Journal of Clinical Immunology

, Volume 37, Issue 5, pp 397–412 | Cite as

Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency

  • Bertrand BoissonEmail author
  • Anne Puel
  • Capucine Picard
  • Jean-Laurent Casanova
CME Review


Germline heterozygous gain-of-function (GOF) mutations of NFKBIA, encoding IκBα, cause an autosomal dominant (AD) form of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). Fourteen unrelated patients have been reported since the identification of the first case in 2003. All mutations enhanced the inhibitory activity of IκBα, by preventing its phosphorylation on serine 32 or 36 and its subsequent degradation. The mutation certainly or probably occurred de novo in 13 patients, whereas it was inherited from a parent with somatic mosaicism in one patient. Eleven mutations, belonging to two groups, were identified: (i) missense mutations affecting S32, S36, or neighboring residues (8 mutations, 11 patients) and (ii) nonsense mutations upstream from S32 associated with the reinitiation of translation downstream from S36 (3 mutations, 3 patients). Thirteen patients had developmental features of EDA, the severity and nature of which differed between cases. All patient cells tested displayed impaired NF-κB-mediated responses to the stimulation of various surface receptors involved in cell-intrinsic (fibroblasts), innate (monocytes), and adaptive (B and T cells) immunity, including TLRs, IL-1Rs, TNFRs, TCR, and BCR. All patients had profound B-cell deficiency. Specific immunological features, found in some, but not all patients, included a lack of peripheral lymph nodes, lymphocytosis, dysfunctional α/β T cells, and a lack of circulating γ/δ T cells. The patients had various pyogenic, mycobacterial, fungal, and viral severe infections. Patients with a missense mutation tended to display more severe phenotypes, probably due to higher levels of GOF proteins. In the absence of hematopoietic stem cell transplantation (HSCT), this condition cause death before the age of 1 year (one child). Two survivors have been on prophylaxis (at 9 and 22 years). Six children died after HSCT. Five survived, four of whom have been on prophylaxis (3 to 21 years post HSCT), whereas one has been well with no prophylaxis. Heterozygous GOF mutations in IκBα underlie a severe and syndromic immunodeficiency, the interindividual variability of which might partly be ascribed to the dichotomy of missense and nonsense mutations, and the hematopoietic component of which can be rescued by HSCT.


NFKBIA gain of function combined immunodeficiency pediatrics hematopoietic stem cell transplantation 



We would first like to thank Dr. Cancrini (P1), Dr. Lankester (P2), Drs. Geha and McDouglas (P3), Drs. Onhishi and Okada (P5), and Drs. Moriya and Morio (P11, P12) for taking the time to answer our questions and sharing information about the reported patients with us. We also thank Dr. Alain Israel for careful review of the manuscript. We thank Stéphanie Boisson-Dupuis, Jacinta Bustamante, Michael Ciancanelli, Emmanuelle Jouanguy, and Shen-Ying Zhang of the Human Genetics of Infectious Diseases Laboratory for helpful discussions. We also thank Maya Chrabieh, Yelena Nemiroskaya, Lahouari Amar, Dominick Papandrea, Mark Woollett, Cécile Patissier, and Céline Desvallees for their assistance. This work was supported by the St. Giles Foundation, the Rockefeller University, INSERM, Paris Descartes University, Howard Hughes Medical Institute, National Institutes of Health (NIH 5P01AI061093), and the French National Research Agency (ANR 14-CE15-0009-01).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Abinun M. Ectodermal dysplasia and immunodeficiency. Arch Dis Child. 1995;73(2):185.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Abinun M, Spickett G, Appleton AL, Flood T, Cant AJ. Anhidrotic ectodermal dysplasia associated with specific antibody deficiency. Eur J Pediatr. 1996;155(2):146–7.CrossRefPubMedGoogle Scholar
  3. 3.
    Doffinger R, Smahi A, Bessia C, Geissmann F, Feinberg J, Durandy A, et al. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat Genet. 2001;27(3):277–85.CrossRefPubMedGoogle Scholar
  4. 4.
