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01.04.2020 | Original Article

T Cell Impairment Is Predictive for a Severe Clinical Course in NEMO Deficiency

verfasst von: Stephanie Heller, Uwe Kölsch, Thomas Magg, Renate Krüger, Andrea Scheuern, Holm Schneider, Anna Eichinger, Volker Wahn, Nadine Unterwalder, Myriam Lorenz, Klaus Schwarz, Christian Meisel, Ansgar Schulz, Fabian Hauck, Horst von Bernuth

Erschienen in: Journal of Clinical Immunology | Ausgabe 3/2020

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Abstract

Purpose

NEMO-deficient patients present with variable degrees of immunodeficiency. Accordingly, treatment ranges from antibiotic prophylaxis and/or IgG-substitution to allogenic hematopoietic stem cell transplantation (HSCT). The correct estimation of the immunodeficiency is essential to avoid over- as well as under-treatment. We compare the immunological phenotype of a NEMO-deficient patient with a newly-described splice site mutation that causes truncation of the NEMO zinc-finger (ZF) domain and a severe clinical course with the immunological phenotype of three NEMO-deficient patients with missense mutations and milder clinical courses and all previously published patients.

Methods

Lymphocyte subsets, proliferation, and intracellular NEMO-expression were assessed by FACS. NF-κB signal transduction was determined by measuring IκBα-degradation and the production of cytokines upon stimulation with TNF-α, IL-1β, and TLR-agonists in immortalized fibroblasts and whole blood, respectively.

Results

The patient with truncated ZF-domain of NEMO showed low levels of IgM and IgG, reduced class-switched memory B cells, almost complete skewing towards naïve CD45RA⁺ T cells, impaired T cell proliferation as well as cytokine production upon stimulation with TNF-α, IL-1β, and TLR-agonists. He suffered from severe infections (sepsis, pneumonia, osteomyelitis) during infancy. In contrast, three patients with missense mutations in IKBKG presented neither skewing of T cells towards naïvety nor impaired T cell proliferation. They are stable on prophylactic IgG-substitution or even off any prophylactic treatment.

Conclusion

The loss of the ZF-domain and the impaired T cell proliferation accompanied by almost complete persistence of naïve T cells despite severe infections are suggestive for a profound immunodeficiency. Allogenic HSCT should be considered early for these patients before chronic sequelae occur.

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Picard C, Bobby Gaspar H, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, et al. International union of immunological societies: 2017 primary immunodeficiency diseases committee report on inborn errors of immunity. J Clin Immunol. 2018;38(1):96–128.PubMed

Bousfiha A, Jeddane L, Picard C, Ailal F, Bobby Gaspar H, Al-Herz W, et al. The 2017 IUIS phenotypic classification for primary immunodeficiencies. J Clin Immunol. 2018;38(1):129–43.PubMed

Sen R, Baltimore D. Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell. 1986;47(6):921–8.PubMed

Zhang Q, Lenardo MJ, Baltimore D. 30 years of NF-kappaB: a blossoming of relevance to human pathobiology. Cell. 2017;168(1–2):37–57.PubMedCentralPubMed

Sun SC. The non-canonical NF-kappaB pathway in immunity and inflammation. Nat Rev Immunol. 2017;17(9):545–58.PubMedCentralPubMed

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.PubMedCentralPubMed

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.PubMed

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.PubMed

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.PubMed

10.

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.PubMedCentralPubMed

11.

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.

12.

Lahtela J, Nousiainen HO, Stefanovic V, Tallila J, Viskari H, Karikoski R, et al. Mutant CHUK and severe fetal encasement malformation. N Engl J Med. 2010;363(17):1631–7.PubMed

13.

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(12):1178–86.PubMedCentralPubMed

14.

Snow AL, Xiao W, Stinson JR, Lu W, Chaigne-Delalande B, Zheng L, et al. Congenital B cell lymphocytosis explained by novel germline CARD11 mutations. J Exp Med. 2012;209(12):2247–61.PubMedCentralPubMed

15.

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.PubMed

16.

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.PubMed

17.

Jabara HH, Ohsumi T, Chou J, Massaad MJ, Benson H, Megarbane A, et al. A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency. J Allergy Clin Immunol. 2013;132(1):151–8.PubMedCentralPubMed

18.

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.PubMed

19.

Torres JM, Martinez-Barricarte R, Garcia-Gomez 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.PubMedCentralPubMed

20.

Boisson B, Laplantine E, Dobbs K, Cobat A, Tarantino N, Hazen M, et al. Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia. J Exp Med. 2015;212(6):939–51.PubMedCentralPubMed

21.

Zhou Q, Wang H, Schwartz DM, Stoffels M, Park YH, Zhang Y, et al. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat Genet. 2016;48(1):67–73.PubMed

22.

