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NFKB2 Defects

  • Shancy P. Jacob
  • Julie E. Feusier
  • Karin ChenEmail author
Chapter
Part of the Rare Diseases of the Immune System book series (RDIS)

Abstract

NF-κB2, encoded by the gene NFKB2, is the primary protein and transcription factor of the noncanonical NF-κB pathway. Human defects in NFKB2 result in primary immunodeficiency syndromes involving an autosomal dominant mode of inheritance. Loss-of-function mutations are more often associated with a common variable immunodeficiency phenotype, while gain-of-function mutations in NFKB2 have been associated with a combined immunodeficiency phenotype. Patients can also develop endocrinopathies including adrenal insufficiency, as well as autoimmune disease manifestations.

Keywords

NFKB2 Adrenal insufficiency Hypogammaglobulinemia Autoimmunity Pituitary hormones 

References

  1. 1.
    Sun SC. Non-canonical NF-kappaB signaling pathway. Cell Res. 2011;21(1):71–85.  https://doi.org/10.1038/cr.2010.177.CrossRefPubMedGoogle Scholar
  2. 2.
    Hayden MS, Ghosh S. Shared principles in NF-kappaB signaling. Cell. 2008;132(3):344–62.  https://doi.org/10.1016/j.cell.2008.01.020.CrossRefPubMedGoogle Scholar
  3. 3.
    Sun SC. The non-canonical NF-kappaB pathway in immunity and inflammation. Nat Rev Immunol. 2017;17(9):545–58.  https://doi.org/10.1038/nri.2017.52.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Senftleben U, Cao Y, Xiao G, Greten FR, Krahn G, Bonizzi G, Chen Y, Hu Y, Fong A, Sun SC, Karin M. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science. 2001;293(5534):1495–9.  https://doi.org/10.1126/science.1062677.CrossRefPubMedGoogle Scholar
  5. 5.
    Xiao G, Harhaj EW, Sun SC. NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100. Mol Cell. 2001;7(2):401–9.CrossRefGoogle Scholar
  6. 6.
    Pone EJ, Zan H, Zhang J, Al-Qahtani A, Xu Z, Casali P. Toll-like receptors and B-cell receptors synergize to induce immunoglobulin class-switch DNA recombination: relevance to microbial antibody responses. Crit Rev Immunol. 2010;30(1):1–29.CrossRefGoogle Scholar
  7. 7.
    Pone EJ, Zhang J, Mai T, White CA, Li G, Sakakura JK, Patel PJ, Al-Qahtani A, Zan H, Xu Z, Casali P. BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-kappaB pathway. Nat Commun. 2012;3:767.  https://doi.org/10.1038/ncomms1769.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Gerondakis S, Siebenlist U. Roles of the NF-kappaB pathway in lymphocyte development and function. Cold Spring Harb Perspect Biol. 2010;2(5):a000182.  https://doi.org/10.1101/cshperspect.a000182.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Weih F, Caamano J. Regulation of secondary lymphoid organ development by the nuclear factor-kappaB signal transduction pathway. Immunol Rev. 2003;195:91–105.CrossRefGoogle Scholar
  10. 10.
    van de Pavert SA, Mebius RE. New insights into the development of lymphoid tissues. Nat Rev Immunol. 2010;10(9):664–74.  https://doi.org/10.1038/nri2832.CrossRefPubMedGoogle Scholar
  11. 11.
    Lawrence T. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol. 2009;1(6):a001651.  https://doi.org/10.1101/cshperspect.a001651.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    De Silva NS, Silva K, Anderson MM, Bhagat G, Klein U. Impairment of mature B cell maintenance upon combined deletion of the alternative NF-kappaB transcription factors RELB and NF-kappaB2 in B cells. J Immunol. 2016;196(6):2591–601.  https://doi.org/10.4049/jimmunol.1501120.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Li Y, Wang H, Zhou X, Xie X, Chen X, Jie Z, Zou Q, Hu H, Zhu L, Cheng X, Brightbill HD, Wu LC, Wang L, Sun SC. Cell intrinsic role of NF-kappaB-inducing kinase in regulating T cell-mediated immune and autoimmune responses. Sci Rep. 2016;6:22115.  https://doi.org/10.1038/srep22115.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Chin RK, Lo JC, Kim O, Blink SE, Christiansen PA, Peterson P, Wang Y, Ware C, Fu YX. Lymphotoxin pathway directs thymic Aire expression. Nat Immunol. 2003;4(11):1121–7.  https://doi.org/10.1038/ni982.CrossRefPubMedGoogle Scholar