    Zonana J, Elder ME, Schneider LC, Orlow SJ, Moss C, Golabi M, et al. A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). Am J Hum Genet. 2000;67(6):1555–62.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Jain A, Ma CA, Liu S, Brown M, Cohen J, Strober W. Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Nat Immunol. 2001;2(3):223–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Smahi A, Courtois G, Vabres P, Yamaoka S, Heuertz S, Munnich A, et al. Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature. 2000;405(6785):466–72.CrossRefPubMedGoogle Scholar
  7. 7.
    Israel A. The IKK complex, a central regulator of NF-kappaB activation. Cold Spring Harb Perspect Biol. 2010;2(3):a000158.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Niehues T, Reichenbach J, Neubert J, Gudowius S, Puel A, Horneff G, et al. A NEMO-deficient child with immunodeficiency yet without anhidrotic ectodermal dysplasia. J Allergy Clin Immunol. 2004;114:1456–62.CrossRefPubMedGoogle Scholar
  9. 9.
    Orange JS, Jain A, Ballas ZK, Schneider LC, Geha RS, Bonilla FA. The presentation and natural history of immunodeficiency caused by nuclear factor kappaB essential modulator mutation. J Allergy Clin Immunol. 2004;113(4):725–33.CrossRefPubMedGoogle Scholar
  10. 10.
    Ku CL, Dupuis-Girod S, Dittrich AM, Bustamante J, Santos OF, Schulze I, et al. NEMO mutations in 2 unrelated boys with severe infections and conical teeth. Pediatrics. 2005;115(5):e615–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Puel A, Reichenbach J, Bustamante J, Ku CL, Feinberg J, Doffinger R, et al. The NEMO mutation creating the most-upstream premature stop codon is hypomorphic because of a reinitiation of translation. Am J Hum Genet. 2006;78(4):691–701.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Ku CL, Picard C, Erdos M, Jeurissen A, Bustamante J, Puel A, et al. IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease. J Med Genet. 2007;44(1):16–23.CrossRefPubMedGoogle Scholar
  13. 13.
    Hanson EP, Monaco-Shawver L, Solt LA, Madge LA, Banerjee PP, May MJ, et al. Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity. J Allergy Clin Immunol. 2008;122(6):1169–77. e16 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Picard C, Casanova JL, Puel A. Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IkappaBalpha deficiency. Clin Microbiol Rev. 2011;24(3):490–7.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Fusco F, Pescatore A, Conte MI, Mirabelli P, Paciolla M, Esposito E, et al. EDA-ID and IP, two faces of the same coin: how the same IKBKG/NEMO mutation affecting the NF-kappaB pathway can cause immunodeficiency and/or inflammation. Int Rev Immunol. 2015;34(6):445–59.CrossRefPubMedGoogle Scholar
  16. 16.
    Courtois G, Smahi A, Reichenbach J, Doffinger 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.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Devriendt K, Kim AS, Mathijs G, Frints SG, Schwartz M, Van Den Oord JJ, et al. Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat Genet. 2001;27(3):313–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Puel A, Picard C, Ku CL, Smahi A, Casanova JL. Inherited disorders of NF-kappaB-mediated immunity in man. Curr Opin Immunol. 2004;16(1):34–41.CrossRefPubMedGoogle Scholar
  19. 19.
    Oeckinghaus A, Ghosh S. The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol. 2009;1(4):a000034.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Courtois G, Israel A. IKK regulation and human genetics. Curr Top Microbiol Immunol. 2011;349:73–95.PubMedGoogle Scholar
  21. 21.
    Zhang Q, Lenardo MJ, Baltimore D. 30 years of NF-kB: a blossoming of relevance to human pathobiology. Cell. 2017;Google Scholar
  22. 22.
    Janssen R, van Wengen A, Hoeve MA, ten Dam M, van der Burg M, van Dongen J, et al. The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes. J Exp Med. 2004;200(5):559–68.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    McDonald DR, Mooster JL, Reddy M, Bawle E, Secord E, Geha RS. Heterozygous N-terminal deletion of IkappaBalpha results in functional nuclear factor kappaB haploinsufficiency, ectodermal dysplasia, and immune deficiency. J Allergy Clin Immunol. 2007;120(4):900–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Lopez-Granados E, Keenan JE, Kinney MC, Leo H, Jain N, Ma CA, et al. A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency. Hum Mutat. 2008;29(6):861–8.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Ohnishi H, Miyata R, Suzuki T, Nose T, Kubota K, Kato Z, et al. A rapid screening method to detect autosomal-dominant ectodermal dysplasia with immune deficiency syndrome. J Allergy Clin Immunol. 2012;129(2):578–80.CrossRefPubMedGoogle Scholar
  26. 26.