Zhou Q, Yu X, Demirkaya E, Deuitch N, Stone D, Tsai WL, et al. Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease. Proc Natl Acad Sci U S A. 2016;113(36):10127–32.PubMedCentralPubMed

23.

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.PubMedCentralPubMed

24.

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.PubMedCentralPubMed

25.

Ma CA, Stinson JR, Zhang Y, Abbott JK, Weinreich MA, Hauk PJ, et al. Germline hypomorphic CARD11 mutations in severe atopic disease. Nat Genet. 2017;49(8):1192–201.PubMedCentralPubMed

26.

Willmann KL, Klaver S, Dogu F, Santos-Valente E, Garncarz W, Bilic I, et al. Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity. Nat Commun. 2014;5:5360.PubMed

27.

Chen K, Coonrod EM, Kumanovics A, Franks ZF, Durtschi JD, Margraf RL, et al. 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.PubMedCentralPubMed

28.

Fliegauf M, Bryant VL, Frede N, Slade C, Woon ST, Lehnert K, et al. Haploinsufficiency of the NF-kappaB1 subunit p50 in common variable immunodeficiency. Am J Hum Genet. 2015;97(3):389–403.PubMedCentralPubMed

29.

Sharfe N, Merico D, Karanxha A, Macdonald C, Dadi H, Ngan B, et al. The effects of RelB deficiency on lymphocyte development and function. J Autoimmun. 2015;65:90–100.PubMed

30.

Badran YR, Dedeoglu F, Leyva Castillo JM, Bainter W, Ohsumi TK, Bousvaros A, et al. Human RELA haploinsufficiency results in autosomal-dominant chronic mucocutaneous ulceration. J Exp Med. 2017;214(7):1937–47.PubMedCentralPubMed

31.

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.PubMedCentralPubMed

32.

Shifera AS. The zinc finger domain of IKKgamma (NEMO) protein in health and disease. J Cell Mol Med. 2010;14(10):2404–14.PubMedCentralPubMed

33.

Kawai T, Nishikomori R, Izawa K, Murata Y, Tanaka N, Sakai H, et al. Frequent somatic mosaicism of NEMO in T cells of patients with X-linked anhidrotic ectodermal dysplasia with immunodeficiency. Blood. 2012;119(23):5458–66.PubMed

34.

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.PubMed

35.

Fusco F, Pescatore A, Bal E, Ghoul A, Paciolla M, Lioi MB, et al. Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations. Hum Mutat. 2008;29(5):595–604.PubMed

36.

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.PubMed

37.

Makris C, Godfrey VL, Krahn-Senftleben G, Takahashi T, Roberts JL, Schwarz T, et al. Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol Cell. 2000;5(6):969–79.PubMed

38.

Courtois G, Israel A. NF-kappa B defects in humans: the NEMO/incontinentia pigmenti connection. Sci STKE 2000;2000(58):pe1.

39.

Miot C, Imai K, Imai C, Mancini AJ, Kucuk ZY, Kawai T, et al. Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations. Blood. 2017;130(12):1456–67.PubMedCentralPubMed

40.

Klemann C, Pannicke U, Morris-Rosendahl DJ, Vlantis K, Rizzi M, Uhlig H, et al. Transplantation from a symptomatic carrier sister restores host defenses but does not prevent colitis in NEMO deficiency. Clin Immunol. 2016;164:52–6.PubMedCentralPubMed

41.

Comans-Bitter WM, de Groot R, van den Beemd R, Neijens HJ, Hop WC, Groeneveld K, et al. Immunophenotyping of blood lymphocytes in childhood. Reference values for lymphocyte subpopulations. J Pediatr. 1997;130(3):388–93.PubMed

42.

Shearer WT, Rosenblatt HM, Gelman RS, Oyomopito R, Plaeger S, Stiehm ER, et al. Lymphocyte subsets in healthy children from birth through 18 years of age: the pediatric AIDS Clinical Trials Group P1009 study. J Allergy Clin Immunol. 2003;112(5):973–80.PubMed

43.

van Gent R, van Tilburg CM, Nibbelke EE, Otto SA, Gaiser JF, Janssens-Korpela PL, et al. Refined characterization and reference values of the pediatric T- and B-cell compartments. Clin Immunol. 2009;133(1):95–107.PubMed

44.

Fusco F, Bardaro T, Fimiani G, Mercadante V, Miano MG, Falco G, et al. Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF-kappaB activation. Hum Mol Genet. 2004;13(16):1763–73.PubMed

45.

Salt BH, Niemela JE, Pandey R, Hanson EP, Deering RP, Quinones R, et al. IKBKG (nuclear factor-kappa B essential modulator) mutation can be associated with opportunistic infection without impairing toll-like receptor function. J Allergy Clin Immunol. 2008;121(4):976–82.PubMedCentralPubMed

46.

