency disorders are associated with immune dysregulation and autoimmune phenomena. This chapter will review current knowledge about those primary immune deficiency disorders that are associated with autoimmunity and the diverse underlying mechanisms of pathogenesis involved in the loss of self-tolerance that are responsible for these associations.

Keywords

Immunologic deficiency syndromes Autoimmune disease Human microbiome Genetic diseases Immune tolerance Regulatory T cells T cells B cells 

Abbreviations

AD

Autosomal dominant

AIRE

Autoimmune regulator

APDS

Activated PI3K-delta syndrome

APECED

Autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia

AR

Autosomal recessive

CHARGE syndrome

Coloboma, heart defects, atresia choanae (also known as choanal atresia), growth retardation, genital abnormalities, and ear abnormalities

CHD7

Chromodomain-helicase-DNA-binding protein 7

CMV

Cytomegalovirus

CTLA4

Cytotoxic T-lymphocyte-associated protein 4

DCLRE1c

DNA cross-link repair 1C (also known as Artemis)

GOF

Gain-of-function

IPEX

Immune dysregulation polyendocrinopathy enteropathy X-linked

ITCH

Itchy E3 ubiquitin protein ligase

ITP

Idiopathic thrombocytopenic purpura

JIA

Juvenile idiopathic arthritis

LIG4

DNA ligase 4

LOF

Loss-of-function

LRBA

Lipopolysaccharide (LPS)-responsive vesicle trafficking, beach- and anchor-containing