    Giancane G, Ferrari S, Carsetti R, Papoff P, Iacobini M, Duse M. Anhidrotic ectodermal dysplasia: a new mutation. J Allergy Clin Immunol. 2013;132(6):1451–3.CrossRefPubMedGoogle Scholar
  27. 27.
    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;33(6):1088–99.CrossRefPubMedGoogle Scholar
  28. 28.
    Yoshioka T, Nishikomori R, Hara J, Okada K, Hashii Y, Okafuji I, et al. Autosomal dominant anhidrotic ectodermal dysplasia with immunodeficiency caused by a novel NFKBIA mutation, p.Ser36Tyr, presents with mild ectodermal dysplasia and non-infectious systemic inflammation. J Clin Immunol. 2013;33(7):1165–74.CrossRefPubMedGoogle Scholar
  29. 29.
    Lee AJ, Moncada-Velez M, Picard C, Llanora G, Huang CH, Abel L, et al. Severe mycobacterial diseases in a patient with GOF IkappaBalpha mutation without EDA. J Clin Immunol. 2016;36(1):12–5.CrossRefPubMedGoogle Scholar
  30. 30.
    Moriya K, Tanita K, Ohnishi H, Ono S, Niizuma H, Rikiishi T, et al. IκBα S32 mutation underlies ectodermal dysplasia with immunodeficiency and severe non-infectious systemic inflammation. European Society for Immunodeficiencies. 2016;Google Scholar
  31. 31.
    Staples E, Morillo-Gutierrez B, Davies J, Slatter M, Doffinger R, Hackett S et al. Disseminated Mycobacterium malmoense and Salmonella infections associated with a novel variant in NFKBIA. J Clin Immunol. 2017. doi: 10.1007/s10875-017-0390-x.
  32. 32.
    Petersheim D, Massad MJ, Lee L, Cancrini C, Morio T, Sasahara Y et al. Severe disease and greater impairment of NF-κB activation in IκBα point mutants versus truncation mutants in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency. J Allergy Clin Immunol. 2017; in press.Google Scholar
  33. 33.
    Ghosh G., Wang V.Y., Huang D.B., Fusco A. NF-κB regulation: lessons from structures. Immunological reviews. 2012;246(1):36–58Google Scholar
  34. 34.
    Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell. 2002;109(Suppl):S81–96.CrossRefPubMedGoogle Scholar
  35. 35.
    Ghosh S, Hayden MS. New regulators of NF-kappa B in inflammation. Nat Rev Immunol. 2008;8(11):837–48.CrossRefPubMedGoogle Scholar
  36. 36.
    Liang Y, Zhou Y, Shen P. NF-kappaB and its regulation on the immune system. Cell Mol Immunol. 2004;1(5):343–50.PubMedGoogle Scholar
  37. 37.
    Mooster JL, Le Bras S, Massaad MJ, Jabara H, Yoon J, Galand C, et al. Defective lymphoid organogenesis underlies the immune deficiency caused by a heterozygous S32I mutation in IkappaBalpha. J Exp Med. 2015;212(2):185–202.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998;16:225–60.CrossRefPubMedGoogle Scholar
  39. 39.
    Hayden MS, Ghosh S. NF-kappaB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev. 2012;26(3):203–34.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Beg AA, Sha WC, Bronson RT, Baltimore D. Constitutive NF-kappa B activation, enhanced granulopoiesis, and neonatal lethality in I kappa B alpha-deficient mice. Genes Dev. 1995;9(22):2736–46.CrossRefPubMedGoogle Scholar
  41. 41.
    Hoffmann A, Levchenko A, Scott ML, Baltimore D. The IkappaB-NF-kappaB signaling module: temporal control and selective gene activation. Science. 2002;298(5596):1241–5.CrossRefPubMedGoogle Scholar
  42. 42.
