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

Heller, Stephanie F.; Kölsch, Uwe; Magg, Thomas; Krüger, Renate; Scheuern, Andrea; Schneider, Holm; Eichinger, Anna; Wahn, V.; Unterwalder, Nadine; Lorenz, Myriam Ricarda; Schwarz, Klaus; Meisel, Christian; Schulz, Ansgar; Hauck, Fabian; Bernuth, Horst von

doi:10.1007/s10875-019-00728-y

Cited by 14 publications

(11 citation statements)

References 82 publications

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“…Our patient with the ∆E88 variant had many similarities in coiled-coil motif 1, including high susceptibility to polysaccharide encapsulated bacteria due to pneumococcal osteomyelitis and impaired response to TNF-α. However, this is the first report to link this site to hyper IgM and deaths ( 11 , 15 ). Not all the effects of IKBKG variants have been revealed and, similarly, there is no correlation between disease severity and the site of an IP variant in females ( 17 ).…”

Section: Discussionmentioning

confidence: 74%

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Case Report: Analysis of Preserved Umbilical Cord Clarified X-Linked Anhidrotic Ectodermal Dysplasia With Immunodeficiency in Deceased, Undiagnosed Uncles

et al. 2021

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Family history is one key in diagnosing inborn errors of immunity (IEI); however, disease status is difficult to determine in deceased relatives. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is one of the hyper IgM syndromes that is caused by a hypomorphic variant in the nuclear factor kappa beta essential modulator. We identified a novel IKBKG variant in a 7-month-old boy with pneumococcal rib osteomyelitis and later found that his mother has incontinentia pigmenti. Genetic analysis of preserved umbilical cords revealed the same variant in two of his deceased maternal uncles. Analysis of preserved umbilical cord tissue from deceased relatives can provide important information for diagnosing IEI in their descendants.

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Section: Discussionmentioning

confidence: 74%

“…Previous reports have described more than 70 IKBKG gene variants, but not ∆E88 ( 15 ). NEMO is a regulatory protein comprising 419 amino acids and is made up of several domains such as coiled-coil motifs, leucine zipper domain, and zinc finger domain ( 16 ).…”

Section: Discussionmentioning

confidence: 94%

Case Report: Analysis of Preserved Umbilical Cord Clarified X-Linked Anhidrotic Ectodermal Dysplasia With Immunodeficiency in Deceased, Undiagnosed Uncles

et al. 2021

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“…IL-6 and IL-10 levels were measured in heparinized whole blood of P3, P5, P6, P7, P8 and P9 incubated for 48 hours in the presence of IL-1β (20 ng/ml, R&D Systems), TNF-α (20 ng/ml, R&D Systems), PMA/Ionomycin (1x10 -7 M/ 1x10 -5 M, Sigma-Aldrich) or TLR-agonists (TLR4-agonist LPS (1 ng/ml, Sigma-Aldrich) or TLR2/6-agonist PAM2CSK4 (100 ng/ml, Invivogen)). The cytokine concentrations were measured by ECLIA by Labor Berlin on an IMMULITE® 1000 (Siemens) and compared to a cohort of healthy controls assessed in our laboratory (n = 179) [70].…”

Section: Cell Stimulation and Cytokine Determination (Elisa)mentioning

confidence: 99%

“…To analyze IRAK1-expression and IκBα-degradation, we stimulated SV40-immortalized fibroblasts of P1, P2, P3 and P4 as well as of healthy controls with IL-1β (10 ng/ml, R&D Systems), TLR4-agonist lipopolysaccharide (LPS) (10 µg/ml, Sigma-Aldrich) and TNF-α (20 ng/ml, R&D Systems) for 5, 15, 30, 45, 60 and 90 minutes as well as 20, 60, 120 and 240 minutes, respectively. The further steps were performed as described previously using the following antibodies: IκBa (sc-371, Santa Cruz Biotechnology), IRAK1 (sc-7883, Santa Cruz Biotechnology), IRAK-4 (ADI-KAP-ST206-E, Enzo), Glycerinaldehyd-3-phosphat-Dehydrogenase (GAPDH) (sc-25778, Santa Cruz Biotechnology), P38 MAPK (9212S, Cell Signaling), Goat Anti Rabbit IgG (111-035-045, Dianova) [70]. Detailed protocols are available upon request.…”