MDA

Melanoma differentiation-associated protein

NFAT

Nuclear factor of activated T cells

NHEJ1

Nonhomologous end-joining factor 1

PIDD

Primary immune deficiency disorders

PRKDC

Protein kinase, DNA-activated, catalytic polypeptide

pTreg

Peripheral regulatory T cells

RAG

Recombinase activating gene

SCID

Severe combined immunodeficiency

SEMA3E

Semaphorin 3E

STAT

Signal transducer and activator of transcription

TBX1

T-box transcription factor 1

TCR

T cell receptor

TLR

Toll-like receptor

Treg

Regulatory T cell

tTreg

Thymic-derived regulatory T cells

XLA

X-linked agammaglobulinemia

References

  1. 1.
    Raje N, Dinakar C. Overview of immunodeficiency disorders. Immunol Allergy Clin North Am. 2015;35(4):599–623.  https://doi.org/10.1016/j.iac.2015.07.001.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Picard C, et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for primary immunodeficiency 2015. J Clin Immunol. 2015;19:19.Google Scholar
  3. 3.
    Bousfiha A, et al. The 2015 IUIS phenotypic classification for primary immunodeficiencies. J Clin Immunol. 2015;7:7.Google Scholar
  4. 4.
    Martin M, Blom AM. Complement in removal of the dead – balancing inflammation. Immunol Rev. 2016;274(1):218–32.  https://doi.org/10.1111/imr.12462.CrossRefPubMedGoogle Scholar
  5. 5.
    Son M, Diamond B, Santiago-Schwarz F. Fundamental role of C1q in autoimmunity and inflammation. Immunol Res. 2015;63(1–3):101–6.  https://doi.org/10.1007/s12026-015-8705-6.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Uzzan M, et al. Gastrointestinal disorders associated with common variable immune deficiency (CVID) and chronic granulomatous disease (CGD). Curr Gastroenterol Rep. 2016;18(4):17.  https://doi.org/10.1007/s11894-016-0491-3.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Lu L, Barbi J, Pan F. The regulation of immune tolerance by FOXP3. Nat Rev Immunol. 2017;31(10):75.Google Scholar
  8. 8.
    Palomares O, et al. Mechanisms of immune regulation in allergic diseases: the role of regulatory T and B cells. Immunol Rev. 2017;278(1):219–36.  https://doi.org/10.1111/imr.12555.CrossRefPubMedGoogle Scholar
  9. 9.
    Wang YM, et al. Development and function of Foxp3(+) regulatory T cells. Nephrology (Carlton). 2016;21(2):81–5.  https://doi.org/10.1111/nep.12652.CrossRefGoogle Scholar
  10. 10.
    Caramalho I, et al. Regulatory T-cell development in the human thymus. Front Immunol. 2015;6:395.  https://doi.org/10.3389/fimmu.2015.00395. eCollection 2015.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol. 2012;30:531–64.  https://doi.org/10.1146/annurev.immunol.25.022106.141623.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Walter JE, et al. Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency. J Clin Invest. 2015;125(11):4135–48.  https://doi.org/10.1172/JCI80477.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Davies EG. Immunodeficiency in DiGeorge syndrome and options for treating cases with complete athymia. Front Immunol. 2013;4:322.  https://doi.org/10.3389/fimmu.2013.00322.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kwan A, Puck JM. History and current status of newborn screening for severe combined immunodeficiency. Semin Perinatol. 2015;39(3):194–205.  https://doi.org/10.1053/j.semperi.2015.03.004.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    McDonald-McGinn DM, et al. 22q11.2 deletion syndrome. Nat Rev Dis Primers. 2015;1:15071.  https://doi.org/10.1038/nrdp.2015.71.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Wong MT, et al. CHARGE syndrome: a review of the immunological aspects. Eur J Hum Genet. 2015;23(11):1451–9.  https://doi.org/10.1038/ejhg.2015.7.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Rota IA, Dhalla F. FOXN1 deficient nude severe combined immunodeficiency. Orphanet J Rare Dis. 2017;12(1):6.  https://doi.org/10.1186/s13023-016-0557-1.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Tison BE, et al. Autoimmunity in a cohort of 130 pediatric patients with partial DiGeorge syndrome. J Allergy Clin Immunol. 2011;128(5):1115–7e1-3.CrossRefPubMedGoogle Scholar
  19. 19.
    Jawad AF, et al. Immunologic features of chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). J Pediatr. 2001;139(5):715–23.CrossRefPubMedGoogle Scholar
  20. 20.
    Ferrando-Martinez S, et al. Low thymic output, peripheral homeostasis deregulation, and hastened regulatory T cells differentiation in children with 22q11.2 deletion syndrome. J Pediatr. 2014;164(4):882–9.  https://doi.org/10.1016/j.jpeds.2013.12.013.CrossRefPubMedGoogle Scholar
  21. 21.
    de Villartay JP. Congenital defects in V(D)J recombination. Br Med Bull. 2015;114(1):157–67.  https://doi.org/10.1093/bmb/ldv020.CrossRefPubMedGoogle Scholar
  22. 22.
    Lee PP, et al. The many faces of Artemis-deficient combined immunodeficiency – two patients with DCLRE1C mutations and a systematic literature review of genotype-phenotype correlation. Clin Immunol. 2013;149(3):464–74.  https://doi.org/10.1016/j.clim.2013.08.006.CrossRefPubMedGoogle Scholar