  15. 15.
    Shinkura R, Kitada K, Matsuda F, Tashiro K, Ikuta K, Suzuki M, Kogishi K, Serikawa T, Honjo T. Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-kappa b-inducing kinase. Nat Genet. 1999;22(1):74–7.  https://doi.org/10.1038/8780.CrossRefPubMedGoogle Scholar
  16. 16.
    Tucker E, O’Donnell K, Fuchsberger M, Hilton AA, Metcalf D, Greig K, Sims NA, Quinn JM, Alexander WS, Hilton DJ, Kile BT, Tarlinton DM, Starr R. A novel mutation in the Nfkb2 gene generates an NF-kappa B2 “super repressor”. J Immunol. 2007;179(11):7514–22.CrossRefGoogle Scholar
  17. 17.
    Zhu M, Chin RK, Christiansen PA, Lo JC, Liu X, Ware C, Siebenlist U, Fu YX. NF-kappaB2 is required for the establishment of central tolerance through an Aire-dependent pathway. J Clin Invest. 2006;116(11):2964–71.  https://doi.org/10.1172/JCI28326.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Quentien MH, Delemer B, Papadimitriou DT, Souchon PF, Jaussaud R, Pagnier A, Munzer M, Jullien N, Reynaud R, Galon-Faure N, Enjalbert A, Barlier A, Brue T. Deficit in anterior pituitary function and variable immune deficiency (DAVID) in children presenting with adrenocorticotropin deficiency and severe infections. J Clin Endocrinol Metab. 2012;97(1):E121–8.  https://doi.org/10.1210/jc.2011-0407.CrossRefPubMedGoogle Scholar
  19. 19.
    Chen K, Coonrod EM, Kumanovics A, Franks ZF, Durtschi JD, Margraf RL, Wu W, Heikal NM, Augustine NH, Ridge PG, Hill HR, Jorde LB, Weyrich AS, Zimmerman GA, Gundlapalli AV, Bohnsack JF, Voelkerding KV. Germline mutations in NFKB2 implicate the noncanonical NF-kappaB pathway in the pathogenesis of common variable immunodeficiency. Am J Hum Genet. 2013;93(5):812–24.  https://doi.org/10.1016/j.ajhg.2013.09.009.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Brue T, Quentien MH, Khetchoumian K, Bensa M, Capo-Chichi JM, Delemer B, Balsalobre A, Nassif C, Papadimitriou DT, Pagnier A, Hasselmann C, Patry L, Schwartzentruber J, Souchon PF, Takayasu S, Enjalbert A, Van Vliet G, Majewski J, Drouin J, Samuels ME. Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies. BMC Med Genet. 2014;15:139.  https://doi.org/10.1186/s12881-014-0139-9.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kuehn HS, Niemela JE, Sreedhara K, Stoddard JL, Grossman J, Wysocki CA, de la Morena MT, Garofalo M, Inlora J, Snyder MP, Lewis DB, Stratakis CA, Fleisher TA, Rosenzweig SD. Novel nonsense gain-of-function NFKB2 mutations associated with a combined immunodeficiency phenotype. Blood. 2017;130(13):1553–64.  https://doi.org/10.1182/blood-2017-05-782177.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Lal RA, Bachrach LK, Hoffman AR, Inlora J, Rego S, Snyder MP, Lewis DB. A case report of hypoglycemia and hypogammaglobulinemia: DAVID syndrome in a patient with a novel NFKB2 mutation. J Clin Endocrinol Metab. 2017;102(7):2127–30.  https://doi.org/10.1210/jc.2017-00341.CrossRefPubMedGoogle Scholar
  23. 23.
    Lee CE, Fulcher DA, Whittle B, Chand R, Fewings N, Field M, Andrews D, Goodnow CC, Cook MC. Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100. Blood. 2014;124(19):2964–72.  https://doi.org/10.1182/blood-2014-06-578542.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Lindsley AW, Qian Y, Valencia CA, Shah K, Zhang K, Assa'ad A. Combined immune deficiency in a patient with a novel NFKB2 mutation. J Clin Immunol. 2014;34(8):910–5.  https://doi.org/10.1007/s10875-014-0095-3.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Liu Y, Hanson S, Gurugama P, Jones A, Clark B, Ibrahim MA. Novel NFKB2 mutation in early-onset CVID. J Clin Immunol. 2014;34(6):686–90.  https://doi.org/10.1007/s10875-014-0064-x.CrossRefPubMedGoogle Scholar