Abbott JK, Quinones RR, de la Morena MT, Gelfand EW. Successful hematopoietic cell transplantation in patients with unique NF-kappaB essential modulator (NEMO) mutations. Bone Marrow Transplant. 2014;49(11):1446–7.PubMed

47.

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.PubMed

48.

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.PubMedCentralPubMed

49.

Schober T, Magg T, Laschinger M, Rohlfs M, Linhares ND, Puchalka J, et al. A human immunodeficiency syndrome caused by mutations in CARMIL2. Nat Commun. 2017;8:14209.PubMedCentralPubMed

50.

Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285–91.PubMedCentralPubMed

51.

Pachlopnik Schmid JM, Junge SA, Hossle JP, Schneider EM, Roosnek E, Seger RA, et al. Transient hemophagocytosis with deficient cellular cytotoxicity, monoclonal immunoglobulin M gammopathy, increased T-cell numbers, and hypomorphic NEMO mutation. Pediatrics. 2006;117(5):e1049–56.PubMed

52.

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.PubMedCentralPubMed

53.

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.PubMed

54.

Orange JS, Levy O, Brodeur SR, Krzewski K, Roy RM, Niemela JE, et al. Human nuclear factor kappa B essential modulator mutation can result in immunodeficiency without ectodermal dysplasia. J Allergy Clin Immunol. 2004;114(3):650–6.PubMed

55.

Johnston AM, Niemela J, Rosenzweig SD, Fried AJ, Delmonte OM, Fleisher TA, et al. A novel mutation in IKBKG/NEMO leads to ectodermal dysplasia with severe immunodeficiency (EDA-ID). J Clin Immunol. 2016;36(6):541–3.PubMedCentralPubMed

56.

Aradhya S, Courtois G, Rajkovic A, Lewis RA, Levy M, Israel A, et al. Atypical forms of incontinentia pigmenti in male individuals result from mutations of a cytosine tract in exon 10 of NEMO (IKK-gamma). Am J Hum Genet. 2001;68(3):765–71.PubMedCentralPubMed

57.

Dupuis-Girod S, Corradini N, Hadj-Rabia S, Fournet JC, Faivre L, Le Deist F, et al. Osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency in a boy and incontinentia pigmenti in his mother. Pediatrics. 2002;109(6):e97.PubMed

58.

Orange JS, Brodeur SR, Jain A, Bonilla FA, Schneider LC, Kretschmer R, et al. Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations. J Clin Invest. 2002;109(11):1501–9.PubMedCentralPubMed

59.

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(12):4565–72.PubMed

60.

Martinez-Pomar N, Munoz-Saa I, Heine-Suner D, Martin A, Smahi A, Matamoros N. A new mutation in exon 7 of NEMO gene: late skewed X-chromosome inactivation in an incontinentia pigmenti female patient with immunodeficiency. Hum Genet. 2005;118(3–4):458–65.PubMed

61.

Cheng LE, Kanwar B, Tcheurekdjian H, Grenert JP, Muskat M, Heyman MB, et al. Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome. Clin Immunol. 2009;132(1):124–31.PubMedCentralPubMed

62.

Haverkamp MH, Marciano BE, Frucht DM, Jain A, van de Vosse E, Holland SM. Correlating interleukin-12 stimulated interferon-gamma production and the absence of ectodermal dysplasia and anhidrosis (EDA) in patients with mutations in NF-kappaB essential modulator (NEMO). J Clin Immunol. 2014;34(4):436–43.PubMed

63.

Ramirez-Alejo N, Alcantara-Montiel JC, Yamazaki-Nakashimada M, Duran-McKinster C, Valenzuela-Leon P, Rivas-Larrauri F, et al. Novel hypomorphic mutation in IKBKG impairs NEMO-ubiquitylation causing ectodermal dysplasia, immunodeficiency, incontinentia pigmenti, and immune thrombocytopenic purpura. Clin Immunol. 2015;160(2):163–71.PubMed

64.

Wu S, Orange JS, Chiou EH, Nicholas SK, Seeborg F, Gwalani LA, et al. Use of enteral immunoglobulin in NEMO syndrome for eradication of persistent symptomatic norovirus enteritis. J Allergy Clin Immunol Pract. 2016;4(3):539–41 e1.PubMed

65.

Jorgensen SE, Bottger P, Kofod-Olsen E, Holm M, Mork N, Orntoft TF, et al. Ectodermal dysplasia with immunodeficiency caused by a branch-point mutation in IKBKG/NEMO. J Allergy Clin Immunol. 2016;138(6):1706–9 e4.PubMed

66.

Yu JC, Khodadadi H, Malik A, Davidson B, Salles E, Bhatia J, et al. Innate Immunity of Neonates and Infants. Front Immunol. 2018;9:1759.PubMedCentralPubMed

67.