  23. 23.
    Buck D, et al. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell. 2006;124(2):287–99.CrossRefPubMedGoogle Scholar
  24. 24.
    Chen K, et al. Autoimmunity due to RAG deficiency and estimated disease incidence in RAG1/2 mutations. J Allergy Clin Immunol. 2014;133(3):880–2e10.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Notarangelo LD, et al. Human RAG mutations: biochemistry and clinical implications. Nat Rev Immunol. 2016;16(4):234–46.  https://doi.org/10.1038/nri.2016.28.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Lee YN, et al. Characterization of T and B cell repertoire diversity in patients with RAG deficiency. Sci Immunol. 2016;1(6):eaah6109.  https://doi.org/10.1126/sciimmunol.aah6109.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    De Ravin SS, et al. Hypomorphic rag mutations can cause destructive midline granulomatous disease. Blood. 2010;116(8):1263–71.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Mathieu AL, et al. PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity. J Allergy Clin Immunol. 2015;135(6):1578–88.e5.  https://doi.org/10.1016/j.jaci.2015.01.040.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Cavadini P, et al. AIRE deficiency in thymus of 2 patients with Omenn syndrome. J Clin Invest. 2005;115(3):728–32.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Poliani PL, et al. Early defects in human T-cell development severely affect distribution and maturation of thymic stromal cells: possible implications for the pathophysiology of Omenn syndrome. Blood. 2009;114(1):105–8.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Anderson MS, et al. Projection of an immunological self shadow within the thymus by the aire protein. Science. 2002;298(5597):1395–401.CrossRefPubMedGoogle Scholar
  32. 32.
    Bansal K, et al. The transcriptional regulator aire binds to and activates super-enhancers. Nat Immunol. 2017;18(3):263–73.  https://doi.org/10.1038/ni.3675.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Villasenor J, Benoist C, Mathis D. AIRE and APECED: molecular insights into an autoimmune disease. Immunol Rev. 2005;204:156–64.CrossRefPubMedGoogle Scholar
  34. 34.
    Nagamine K, et al. Positional cloning of the APECED gene. Nat Genet. 1997;17(4):393–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Bennett CL, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27(1):20–1.CrossRefPubMedGoogle Scholar
  36. 36.
    Reichert SL, McKay EM, Moldenhauer JS. Identification of a novel nonsense mutation in the FOXP3 gene in a fetus with hydrops – expanding the phenotype of IPEX syndrome. Am J Med Genet A. 2016;170A(1):226–32.  https://doi.org/10.1002/ajmg.a.37401.CrossRefPubMedGoogle Scholar
  37. 37.
    Xavier-da-Silva MM, et al. Fetal-onset IPEX: report of two families and review of literature. Clin Immunol. 2014;156(2):131–40.CrossRefPubMedGoogle Scholar
  38. 38.
    Hannibal MC, Torgerson T. IPEX syndrome. In:GeneReviews – NCBI bookshelf. Seattle: University of Washington; 2011.Google Scholar
  39. 39.
    van der Vliet HJ, Nieuwenhuis EE. IPEX as a result of mutations in FOXP3. Clin Dev Immunol. 2007;2007:89017.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Lohr NJ, et al. Human ITCH E3 ubiquitin ligase deficiency causes syndromic multisystem autoimmune disease. Am J Hum Genet. 2010;86(3):447–53.  https://doi.org/10.1016/j.ajhg.2010.01.028.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Venuprasad K. Cbl-b and itch: key regulators of peripheral T-cell tolerance. Cancer Res. 2010;70(8):3009–12.  https://doi.org/10.1158/0008-5472.CAN-09-4076.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Venuprasad K, et al. The E3 ubiquitin ligase itch regulates expression of transcription factor Foxp3 and airway inflammation by enhancing the function of transcription factor TIEG1. Nat Immunol. 2008;9(3):245–53.  https://doi.org/10.1038/ni1564.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Sharfe N, et al. Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor. Proc Natl Acad Sci U S A. 1997;94(7):3168–71.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Caudy AA, et al. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J Allergy Clin Immunol. 2007;119(2):482–7.CrossRefPubMedGoogle Scholar
  45. 45.
    Lorenzini T, et al. STAT mutations as program switchers: turning primary immunodeficiencies into autoimmune diseases. J Leukoc Biol. 2017;101(1):29–38.  https://doi.org/10.1189/jlb.5RI0516-237RR.CrossRefPubMedGoogle Scholar
  46. 46.
    Casanova JL, Holland SM, Notarangelo LD. Inborn errors of human JAKs and STATs. Immunity. 2012;36(4):515–28.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Rieux-Laucat F, Casanova JL. Immunology. Autoimmunity by haploinsufficiency. Science. 2014;345(6204):1560–1.  https://doi.org/10.1126/science.1260791.CrossRefPubMedGoogle Scholar
  48. 48.
