Abstract
Mendelian primary immunodeficiency diseases (MPIDs) are rare disorders affecting distinct constituents of the innate and adaptive immune system. Although they are genetically heterogeneous, a substantial group of MPIDs is due to mutations in genes affecting the nuclear factor-κB (NF-κB) transcription pathway, essential for cell proliferation and cell survival and involved in innate immunity and inflammation. Many of these genes encode for crucial regulatory components of the NF-κB pathway and their mutations are associated with immunological and developmental signs somehow overlapping in patients with MPIDs. At present, nine different MPIDs listed in the online mendelian inheritance in man (OMIM) are caused by mutations in at least nine different genes strictly involved in the NF-κB pathway that result in defects in immune responses. Here we report on the distinct function of each causative gene, on the impaired NF-κB step and more in general on the molecular mechanisms underlining the pathogenesis of the disease. Overall, the MPIDs affecting the NF-κB signalosome require a careful integrated diagnosis and appropriate genetic tests to be molecularly identified. Their discovery at an ever-increasing rate will help establish a common therapeutic strategy for a subclass of immunodeficient patients.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 digital issues and online access to articles
$119.00 per year
only $19.83 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hayden MS, Ghosh S . NF-κB in immunobiology. Cell Res 2011; 21: 223–244.
Vallabhapurapu S, Karin M . Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 2009; 27: 693–733.
Ghosh S, Hayden MS . Celebrating 25 years of NF-κB research. Immunol Rev 2012; 246: 5–13.
Hinz M, Arslan SÇ, Scheidereit C . It takes two to tango: IκBs, the multifunctional partners of NF-κB. Immunol Rev 2012; 246: 59–76.
Huang B, Yang XD, Lamb A, Chen LF . Posttranslational modifications of NF-kappaB: another layer of regulation for NF-kappaB signaling pathway. Cell Signal 2010; 22: 1282–1290.
Ea CK, Baltimore D . Regulation of NF-kappaB activity through lysine monomethylation of p65. Proc Natl Acad Sci USA 2009; 106: 18972–18977.
Sun SC . The noncanonical NF-κB pathway. Immunol Rev 2012; 246: 125–140.
Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, Cunningham-Rundles C et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol 2014; 5: 162.
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: 1108–1115.
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: 578–580.
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: 861–868.
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: 900–907.
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: 559–568.
Puel A, Yang K, Ku CL, von Bernuth H, Bustamante J, Santos OF et al. Heritable defects of the human TLR signalling pathways. J Endotoxin Res 2005; 11: 220–224.
Picard C, Casanova JL, Puel A . Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IκBα deficiency. Clin Microbiol Rev 2011; 24: 490–497.
Kawai T, Nishikomori R, Heike T . Diagnosis and treatment in anhidrotic ectodermal dysplasia with immunodeficiency. Allergol Int 2012; 61: 207–217.
Cunningham-Rundles C, Ponda PP . Molecular defects in T- and B-cell primary immunodeficiency diseases. Nat Rev Immunol 2005; 5: 880–892.
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: 1165–1174.
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: 1088–1099.
Nishikomori R, Akutagawa H, Maruyama K, Nakata-Hizume M, Ohmori K, Mizuno K et al. X-linked ectodermal dysplasia and immunodeficiency caused by reversion mosaicism of NEMO reveals a critical role for NEMO in human T-cell development and/or survival. Blood 2004; 103: 4565–4572.
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: e205–e211.
Mancini AJ, Lawley LP, Uzel G . X-linked ectodermal dysplasia with immunodeficiency caused by NEMO mutation: early recognition and diagnosis. Arch Dermatol 2008; 144: 342–346.
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: 1169–1177.
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: 1555–1562.
Doffinger R, Smahi A, Bessia C, Feinberg J, Durandy A, Bodemer C et al. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat Genet 2001; 27: 277–285.
Picard C, Casanova JL, Puel A . Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IκBα deficiency. Clin Microbiol Rev 2011; 26: 490–497.
Puel A, Picard C, Ku CL, Smahi A, Casanova JL . Inherited disorders of NF-kappaB-mediated immunity in man. Curr Opin Immunol 2004; 16: 34–41.
