Deficiency of Innate and Acquired Immunity Caused by an <i>IKBKB</i> Mutation

Pannicke, Ulrich; Baumann, Bernd; Fuchs, Sebastian; Henneke, Philipp; Rensing‐Ehl, Anne; Rizzi, Marta; Janda, Aleš; Hese, Katrin; Schlesier, Michael; Holzmann, Karlheinz; Borte, Stephan; Laux, Constanze; Rump, Eva-Maria; Rosenberg, Alan; Zelinski, Teresa; Schrezenmeier, Hubert; Wirth, Thomas; Ehl, Stephan; Schroeder, Marlis L.; Schwarz, Klaus

doi:10.1056/nejmoa1309199

Cited by 160 publications

(164 citation statements)

References 35 publications

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“…IKK complex, hindering the phosphorylation of IκB. Mutations affect the innate and adaptive immunity, without clear EDA features (Pannicke et al 2013;Mousallem et al 2014). …”

Section: Autosomal Dominant Ectodermal Dysplasia With Immunodeficiencymentioning

confidence: 99%

Hematopoietic stem cell transplantations for primary immune deficiencies associated with NFκB mutations: A review of the literature

Scott

Grunebaum

2017

LymphoSign Journal

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The nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) family of transcription factors plays an instrumental role in human immunity and lymphoid organ development. Inherited defects affecting these factors or their regulation are associated with increased susceptibility to infections, as well as non-immune abnormalities. Hematopoietic stem cell transplantations (HSCT) have been shown to correct the immune abnormalities in a few patients with NFκB pathway defects. Here we review the pre-HSCT characteristics, as well as the HSCT and outcome of 35 patients who received HSCT for NFκB defects. Twenty-three patients (65.7%) were reported to have survived HSCT. Survival was higher among patients with X-linked ectodermal dysplasia and immunodeficiency (XL-EDA-ID), and those with CARD11-BCL10-MALT1 (CBM) complex defects, in comparison to patients with autosomal dominant ectodermal dysplasia and immunodeficiency (AD-EDA-ID) and IKBKB defects. Survival following myeloablative conditioning was similar to that after reduced intensity conditioning, although donor cells engraftment and immune reconstitution after HSCT was not complete in some patients. The effects of HSCT on organ dysfunction associated with NFκB defects, such as liver toxicity or bowel inflammation, are still not clear. Earlier identification and transplantation of affected patients, as well as better understanding of the pathogenesis and complications of the different NFκB mutations, might improve outcome of HSCT for specific patient populations. Statement of novelty:This review highlights the current indications, regimens, and outcome of HSCT for inherited defects involving various components of the canonical and non-canonical NFκB pathways.

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“…IKK complex, hindering the phosphorylation of IκB. Mutations affect the innate and adaptive immunity, without clear EDA features (Pannicke et al 2013;Mousallem et al 2014). …”

Section: Autosomal Dominant Ectodermal Dysplasia With Immunodeficiencymentioning

confidence: 99%

Hematopoietic stem cell transplantations for primary immune deficiencies associated with NFκB mutations: A review of the literature

Scott

Grunebaum

2017

LymphoSign Journal

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“…[54,67,68] IKK/NF-kB regulate expression of these cytokines. [69,70] APECED patients have high titers of neutralizing autoantibodies against these cytokines, [71,72] suggesting that loss of IL-17, IL-22, and IFN-γ may contribute to increased fungal infection. On the other hand, occasional or weak autoantibodies against IL-6, IL-9, IL-12, IL-21, IL-23, IL-26, and IL-29 were found, while no autoantibodies against IL-1α/β, IL-2, IL-4, IL-8, IL-10, IL-18, TGF-β1, and TNF were found in APECED patients, [72] suggesting that the cytokines that are not neutralized may promote inflammation and tumorigenesis.…”

Section: Aire and Apeced/chronic Mucocutaneous Candidiasis (Cmc)mentioning

confidence: 99%

“…[69,85] Affected infants are usually identified in the first months of life with Pneumocystis jiroveci pneumonia, bacterial sepsis, cytomegalovirus, oral candida infection, persistent respiratory, or gastrointestinal viral infection that is often associated with protracted diarrhea and failure to thrive. SCID involves a defective antibody response due to either direct involvement with B cells or improper B-cell activation caused by nonfunctional T helper cells.…”