    Schubert D, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014;20(12):1410–6.  https://doi.org/10.1038/nm.3746.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Kuehn HS, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2014;345(6204):1623–7.  https://doi.org/10.1126/science.1255904.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Jouhadi Z, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Pediatrics. 2014;134(5):e1458–63.  https://doi.org/10.1542/peds.2013-1383.CrossRefPubMedGoogle Scholar
  51. 51.
    Lo B, et al. Autoimmune disease. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. 2015;349(6246):436–40.  https://doi.org/10.1126/science.aaa1663.CrossRefPubMedGoogle Scholar
  52. 52.
    Boland BS, et al. Immunodeficiency and autoimmune enterocolopathy linked to NFAT5 haploinsufficiency. J Immunol. 2015;194(6):2551–60.  https://doi.org/10.4049/jimmunol.1401463.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Toubiana J, et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood. 2016;127(25):3154–64.  https://doi.org/10.1182/blood-2015-11-679902.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Depner M, et al. The extended clinical phenotype of 26 patients with chronic mucocutaneous candidiasis due to gain-of-function mutations in STAT1. J Clin Immunol. 2015;25:25.Google Scholar
  55. 55.
    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. 2013;131(6):1611–23.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Tsumura M, et al. Dominant-negative STAT1 SH2 domain mutations in unrelated patients with Mendelian susceptibility to mycobacterial disease. Hum Mutat. 2012;33(9):1377–87.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Boisson-Dupuis S, et al. Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes. Curr Opin Immunol. 2012;24(4):364–78.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Smeekens SP, et al. STAT1 hyperphosphorylation and defective IL12R/IL23R signaling underlie defective immunity in autosomal dominant chronic mucocutaneous candidiasis. PLoS One. 2011;6(12):e29248.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    van de Veerdonk FL, et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med. 2011;365(1):54–61.CrossRefPubMedGoogle Scholar
  60. 60.
    Liu L, et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med. 2011;208(8):1635–48.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Mossner R, et al. Ruxolitinib induces interleukin 17 and ameliorates chronic mucocutaneous candidiasis caused by STAT1 gain-of-function mutation. Clin Infect Dis. 2016;62(7):951–3.  https://doi.org/10.1093/cid/ciw020.CrossRefPubMedGoogle Scholar
  62. 62.
    Vogel TP, Milner JD, Cooper MA. The Ying and Yang of STAT3 in human disease. J Clin Immunol. 2015;35(7):615–23.  https://doi.org/10.1007/s10875-015-0187-8.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Milner JD, et al. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood. 2015;125(4):591–9.  https://doi.org/10.1182/blood-2014-09-602763.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Milner JD, et al. Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3. Blood. 2015;125(4):591–9.  https://doi.org/10.1182/blood-2014-09-602763.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Lucas CL, et al. PI3Kdelta and primary immunodeficiencies. Nat Rev Immunol. 2016;16(11):702–14.  https://doi.org/10.1038/nri.2016.93.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Heurtier L, Deau MC, Kracker S. Hyper-activated PI3K-delta in immunodeficiency. Oncotarget. 2015;6(21):18242–3.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Angulo I, et al. Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science. 2013;342(6160):866–71.  https://doi.org/10.1126/science.1243292.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Lucas CL, et al. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency. Nat Immunol. 2014;15(1):88–97.  https://doi.org/10.1038/ni.2771.CrossRefPubMedGoogle Scholar
  69. 69.
    Coulter TI, et al. Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: a large patient cohort study. J Allergy Clin Immunol. 2017;139(2):597–606.e4.  https://doi.org/10.1016/j.jaci.2016.06.021.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Corneth OB, Klein Wolterink RG, Hendriks RW. BTK signaling in B cell differentiation and autoimmunity. Curr Top Microbiol Immunol. 2016;393:67–105.  https://doi.org/10.1007/82_2015_478.CrossRefPubMedGoogle Scholar
  71. 71.
    Hernandez-Trujillo VP, et al. Autoimmunity and inflammation in X-linked agammaglobulinemia. J Clin Immunol. 2014;34(6):627–32.  https://doi.org/10.1007/s10875-014-0056-x.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Ng YS, et al. Bruton’s tyrosine kinase is essential for human B cell tolerance. J Exp Med. 2004;200(7):927–34.CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Pediatric Allergy, Asthma and ImmunologyUniversity of Alabama at BirminghamBirminghamUSA

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