  26. 26.
    Lougaris V, Tabellini G, Vitali M, Baronio M, Patrizi O, Tampella G, Biasini A, Moratto D, Parolini S, Plebani A. Defective natural killer-cell cytotoxic activity in NFKB2-mutated CVID-like disease. J Allergy Clin Immunol. 2015;135(6):1641–3.  https://doi.org/10.1016/j.jaci.2014.11.038.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Maccari ME, Scarselli A, Di Cesare S, Floris M, Angius A, Deodati A, Chiriaco M, Cambiaso P, Corrente S, Colafati GS, Utz PJ, Angelini F, Fierabracci A, Aiuti A, Carsetti R, Rosenberg JM, Cappa M, Rossi P, Bacchetta R, Cancrini C. Severe Toxoplasma gondii infection in a member of a NFKB2-deficient family with T and B cell dysfunction. Clin Immunol. 2017;183:273–7.  https://doi.org/10.1016/j.clim.2017.09.011.CrossRefPubMedGoogle Scholar
  28. 28.
    Ramakrishnan KA, Rae W, Barcenas-Morales G, Gao Y, Pengelly RJ, Patel SV, Kumararatne DS, Ennis S, Doffinger R, Faust SN, Williams AP. Anticytokine autoantibodies in a patient with a heterozygous NFKB2 mutation. J Allergy Clin Immunol. 2017;141:1479–82.  https://doi.org/10.1016/j.jaci.2017.11.014.CrossRefPubMedGoogle Scholar
  29. 29.
    Shi C, Wang F, Tong A, Zhang XQ, Song HM, Liu ZY, Lyu W, Liu YH, Xia WB. NFKB2 mutation in common variable immunodeficiency and isolated adrenocorticotropic hormone deficiency: a case report and review of literature. Medicine (Baltimore). 2016;95(40):e5081.  https://doi.org/10.1097/MD.0000000000005081.CrossRefGoogle Scholar
  30. 30.
    Caamano J, Tato C, Cai G, Villegas EN, Speirs K, Craig L, Alexander J, Hunter CA. Identification of a role for NF-kappa B2 in the regulation of apoptosis and in maintenance of T cell-mediated immunity to Toxoplasma gondii. J Immunol. 2000;165(10):5720–8.CrossRefGoogle Scholar
  31. 31.
    Willmann KL, Klaver S, Dogu F, Santos-Valente E, Garncarz W, Bilic I, Mace E, Salzer E, Conde CD, Sic H, Majek P, Banerjee PP, Vladimer GI, Haskologlu S, Bolkent MG, Kupesiz A, Condino-Neto A, Colinge J, Superti-Furga G, Pickl WF, van Zelm MC, Eibel H, Orange JS, Ikinciogullari A, Boztug K. Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity. Nat Commun. 2014;5:5360.  https://doi.org/10.1038/ncomms6360.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Caamano JH, Rizzo CA, Durham SK, Barton DS, Raventos-Suarez C, Snapper CM, Bravo R. Nuclear factor (NF)-kappa B2 (p100/p52) is required for normal splenic microarchitecture and B cell-mediated immune responses. J Exp Med. 1998;187(2):185–96.CrossRefGoogle Scholar
  33. 33.
    Yin L, Wu L, Wesche H, Arthur CD, White JM, Goeddel DV, Schreiber RD. Defective lymphotoxin-beta receptor-induced NF-kappaB transcriptional activity in NIK-deficient mice. Science. 2001;291(5511):2162–5.  https://doi.org/10.1126/science.1058453.CrossRefPubMedGoogle Scholar
  34. 34.
    Weih F, Carrasco D, Durham SK, Barton DS, Rizzo CA, Ryseck RP, Lira SA, Bravo R. Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell. 1995;80(2):331–40.CrossRefGoogle Scholar
  35. 35.
    Weih F, Durham SK, Barton DS, Sha WC, Baltimore D, Bravo R. Both multiorgan inflammation and myeloid hyperplasia in RelB-deficient mice are T cell dependent. J Immunol. 1996;157(9):3974–9.PubMedGoogle Scholar
  36. 36.
    Beinke S, Ley SC. Functions of NF-κB1 and NF-κB2 in immune cell biology. Biochem. J. 2004;382(2):393–409.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Shancy P. Jacob
    • 1
  • Julie E. Feusier
    • 2
  • Karin Chen
    • 1
    Email author
  1. 1.Division of Allergy and Immunology, Department of PediatricsUniversity of Utah School of MedicineSalt Lake CityUSA
  2. 2.Department of Human GeneticsUniversity of Utah School of MedicineSalt Lake CityUSA

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