Fusco F, Pescatore A, Steffann J, Royer G, Bonnefont JP, Ursini MV . Clinical Utility Gene Card for: incontinentia pigmenti. Eur J Hum Genet 2013; 21 e-pub ahead of print 21 July 2013 doi:10.1038/ejhg.2012.227.
Fusco F, Fimiani G, Tadini G, Michele D, Ursini MV . Clinical diagnosis of incontinentia pigmenti in a cohort of male patients. J Am Acad Dermatol 2007; 56: 264–267.
Cordier F, Vinolo E, Veron M, Delepierre M, Agou F . Solution structure of NEMO zinc finger and impact of an anhidrotic ectodermal dysplasia with immunodeficiency-related point mutation. J Mol Biol 2008; 377: 1419–1432.
Zeng W, Xu M, Liu S, Sun L, Chen ZJ . Key role of Ubc5 and lysine-63 polyubiquitination in viral activation of IRF3. Mol Cell 2009; 36: 315–325.
Laplantine E, Fontan E, Chiaravalli J, Lopez T, Lakisic G, Véron M et al. NEMO specifically recognizes K63-linked polyubiquitin chains through a new bipartite ubiquitin binding domain. EMBO J 2009; 28: 2885–2895.
Tokunaga F, Sakata S, Saeki Y, Satomi Y, Kirisako T, Kamei K et al. Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat Cell Biol 2009; 11: 123–132.
Rahighi S, Ikeda F, Kawasaki M, Akutsu M, Suzuki N, Kato R et al. Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation. Cell 2009; 136: 1098–1109.
Cordier F, Grubisha O, Traincard F, Véron M, Delepierre M, Agou F . The zinc finger of NEMO is a functional ubiquitin-binding domain. J Biol Chem 2009; 284: 2902–2907.
Chen ZJ, Sun LJ . Nonproteolytic functions of ubiquitin in cell signaling. Mol Cell 2009; 33: 275–286.
Vinolo E, Sebban H, Chaffotte A, Israël A, Courtois G, Véron M et al. A point mutation in NEMO associated with anhidrotic ectodermal dysplasia with immunodeficiency pathology results in destabilization of the oligomer and reduces lipopolysaccharide- and tumor necrosis factor-mediated NF-kB activation. J Biol Chem 2006; 281: 6334–6348.
Hubeau M, Ngadjeua F, Puel A, Israel L, Feinberg J, Chrabieh M et al. New mechanism of X-linked anhidrotic ectodermal dysplasia with immunodeficiency: impairment of ubiquitin binding despite normal folding of NEMO protein. Blood 2011; 118: 926–935.
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: 1745–1759.
Bustamante J, Boisson-Dupuis S, Jouanguy E, Picard C, Puel A, Abel L et al. Novel primary immunodeficiencies revealed by the investigation of paediatric infectious diseases. Curr Opin Immunol 2008; 20: 39–48.
Lo YC, Lin SC, Rospigliosi CC, Conze DB, Wu CJ, Ashwell JD et al. Structural basis for recognition of diubiquitins by NEMO. Mol Cell 2009; 33: 602–615.
Temmerman ST, Ma CA, Borges L, Kubin M, Liu S, Derry JM et al. Impaired dendritic-cell function in ectodermal dysplasia with immune deficiency is linked to defective NEMO ubiquitination. Blood 2006; 108: 2324–2331.
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: 2504–2514.
Suzuki N, Saito T . IRAK-4 a shared NF-kappaB activator in innate and acquired immunity. Trends Immunol 2006; 27: 566–572.
Kawagoe T, Sato S, Jung A, Yamamoto M, Matsui K, Kato H et al. Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor-mediated immune responses but not in TCR signaling. J Exp Med 2007; 204: 1013–1024.
Picard C, von Bernuth H, Ku CL, Yamamoto M, Matsui K, Kato H et al. Inherited human IRAK-4 deficiency: an update. Immunol Res 2007; 38: 347–352.
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: 2076–2079.
Picard C, Puel A, Bustamante J, Ku CL, Casanova JL . Primary immunodeficiencies associated with pneumococcal disease. Curr Opin Allergy Clin Immunol 2003; 3: 451–459.
