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Autoimmunity and Primary Immunodeficiency Disorders

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Abstract

Advances in DNA sequencing technologies have led to a quickening in the pace at which new genetic immunodeficiency disorders have been identified. Among the newly identified defects are a number of disorders that present primarily with autoimmunity as opposed to recurrent infections. These “immune dysregulation” disorders have begun to cluster together to form an increased understanding of some of the basic molecular mechanisms that underlie the establishment and maintenance of immune tolerance and the development of autoimmunity. This review will present three major themes that have emerged in our understanding of the mechanisms that underlie autoimmunity and immune dysregulation in humans.

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References

  1. Hertzog PJ. Overview. Type I interferons as primers, activators and inhibitors of innate and adaptive immune responses. Immunol Cell Biol. 2012;90:471–3.

    Article  CAS  PubMed  Google Scholar 

  2. Furze RC, Rankin SM. Neutrophil mobilization and clearance in the bone marrow. Immunology. 2008;125(3):281–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Vandivier RW, Henson PM, Douglas IS. Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease. Chest. 2006;129(6):1673–82.

    Article  PubMed  Google Scholar 

  4. Hochreiter-Hufford A, Ravichandran KS. Clearing the dead: apoptotic cell sensing, recognition, engulfment, and digestion. Cold Spring Harb Perspect Biol. 2013;5(1):a008748.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Pisetsky DS. The danger of sex and death in Scarf1 −/− autoimmune mice. Nat Immunol. 2013;14:888–9.

    Article  CAS  PubMed  Google Scholar 

  6. Walport MJ, Davies KA, Botto M. C1q and systemic lupus erythematosus. Immunobiology. 1998;199(2):265–85.

    Article  CAS  PubMed  Google Scholar 

  7. Steinsson K, Erlendsson K, Valdimarsson H. Successful plasma infusion treatment of a patient with C2 deficiency and systemic lupus erythematosus: clinical experience over forty-five months. Arthritis Rheum. 1989;32:906–13.

    CAS  PubMed  Google Scholar 

  8. Cale CM, Morton L, Goldblatt D. Cutaneous and other lupus-like symptoms in carriers of X-linked chronic granulomatous disease: incidence and autoimmune serology. Clin Exp Immunol. 2007;148(1):79–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Samejima K, Earnshaw WC. Trashing the genome: the role of nucleases during apoptosis. Nat Rev Mol Cell Biol. 2005;6:677–88.

    Article  CAS  PubMed  Google Scholar 

  10. Yasutomo K, Horiuchi T, Kagami S, Tsukamoto H, Hashimura C, Urushihara M, et al. Mutation of DNASE1 in people with systemic lupus erythematosus. Nat Genet. 2001;28(4):313–4.

    Article  CAS  PubMed  Google Scholar 

  11. Lee-Kirsch MA, Gong M, Chowdhury D, Senenko L, Engel K, Lee YA, et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet. 2007;39(9):1065–7.

    Article  CAS  PubMed  Google Scholar 

  12. Rice G, Newman WG, Dean J, Patrick T, Parmar R, Flintoff K, et al. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. Am J Hum Genet. 2007;80(4):811–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fye JM, Orebaugh CD, Coffin SR, Hollis T, Perrino FW. Dominant mutations of the TREX1 exonuclease gene in lupus and Aicardi-Goutières syndrome. J Biol Chem. 2011;286(37):32373–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rice GI, del Toro Duany Y, Jenkinson EM, Forte GM, Anderson BH, Ariaudo G, et al. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat Genet. 2014;46(5):503–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Miner JJ, Diamond MS. MDA5 and autoimmune disease. Nat Genet. 2014;46(5):418–9.

    Article  CAS  PubMed  Google Scholar 

  16. Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Montealegre Sanchez GA, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014;371(6):507–18.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Campbell DJ. Control of regulatory T cell migration, function, and homeostasis. J Immunol. 2015;195(6):2507–13.

    Article  CAS  PubMed  Google Scholar 

  18. Attridge K, Walker LS. Homeostasis and function of regulatory T cells (Tregs) in vivo: lessons from TCR-transgenic Tregs. Immunol Rev. 2014;259(1):23–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Palomares O, Martín-Fontecha M, Lauener R, Traidl-Hoffmann C, Cavkaytar O, Akdis M, et al. Regulatory T cells and immune regulation of allergic diseases: roles of IL-10 and TGF-β. Genes Immun. 2014;15(8):511–20.