    Memet S, Laouini D, Epinat JC, Whiteside ST, Goudeau B, Philpott D, et al. IkappaBepsilon-deficient mice: reduction of one T cell precursor subspecies and enhanced Ig isotype switching and cytokine synthesis. J Immunol. 1999;163(11):5994–6005.PubMedGoogle Scholar
  43. 43.
    Kanarek N, London N, Schueler-Furman O, Ben-Neriah Y. Ubiquitination and degradation of the inhibitors of NF-kappaB. Cold Spring Harb Perspect Biol. 2010;2(2):a000166.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Kanarek N, Ben-Neriah Y. Regulation of NF-kappaB by ubiquitination and degradation of the IkappaBs. Immunol Rev. 2012;246(1):77–94.CrossRefPubMedGoogle Scholar
  45. 45.
    Smale ST. Dimer-specific regulatory mechanisms within the NF-kappaB family of transcription factors. Immunol Rev. 2012;246(1):193–204.CrossRefPubMedGoogle Scholar
  46. 46.
    Sun SC. Non-canonical NF-kappaB signaling pathway. Cell Res. 2011;21(1):71–85.CrossRefPubMedGoogle Scholar
  47. 47.
    Wegener E, Krappmann D. CARD-Bcl10-Malt1 signalosomes: missing link to NF-kappaB. Sci STKE 2007;2007(384):pe21.Google Scholar
  48. 48.
    Notarangelo LD, Kim MS, Walter JE, Lee YN. Human RAG mutations: biochemistry and clinical implications. Nat Rev Immunol. 2016;16(4):234–46.CrossRefPubMedGoogle Scholar
  49. 49.
    Bousfiha A, Jeddane L, Al-Herz W, Ailal F, Casanova JL, Chatila T, et al. The 2015 IUIS phenotypic classification for primary immunodeficiencies. J Clin Immunol. 2015;35(8):727–38.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Dupuis-Girod S, Cancrini C, Le Deist F, Palma P, Bodemer C, Puel A, et al. Successful allogeneic hemopoietic stem cell transplantation in a child who had anhidrotic ectodermal dysplasia with immunodeficiency. Pediatrics. 2006;118(1):e205–11.CrossRefPubMedGoogle Scholar
  51. 51.
    Fried AJ, Bonilla FA. Pathogenesis, diagnosis, and management of primary antibody deficiencies and infections. Clin Microbiol Rev. 2009;22(3):396–414.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    von Bernuth H, Picard C, Jin Z, Pankla R, Xiao H, Ku CL, et al. Pyogenic bacterial infections in humans with MyD88 deficiency. Science. 2008;321(5889):691–6.CrossRefGoogle Scholar
  53. 53.
    Picard C, Puel A, Bonnet M, Ku CL, Bustamante J, Yang K, et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science. 2003;299(5615):2076–9.CrossRefPubMedGoogle Scholar
  54. 54.
    Picard C, von Bernuth H, Ghandil P, Chrabieh M, Levy O, Arkwright PD, et al. Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine (Baltimore). 2010;89(6):403–25.CrossRefGoogle Scholar
  55. 55.
    von Bernuth H, Picard C, Puel A, Casanova JL. Experimental and natural infections in MyD88- and IRAK-4-deficient mice and humans. Eur J Immunol. 2012;42(12):3126–35.CrossRefGoogle Scholar
  56. 56.
    Filipe-Santos O, Bustamante J, Haverkamp MH, Vinolo E, Ku CL, Puel A, et al. X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production. J Exp Med. 2006;203(7):1745–59.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Bustamante J, Picard C, Boisson-Dupuis S, Abel L, Casanova JL. Genetic lessons learned from X-linked Mendelian susceptibility to mycobacterial diseases. Ann N Y Acad Sci. 2011;1246:92–101.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 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-gamma immunity. Semin Immunol. 2014;26(6):454–70.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Boisson-Dupuis S, Bustamante J, El-Baghdadi J, Camcioglu Y, Parvaneh N, El Azbaoui S, et al. Inherited and acquired immunodeficiencies underlying tuberculosis in childhood. Immunol Rev. 2015;264(1):103–20.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Puel A, Cypowyj S, Marodi L, Abel L, Picard C, Casanova JL. Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis. Curr Opin Allergy Clin Immunol. 2012;12(6):616–22.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Allen RC, Armitage RJ, Conley ME, Rosenblatt H, Jenkins NA, Copeland NG, et al. CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science. 1993;259(5097):990–3.CrossRefPubMedGoogle Scholar
  62. 62.