Section: Western Blotsmentioning

confidence: 99%

IRAK1 Duplication in MECP2 Duplication Syndrome Does Not Increase Canonical NF-κB-Induced Inflammation

Gottschalk

Kölsch

Wagner

et al. 2022

Preprint

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Purpose Besides their developmental and neurological phenotype, most patients with MECP2/IRAK1 duplication syndrome present with recurrent and severe infections, accompanied by strong inflammation. Respiratory infections are the most common cause of death. Standardized pneumological diagnostics, targeted anti-infectious treatment and knowledge of the underlying pathomechanism that triggers strong inflammation are unmet clinical needs. We investigated the influence of IRAK1 overexpression on the canonical NF-κB signaling as a possible cause for excessive inflammation in these patients. Methods NF-κB signaling was examined by measuring the production of proinflammatory cytokines as well as evaluating the IRAK1 phosphorylation and degradation as well as the IκBα-degradation upon stimulation with IL-1β and TLR-agonists in SV40 immortalized fibroblasts, PBMCs and whole blood of 9 patients with MECP2/IRAK1 duplication syndrome, respectively. Results Both, MECP2/IRAK1-duplicated patients and healthy controls, showed similar production of IL-6 and IL-8 upon activation with IL-1β and TLR4/2/6-agonists in immortalized fibroblasts, PBMCs and whole blood. Patients and controls have equivalent patterns of IRAK1 phosphorylation and degradation as well as IκBα degradation upon stimulation with IL-1β. Conclusion Patients with MECP2/IRAK1 duplication syndrome do not show increased canonical NF-κB signaling in immortalized fibroblasts, PBMCs and whole blood. Therefore, we assume that these patients do not benefit from a therapeutic suppression of this pathway.

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“…Immunodeficiency 33 is also X-linked recessive and is caused by hemizygous mutation that results in loss-of-function and is characterized by early onset severe infections. Patients with C-terminal zinc finger domain variants have a more severe phenotype that includes ectodermal dysplasia; variants in the leucine zipper domain or N-terminal coiled-coil domains present with milder phenotypes without ectodermal dysplasia, though the latter may have conical teeth and hypodontia [ 79 , 80 ]. While other ectodermal dysplasias have been associated with dry eye [ 81 ], no ocular features have been described in association specifically with the EDAID1 subtype.…”

Section: Genetic Disorders and Features Of Innate Immune Pathway Componentsmentioning

confidence: 99%

Immunogenetics of the Ocular Anterior Segment: Lessons from Inherited Disorders

Serpen

Armenti

Prasov

2021

Journal of Ophthalmology

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Autoimmune and autoinflammatory diseases cause morbidity in multiple organ systems including the ocular anterior segment. Genetic disorders of the innate and adaptive immune system present an avenue to study more common inflammatory disorders and host-pathogen interactions. Many of these Mendelian disorders have ophthalmic manifestations. In this review, we highlight the ophthalmic and molecular features of disorders of the innate immune system. A comprehensive literature review was performed using PubMed and the Online Mendelian Inheritance in Man databases spanning 1973–2020 with a focus on three specific categories of genetic disorders: RIG-I-like receptors and downstream signaling, inflammasomes, and RNA processing disorders. Tissue expression, clinical associations, and animal and functional studies were reviewed for each of these genes. These genes have broad roles in cellular physiology and may be implicated in more common conditions with interferon upregulation including systemic lupus erythematosus and type 1 diabetes. This review contributes to our understanding of rare inherited conditions with ocular involvement and has implications for further characterizing the effect of perturbations in integral molecular pathways.

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

Cited by 14 publications

References 82 publications

Case Report: Analysis of Preserved Umbilical Cord Clarified X-Linked Anhidrotic Ectodermal Dysplasia With Immunodeficiency in Deceased, Undiagnosed Uncles

Case Report: Analysis of Preserved Umbilical Cord Clarified X-Linked Anhidrotic Ectodermal Dysplasia With Immunodeficiency in Deceased, Undiagnosed Uncles

IRAK1 Duplication in MECP2 Duplication Syndrome Does Not Increase Canonical NF-κB-Induced Inflammation

Immunogenetics of the Ocular Anterior Segment: Lessons from Inherited Disorders

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