Orange JS, Levy O, Geha RS. Human disease resulting from gene mutations that interfere with appropriate nuclear factor-kappaB activation. Immunol Rev. 2005;203:21–37.PubMed

68.

Courtois G, Gilmore TD. Mutations in the NF-kappaB signaling pathway: implications for human disease. Oncogene. 2006;25(51):6831–43.PubMed

69.

Ivins FJ, Montgomery MG, Smith SJ, Morris-Davies AC, Taylor IA, Rittinger K. NEMO oligomerization and its ubiquitin-binding properties. Biochem J. 2009;421(2):243–51.PubMed

70.

Clark K, Nanda S, Cohen P. Molecular control of the NEMO family of ubiquitin-binding proteins. Nat Rev Mol Cell Biol. 2013;14(10):673–85.PubMed

71.

Tang ED, Wang CY, Xiong Y, Guan KL. A role for NF-kappaB essential modifier/IkappaB kinase-gamma (NEMO/IKKgamma) ubiquitination in the activation of the IkappaB kinase complex by tumor necrosis factor-alpha. J Biol Chem. 2003;278(39):37297–305.PubMed

72.

Cordier F, Grubisha O, Traincard F, Veron M, Delepierre M, Agou F. The zinc finger of NEMO is a functional ubiquitin-binding domain. J Biol Chem. 2009;284(5):2902–7.PubMed

73.

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.PubMed

74.

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.PubMed

75.

Boisson B, Puel A, Picard C, Casanova JL. Human IkappaBalpha gain of function: a severe and syndromic immunodeficiency. J Clin Immunol. 2017;37(5):397–412.PubMedCentralPubMed

76.

Staples E, Morillo-Gutierrez B, Davies J, Petersheim D, Massaad M, Slatter M, et al. Disseminated Mycobacterium malmoense and Salmonella infections associated with a novel variant in NFKBIA. J Clin Immunol. 2017;37(5):415–8.PubMedCentralPubMed

77.

Moriya K, Sasahara Y, Ohnishi H, Kawai T, Kanegane H. IKBA S32 mutations underlie ectodermal dysplasia with immunodeficiency and severe noninfectious systemic inflammation. J Clin Immunol. 2018;38(5):543–5.PubMed

78.

Nielsen C, Jakobsen MA, Larsen MJ, Muller AC, Hansen S, Lillevang ST, et al. Immunodeficiency associated with a nonsense mutation of IKBKB. J Clin Immunol. 2014;34(8):916–21.PubMed

79.

Sorte HS, Osnes LT, Fevang B, Aukrust P, Erichsen HC, Backe PH, et al. A potential founder variant in CARMIL2/RLTPR in three Norwegian families with warts, molluscum contagiosum, and T-cell dysfunction. Mol Genet Genomic Med. 2016;4(6):604–16.PubMedCentralPubMed

80.

Alazami AM, Al-Helale M, Alhissi S, Al-Saud B, Alajlan H, Monies D, et al. Novel CARMIL2 mutations in patients with variable clinical dermatitis, infections, and combined immunodeficiency. Front Immunol. 2018;9:203.PubMedCentralPubMed

81.

Cardinez C, Miraghazadeh B, Tanita K, da Silva E, Hoshino A, Okada S, et al. Gain-of-function IKBKB mutation causes human combined immune deficiency. J Exp Med. 2018;215(11):2715–24.PubMedCentralPubMed

82.

Cuvelier GDE, Rubin TS, Junker A, Sinha R, Rosenberg AM, Wall DA, et al. Clinical presentation, immunologic features, and hematopoietic stem cell transplant outcomes for IKBKB immune deficiency. Clin Immunol. 2018.

83.

Lu HY, Bauman BM, Arjunaraja S, Dorjbal B, Milner JD, Snow AL, et al. The CBM-opathies-a rapidly expanding Spectrum of human inborn errors of immunity caused by mutations in the CARD11-BCL10-MALT1 complex. Front Immunol. 2018;9:2078.PubMedCentralPubMed

Titel: T Cell Impairment Is Predictive for a Severe Clinical Course in NEMO Deficiency
verfasst von: Stephanie Heller
Uwe Kölsch
Thomas Magg
Renate Krüger
Andrea Scheuern
Holm Schneider
Anna Eichinger
Volker Wahn
Nadine Unterwalder
Myriam Lorenz
Klaus Schwarz
Christian Meisel
Ansgar Schulz
Fabian Hauck
Horst von Bernuth
Publikationsdatum: 01.04.2020
Verlag: Springer US
Erschienen in: Journal of Clinical Immunology / Ausgabe 3/2020
Print ISSN: 0271-9142
Elektronische ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-019-00728-y

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T Cell Impairment Is Predictive for a Severe Clinical Course in NEMO Deficiency