Hoarau C, Gérard B, Lescanne E, Henry D, François S, Lacapère JJ et al. TLR9 activation induces normal neutrophil responses in a child with IRAK-4 deficiency: involvement of the direct PI3K pathway. J Immunol 2007; 179: 4754–4765.
Takada H, Yoshikawa H, Imaizumi M, Kitamura T, Takeyama J, Kumaki S et al. Delayed separation of the umbilical cord in two siblings with interleukin-1 receptor-associated kinase 4 deficiency: rapid screening by flow cytometer. J Pediat 2006; 148: 546–548.
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: 2407–2422.
Enders A, Pannicke U, Berner R, Henneke P, Radlinger K, Schwarz K et al. Two siblings with lethal pneumococcal meningitis in a family with a mutation in interleukin-1 receptor-associated kinase 4. J Pediatr 2004; 145: 698–700.
Medvedev AE, Lentschat A, Kuhns DB, Blanco JC, Salkowski C, Zhang S et al. Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J Exp Med 2003; 198: 521–531.
Kuhns DB, Long Priel DA, Gallin JI . Endotoxin and IL-1 hyporesponsiveness in a patient with recurrent bacterial infections. J Immunol 1997; 158: 3959–3964.
Cardenes M, von Bernuth H, Garcia-Saavedra A, Santiago E, Puel A, Ku CL et al. Autosomal recessive interleukin-1 receptor-associated kinase 4 deficiency in fourth-degree relatives. J Pediatr 2006; 148: 549–551.
Li S, Strelow A, Fontana EJ, Wesche H . IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proc Natl Acad Sci USA 2002; 99: 5567–5572.
Courtois G, Gilmore TD 2006 Mutations in the NF-kappaB signaling pathway: implications for human disease. Oncogene; 25: 6831–6843.
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: 691–696.
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: 3126–3135.
Gaschignard J, Levy C, Chrabieh M, Boisson B, Bost-Bru C, Dauger S et al. Invasive pneumococcal disease in children can reveal a primary immunodeficiency. Clin Infect Dis 2014; 59: 244–251.
Sancho-Shimizu V, Pérez de Diego R, Lorenzo L, Halwani R, Alangari A, Israelsson E et al. Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency. J Clin Invest 2011; 121: 4889–4902.
Pérez de Diego R, Sancho-Shimizu V, Lorenzo L, Puel A, Plancoulaine S, Picard C et al. Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis. Immunity 2010; 33: 400–411.
Annunziata CM, Davis RE, Demchenko Y, Bellamy W, Gabrea A, Zhan F et al. Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 2007; 12: 115–130.
Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ et al. Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 2007; 12: 131–144.
Boisson B, Laplantine E, Prando C, Giliani S, Israelsson E, Xu Z et al. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat Immunol 2012; 13: 1178–1186.
Chen K, Coonrod EM, Kumanovics A, Franks ZF, Durtschi JD, Margraf RL et al. Germline mutations in NFKB2 implicate the noncanonical NF-kappa-B pathway in the pathogenesis of common variable immunodeficiency. Am J Hum Genet 2013; 93: 812–824.
Liu Y, Hanson S, Gurugama P, Jones A, Clark B, Ibrahim MA . Novel NFKB2 mutation in early-onset CVID. J Clin Immun 2014; 34: 686–690.
Acknowledgements
We are grateful to the Incontinentia Pigmenti International Foundation (IPIF, [http://www.ipif.org/]), the association France Incontinentia Pigmenti (FIP, [http://incontinentia-pigmenti.fr/]), the Italian Incontinentia Pigmenti ASSociation (IPASSI, [http://www.incontinentiapigmenti.it/]), DHITECH, Progetto Formazione PON n°01-02342 for the fellowship to MIC and the Basilicata Innovazione [http://www.basilicatainnovazione.it] for supporting MP.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Paciolla, M., Pescatore, A., Conte, M. et al. Rare mendelian primary immunodeficiency diseases associated with impaired NF-κB signaling. Genes Immun 16, 239–246 (2015). https://doi.org/10.1038/gene.2015.3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/gene.2015.3