    Article  CAS  PubMed  Google Scholar 

  20. Bacchetta R, Passerini L, Gambineri E, Dai M, Allan SE, Perroni L, et al. Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J Clin Invest. 2006;116(6):1713–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fuchizawa T, Adachi Y, Ito Y, Higashiyama H, Kanegane H, Futatani T, et al. Developmental changes of FOXP3-expressing CD4+CD25+ regulatory T cells and their impairment in patients with FOXP3 gene mutations. Clin Immunol. 2007;125(3):237–46.

    Article  CAS  PubMed  Google Scholar 

  22. Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: forkhead box protein 3 mutations and lack of regulatory T cells. J Allergy Clin Immunol. 2007;120(4):744–50.

    Article  CAS  PubMed  Google Scholar 

  23. Goudy K, Aydin D, Barzaghi F, Gambineri E, Vignoli M, Ciullini Mannurita S, et al. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clin Immunol. 2013;146(3):248–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Caudy AA, Reddy ST, Chatila T, Atkinson JP, Verbsky JW. 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.

    Article  CAS  PubMed  Google Scholar 

  25. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol. 2005;6(11):1142–51.

    Article  CAS  PubMed  Google Scholar 

  26. Kanai T, Jenks J, Nadeau KC. The STAT5b pathway defect and autoimmunity. Front Immunol. 2012;3:234.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2014;345(6204):1623–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB, Kennedy A, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014;20(12):1410–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lo B, Zhang K, Lu W, Zheng L, Zhang Q, Kanellopoulou C, et al. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. 2015;349(6246):436–40.

    Article  CAS  PubMed  Google Scholar 

  30. Kotlarz D, Beier R, Murugan D, Diestelhorst J, Jensen O, Boztug K, et al. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology. 2012;143(2):347–55.

    Article  CAS  PubMed  Google Scholar 

  31. Murugan D, Albert MH, Langemeier J, Bohne J, Puchalka J, Järvinen PM, et al. Very early onset inflammatory bowel disease associated with aberrant trafficking of IL-10R1 and cure by T cell replete haploidentical bone marrow transplantation. J Clin Immunol. 2014;34(3):331–9.

    Article  CAS  PubMed  Google Scholar 

  32. Huang W, August A. The signaling symphony: T cell receptor tunes cytokine-mediated T cell differentiation. J Leukoc Biol. 2015;97(3):477–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Coutinho A, Caramalho I, Seixas E, Demengeot J. Thymic commitment of regulatory T cells is a pathway of TCR-dependent selection that isolates repertoires undergoing positive or negative selection. Curr Top Microbiol Immunol. 2005;293:43–71.

    CAS  PubMed  Google Scholar 

  34. Lechouane F, Bonaud A, Delpy L, Casola S, Oruc Z, Chemin G, et al. B-cell receptor signal strength influences terminal differentiation. Eur J Immunol. 2013;43(3):619–28.

    Article  CAS  PubMed  Google Scholar 

  35. Habib T, Funk A, Rieck M, Brahmandam A, Dai X, Panigrahi AK, et al. Altered B cell homeostasis is associated with type I diabetes and carriers of the PTPN22 allelic variant. J Immunol. 2012;188(1):487–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hayden MS, Ghosh S. NF-κB in immunobiology. Cell Res. 2011;21(2):223–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Villarino AV, Kanno Y, Ferdinand JR, O’Shea JJ. Mechanisms of Jak/STAT signaling in immunity and disease. J Immunol. 2015;194(1):21–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, et al. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat Immunol. 2014;15(1):88–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Angulo I, Vadas O, Garçon F, Banham-Hall E, Plagnol V, Leahy TR, et al. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science. 2013;342(6160):866–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Deau MC, Heurtier L, Frange P, Suarez F, Bole-Feysot C, Nitschke P, et al. A human immunodeficiency caused by mutations in the PIK3R1 gene. J Clin Invest. 2014;124(9):3923–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. McKinnon ML, Rozmus J, Fung SY, Hirschfeld AF, Del Bel KL, Thomas L, et al. Combined immunodeficiency associated with homozygous MALT1 mutations. J Allergy Clin Immunol. 2014;133(5):1458–62. 1462.e1-7.