Section: Ikbkb Inborn Errors Severe Combined Immunodeficiency (Scid)mentioning

confidence: 99%

“…Inborn errors in the IKBKB locus, which encodes IKKβ, were found in SCID [69,[86][87][88] (Table 2). Pannicke et al [69] reported four SCID cases that carried a homozygous duplication of the frameshift mutation in IKBKB that leads to a premature stop codon, resulting in a complete loss of the IKKβ protein.…”

Section: Ikbkb Inborn Errors Severe Combined Immunodeficiency (Scid)mentioning

confidence: 99%

“…[89][90][91] Tnfr deletion-rescued p65 À/À mice develop severe infections, leading to failure to thrive. [92,93] Furthermore, Hassall's corpuscles, which are differentiated from mTECs due to a lack of AIRE expression, [94] were observed in the medulla of human SCID patients, and a scant lymphoid population was seen in the thymus but was largely located in the medulla, [69] indicating that IKKβ mutations impair AIRE expression and mTEC development in SCID patients. A germline mutation delivers the inborn error to most cell populations in humans.…”

Section: Ikbkb Inborn Errors Severe Combined Immunodeficiency (Scid)mentioning

confidence: 99%

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Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

Zhu

2018

BioEssays

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A pathogenic connection between autoreactive T cells, fungal infection, and carcinogenesis has been demonstrated in studies of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) as well as in a mouse model in which kinase-dead Ikkα knock-in mice develop impaired central tolerance, autoreactive T cell-mediated autoimmunity, chronic fungal infection, and esophageal squamous cell carcinoma, which recapitulates APECED. IkB kinase α (IKKα) is one subunit of the IKK complex required for NF-kB activation. IKK/NF-kB is essential for central tolerance establishment by regulating the development of medullary thymic epithelial cells (mTECs) that facilitate the deletion of autoreactive T cells in the thymus. In this review, we extensively discuss the pathogenic roles of inborn errors in the IKK/NF-kB loci in the phenotypically related diseases APECED, immune deficiency syndrome, and severe combined immunodeficiency; differentiate how IKK/NF-kB components, through mTEC (stroma), T cells/leukocytes, or epithelial cells, contribute to the pathogenesis of infectious diseases, autoimmunity, and cancer; and highlight the medical significance of IKK/NF-kB in these diseases.

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Identification of a de novo variant in CHUK in a patient with an EEC/AEC syndrome‐like phenotype and hypogammaglobulinemia

Khandelwal

Ockeloen

Venselaar³

et al. 2017

American J of Med Genetics Pt A

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The cardinal features of Ectrodactyly, Ectodermal dysplasia, Cleft lip/palate (EEC), and Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndromes are ectodermal dysplasia (ED), orofacial clefting, and limb anomalies. EEC and AEC are caused by heterozygous mutations in the transcription factor p63 encoded by TP63. Here, we report a patient with an EEC/AEC syndrome-like phenotype, including ankyloblepharon, ED, cleft palate, ectrodactyly, syndactyly, additional hypogammaglobulinemia, and growth delay. Neither pathogenic mutations in TP63 nor CNVs at the TP63 locus were identified. Exome sequencing revealed de novo heterozygous variants in CHUK (conserved helix-loop-helix ubiquitous kinase), PTGER4, and IFIT2. While the variant in PTGER4 might contribute to the immunodeficiency and growth delay, the variant in CHUK appeared to be most relevant for the EEC/AEC-like phenotype. CHUK is a direct target gene of p63 and encodes a component of the IKK complex that plays a key role in NF-κB pathway activation. The identified CHUK variant (g.101980394T>C; c.425A>G; p.His142Arg) is located in the kinase domain which is responsible for the phosphorylation activity of the protein. The variant may affect CHUK function and thus contribute to the disease phenotype in three ways: (1) the variant exhibits a dominant negative effect and results in an inactive IKK complex that affects the canonical NF-κB pathway; (2) it affects the feedback loop of the canonical and non-canonical NF-κB pathways that are CHUK kinase activity-dependent; and (3) it disrupts NF-κB independent epidermal development that is often p63-dependent. Therefore, we propose that the heterozygous CHUK variant is highly likely to be causative to the EEC/AEC-like and additional hypogammaglobulinemia phenotypes in the patient presented here.

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Deficiency of Innate and Acquired Immunity Caused by an IKBKB Mutation

Cited by 160 publications

References 35 publications

Hematopoietic stem cell transplantations for primary immune deficiencies associated with NFκB mutations: A review of the literature

Hematopoietic stem cell transplantations for primary immune deficiencies associated with NFκB mutations: A review of the literature

Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

Identification of a de novo variant in CHUK in a patient with an EEC/AEC syndrome‐like phenotype and hypogammaglobulinemia

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