    Ferrari S, Giliani S, Insalaco A, Al-Ghonaium A, Soresina AR, Loubser M, et al. Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc Natl Acad Sci U S A. 2001;98(22):12614–9.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Conzelmann KK. Transcriptional activation of alpha/beta interferon genes: interference by nonsegmented negative-strand RNA viruses. J Virol. 2005;79(9):5241–8.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Audry M, Ciancanelli M, Yang K, Cobat A, Chang HH, Sancho-Shimizu V, et al. NEMO is a key component of NF-kappaB- and IRF-3-dependent TLR3-mediated immunity to herpes simplex virus. J Allergy Clin Immunol. 2011;128(3):610–7. e1-4 CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Ciancanelli MJ, Huang SX, Luthra P, Garner H, Itan Y, Volpi S, et al. Infectious disease. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency. Science. 2015;348(6233):448–53.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Ciancanelli MJ, Itan Y, Herman M, Audry M, Byun M, Sancho-Shimizu V, et al. Human Tlr3 controls constitutive interferon-B immunity. J Clin Immunol. 2012;32:22.Google Scholar
  67. 67.
    Nagasawa M, Ohkawa T, Takagi M, Imai K, Morio T. A stable mixed chimera after SCT with RIC in an infant with IkappaBa hypermorphic mutation. J Clin Immunol. 2017. doi: 10.1007/s10875-017-0375-9.
  68. 68.
    Casanova JL, Conley ME, Seligman SJ, Abel L, Notarangelo LD. Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies. J Exp Med. 2014;211(11):2137–49.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Boisson B, Quartier P, Casanova JL. Immunological loss-of-function due to genetic gain-of-function in humans: autosomal dominance of the third kind. Curr Opin Immunol. 2015;32:90–105.CrossRefPubMedGoogle Scholar
  70. 70.
    Casanova JL. Severe infectious diseases of childhood as monogenic inborn errors of immunity. Proc Natl Acad Sci U S A. 2015;112(51):E7128–37.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Casanova JL. Human genetic basis of interindividual variability in the course of infection. Proc Natl Acad Sci U S A. 2015;112(51):E7118–27.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Zhang Y, Su HC, Lenardo MJ. Genomics is rapidly advancing precision medicine for immunological disorders. Nat Immunol. 2015;16(10):1001–4.CrossRefPubMedGoogle Scholar
  73. 73.
    Perez de Diego R, Sanchez-Ramon S, Lopez-Collazo E, Martinez-Barricarte R, Cubillos-Zapata C, Ferreira Cerdan A, et al. Genetic errors of the human caspase recruitment domain-B-cell lymphoma 10-mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: molecular, immunologic, and clinical heterogeneity. J Allergy Clin Immunol. 2015;136(5):1139–49.CrossRefPubMedGoogle Scholar
  74. 74.
    Ku CL, von Bernuth H, Picard C, Zhang SY, Chang HH, Yang K, et al. Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J Exp Med. 2007;204(10):2407–22.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Della Mina E, Borghesi A, Zhou H, Bougarn S, Boughorbel S, Israel L, et al. Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts. Proc Natl Acad Sci U S A. 2017;114(4):E514–E23.CrossRefPubMedGoogle Scholar
  76. 76.
    Israel L, Wang Y, Bulek K, Della Mina E, Zhang Z, Pedergnana V, et al. Human adaptive immunity rescues an inborn error of innate immunity. Cell. 2017;168(5):789–800. e10 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller BranchRockefeller UniversityNew YorkUSA
  2. 2.Laboratory of Human Genetics of Infectious Diseases, Necker BranchINSERM UMR1163, Necker Hospital for Sick ChildrenParisFrance
  3. 3.Imagine InstituteParis Descartes UniversityParisFrance
  4. 4.Pediatric Hematology-Immunology and Rheumatology UnitAP-HP, Necker Hospital for Sick ChildrenParisFrance
  5. 5.Study Center for ImmunodeficienciesAP-HP, Necker Hospital for Sick ChildrenParisFrance
  6. 6.Howard Hughes Medical InstituteNew YorkUSA

Personalised recommendations