    Article  CAS  PubMed  Google Scholar 

  42. Stepensky P, Keller B, Buchta M, Kienzler AK, Elpeleg O, Somech R, et al. Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects. J Allergy Clin Immunol. 2013;131(2):477–85.e1.

    Article  CAS  PubMed  Google Scholar 

  43. Greil J, Rausch T, Giese T, Bandapalli OR, Daniel V, Bekeredjian-Ding I, et al. Whole-exome sequencing links caspase recruitment domain 11 (CARD11) inactivation to severe combined immunodeficiency. J Allergy Clin Immunol. 2013;131(5):1376–83.e3.

    Article  CAS  PubMed  Google Scholar 

  44. Torres JM, Martinez-Barricarte R, García-Gómez S, Mazariegos MS, Itan Y, Boisson B, et al. Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity. J Clin Invest. 2014;124(12):5239–48.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Pannicke U, Baumann B, Fuchs S, Henneke P, Rensing-Ehl A, Rizzi M, et al. Deficiency of innate and acquired immunity caused by an IKBKB mutation. N Engl J Med. 2013;369(26):2504–14.

    Article  CAS  PubMed  Google Scholar 

  46. Mousallem T, Yang J, Urban TJ, Wang H, Adeli M, Parrott RE, et al. A nonsense mutation in IKBKB causes combined immunodeficiency. Blood. 2014;124(13):2046–50.

  47. Pai SY, Levy O, Jabara HH, Glickman JN, Stoler-Barak L, Sachs J, et al. Allogeneic transplantation successfully corrects immune defects, but not susceptibility to colitis, in a patient with nuclear factor-kappaB essential modulator deficiency. J Allergy Clin Immunol. 2008;122(6):1113–8.

  48. Mizukami T, Obara M, Nishikomori R, Kawai T, Tahara Y, Sameshima N, et al. Successful treatment with infliximab for inflammatory colitis in a patient with X-linked anhidrotic ectodermal dysplasia with immunodeficiency. J Clin Immunol. 2012;32(1):39–49.

  49. Courtois G, Smahi A, Reichenbach J, Döffinger R, Cancrini C, Bonnet M, et al. A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. J Clin Invest. 2003;112(7):1108–15.

  50. Schimke LF, Rieber N, Rylaarsdam S, Cabral-Marques O, Hubbard N, Puel A, et al. A novel gain-of-function IKBA mutation underlies ectodermal dysplasia with immunodeficiency and polyendocrinopathy. J Clin Immunol. 2013;3(6):1088–99.

  51. Fliegauf M, Bryant VL, Frede N, Slade C, Woon ST, Lehnert K, et al. Haploinsufficiency of the NF-kB1 Subunit p50 in Common Variable Immunodeficiency. Am J Hum Genet. 2015;97(3):389–403.

  52. Chen K, Coonrod EM, Kumánovics A, Franks ZF, Durtschi JD, Margraf RL, et al. Germline mutations in NFKB2 implicate the noncanonical NF-kB pathway in the pathogenesis of common variable immunodeficiency. Am J Hum Genet. 2013;93(5):812–24.

  53. Lee CE, Fulcher DA, Whittle B, Chand R, Fewings N, Field M, et al. Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100. Blood. 2014 Nov 6;124(19):2964–72.

  54. Stein BL, Oh ST, Berenzon D, Hobbs GS, Kremyanskaya M, Rampal RK, et al. Polycythemia Vera: An Appraisal of the Biology and Management 10 Years After the Discovery of JAK2 V617F. J Clin Oncol. 2015. doi:10.1200/JCO.2015.61.6474.

  55. Macchi P, Villa A, Giliani S, Sacco MG, Frattini A, Porta F, et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature. 1995;377(6544):65–8.

  56. Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity. 2006;25(5):745–55.

  57. Kreins AY, Ciancanelli MJ, Okada S, Kong XF, Ramírez-Alejo N, Kilic SS, et al. Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome. J Exp Med. 2015;212(10):1641–62.

  58. Bustamante J, Boisson-Dupuis S, Abel L, Casanova JL. Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity. Semin Immunol. 2014;26(6):454–70.

  59. Uzel G, Sampaio EP, Lawrence MG, Hsu AP, Hackett M, Dorsey MJ, 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.

  60. Hambleton S, Goodbourn S, Young DF, Dickinson P, Mohamad SM, Valappil M, et al. STAT2 deficiency and susceptibility to viral illness in humans. Proc Natl Acad Sci U S A. 2013;110(8):3053–8.

  61. Flanagan SE, Haapaniemi E, Russell MA, Caswell R, Lango Allen H, De Franco E, et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat Genet. 2014;46(8):812–4.

  62. Milner JD, Vogel TP, Forbes L, Ma CA, Stray-Pedersen A, Niemela JE, et al. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood. 2015;125(4):591–9.

  63. Lechner K, Jäger U. How I treat autoimmune hemolytic anemias in adults. Blood. 2010;116(11):1831–8.

    Article  CAS  PubMed  Google Scholar 

  64. Akpek G, McAneny D, Weintraub L. Comparative response to splenectomy in Coombs-positive auto-immune hemolytic anemia with or without associated disease. Am J Hematol. 1999;61:98–102.

    Article  CAS  PubMed  Google Scholar 

  65. Lum LG, Tubergen DG, Corash L, Blaese RM. Splenectomy in the management of the thrombocytopenia of the Wiskott-Aldrich syndrome. N Engl J Med. 1980;302(16):892–6.

    Article  CAS  PubMed  Google Scholar 

  66. Albert MH, Bittner TC, Nonoyama S, Notarangelo LD, Burns S, Imai K, et al. X-linked thrombocytopenia (XLT) due to WAS mutations: clinical characteristics, long-term outcome, and treatment options. Blood. 2010;115(16):3231–8.

    Article  CAS  PubMed  Google Scholar 

  67. Cuker A, Neunert CE. How I treat refractory immune thrombocytopenia. Blood. 2016 Apr 6. pii: Blood-2016-03-603365. [Epub ahead of print]

  68. Reboursiere E, Fouques H, Maigne G, Johnson H, Chantepie S, Gac AC, Reman O, Macro M, Benabed K, Troussard X, Damaj G, Cheze S. Rituximab salvage therapy in adults with immune thrombocytopenia: retrospective study on efficacy and safety profiles. Int J Hematol. 2016 Apr 4. [Epub ahead of print]

  69. Ay Y, Karapinar TH, Oymak Y, Toret E, Demirag B, Ince D, Ozcan E, Moueminoglou N, Koker SA, Vergin C. Retrospective analysis of rituximab therapy and splenectomy in childhood chronic and refractory immune thrombocytopenic purpura. Blood Coagul Fibrinolysis. 2015 Dec 11. [Epub ahead of print]

  70. Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2012;119(7):1650–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bates CA, Ellison MC, Lynch DA, Cool CD, Brown KK, Routes JM. Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol. 2004;114(2):415–21.

    Article  PubMed  Google Scholar 

  72. Chase NM, Verbsky JW, Hintermeyer MK, Waukau JK, Tomita-Mitchell A, Casper JT, et al. Use of combination chemotherapy for treatment of granulomatous and lymphocytic interstitial lung disease (GLILD) in patients with common variable immunodeficiency (CVID). J Clin Immunol. 2013;33(1):30–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Lucas M, Lee M, Lortan J, Lopez-Granados E, Misbah S, Chapel H. Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin therapy over 22 years. J Allergy Clin Immunol. 2010;125(6):1354–60. e4.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA

    Eric Allenspach & Troy R. Torgerson

  2. Seattle Children’s Research Institute, 1900 9th Ave., JMB-7, Seattle, WA, 98101-1304, USA

    Eric Allenspach & Troy R. Torgerson

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Correspondence to Troy R. Torgerson.

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Allenspach, E., Torgerson, T.R. Autoimmunity and Primary Immunodeficiency Disorders. J Clin Immunol 36 (Suppl 1), 57–67 (2016). https://doi.org/10.1007/s10875-016-0294-1

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