Disseminated Mycobacterium malmoense and Salmonella Infections Associated with a Novel Variant in NFKBIA

Staples, Emily; Morillo-Gutierrez, Beatriz; Davies, J; Petersheim, Daniel; Massaad, Michel J.; Slatter, Mary; Dimou, Dimitra S.; Döffinger, Rainer; Hackett, Scott; Hadfield, James; Eldridge, Matthew; Geha, Raif S.; Abinun, Mario; Thaventhiran, James

doi:10.1007/s10875-017-0390-x

Cited by 14 publications

(7 citation statements)

References 12 publications

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“…We report outcome of patients transplanted in our center, excluding those with CGD who have recently been reported [12,13]. Patients 9 and 11 have previously been published [14,15].…”

Section: Introductionmentioning

confidence: 99%

Outcome of Hematopoietic Stem Cell Transplantation in patients with Mendelian Susceptibility to Mycobacterial Diseases

et al. 2021

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Predisposition to mycobacterial infection is a key presenting feature of several rare inborn errors of intrinsic and innate immunity. Hematopoietic stem cell transplantation (HSCT) can be curative for such conditions, but published reports are few. We present a retrospective survey of the outcome of 11 affected patients (7 males, 4 females) who underwent HSCT between 2007 and 2019. Eight patients had disseminated mycobacterial infection prior to transplant. Median age at first transplant was 48 months (9 -192); three patients were successfully re-transplanted due to secondary graft failure. Donors were matched family (1), matched unrelated (3), and mismatched unrelated and haploidentical family (5 each). Stem cell source was peripheral blood (9), bone marrow (4), and cord blood (1). TCRαβ/CD19 + depletion was performed in 6. Conditioning regimens were treosulfan, fludarabine (4), with additional thiotepa (in 8), and fludarabine, melphalan (2); all had serotherapy with alemtuzumab (8) or anti T-lymphocyte globulin (6). Median hospital stay was 113 days (36–330). Three patients developed acute grade I-II skin and one grade IV skin graft versus host disease. Four patients had immune-reconstitution syndrome. Two reactivated cytomegalovirus (CMV), 1 Epstein-Barr virus, and 3 adenovirus post HSCT. Nine are alive, 1 died early post-transplant from CMV, and the other was a late death from pneumococcal sepsis. Patients with active mycobacterial infection at HSCT continued anti-mycobacterial therapy for almost 12 months. In conclusion, HSCT is a successful treatment for patients with mycobacterial susceptibility even with disseminated mycobacterial infection and in the absence of an HLA matched donor.

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“…We report outcome of patients transplanted in our center, excluding those with CGD who have recently been reported [12,13]. Patients 9 and 11 have previously been published [14,15].…”

Section: Introductionmentioning

confidence: 99%

Outcome of Hematopoietic Stem Cell Transplantation in patients with Mendelian Susceptibility to Mycobacterial Diseases

et al. 2021

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“…Six died during or after the transplantation period, from bacterial sepsis (S32R: P11; M37K: P7; E14X: P4), progressive neurodegenerative disease (Dr Lankester, personal communication; S32I: P2), acute respiratory distress (S32N: P12), or cerebellar hemorrhage (S36Y: P6). Five cases of successful HSCT have been reported: the first of these patients (S32I: P1) is now 21 years old and underwent haplo-identical HSCT at the age of one year ([49] and Dr Cancrini, personal communication); the second patient (Q9X: P5) is 7 years old and received HSCT from an unrelated donor at the age of two years [66]; the third one (S32G: P10) is 6 years old and received HSCT from an unrelated donor at the age of four years [31]. The two last patients (S32I: P13; G33V: P14) are both 10 years old and received the HSCT 3 and 8 years earlier, respectively [32].…”

Section: Introductionmentioning

confidence: 99%

Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency

et al. 2017

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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 enhance the inhibitory activity of IκBα, by preventing its phosphorylation on serine 32 or 36 and its subsequent degradation. The mutations 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, have been 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 have profound B-cell deficiency. Specific immunological features, found in some, but not all patients, include 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 tend to display more severe phenotypes, probably due to higher levels of GOF proteins. In the absence of hematopoietic stem cell transplantation (HSCT), this condition can cause death before the age of 1 year (one child). Two survivors are on prophylaxis (at 9 and 22 years). Six children died after HSCT. Five survived, four of whom are on prophylaxis (3 to 21 years post HSCT), whereas one is well with no prophylaxis. Heterozygous GOF mutations in IκBα underlie a severe and syndromic immunodeficiency, the inter-individual 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.

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“…The priming phase of apoptosis is triggered by the first signals, including lipopolysaccharides (LPS) and damage-associated molecular patterns (DAMP). IκBα is ubiquitinated and degraded, resulting in NF-κB activation through phosphorylation of TLRs in the stimulated cells, which rapidly localized to the nucleus to allow the transcription of proinflammatory cytokines, such as TNF-α, IL-1β and IL-6 ( 5 , 22 , 23 ), thus ultimately contributing to tumor cell apoptosis. The second delayed priming phase activates several signaling pathways, such as TNF-α that suppresses phosphor-NF-κB/p65 expression, and further induces a wide spectrum of inflammatory reactions by producing adenosine triphosphate (ATP), and eventually lead to cell injury caused by the release of proinflammatory cytokines ( 24 , 25 ).…”

Section: Discussionmentioning

confidence: 99%

RNA sequencing analysis reveals apoptosis induction by hydrogen treatment in endometrial cancer via TNF and NF-κB pathways

Ys¹,

Liu²,

Bao³

et al. 2020

Transl Cancer Res TCR

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Background To evaluate the activity of hydrogen in endometrial cancer and elucidate its underlying molecular mechanisms. Methods Ishikawa, HEC1A and AN3CA cells were incubated in DMEM medium with or without hydrogen. RNA sequencing was used to explore the association of hydrogen treatment with signaling pathways and functional genes in endometrial cancer cells. The apoptotic rates of the three endometrial cancer cells were evaluated by fluorescein isothiocyanate (FITC) Annexin V and Annexin V-allophycocyanin (APC)/propidium iodide double staining. Results RNA sequencing analysis revealed that hydrogen induced TNF/NF-κB and apoptosis pathways in endometrial cancer cells. The gene sets between hydrogen treatment groups and non-treated groups were mapped in accordance with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) terms. Hydrogen treatment significantly increased the apoptotic rates of endometrial cancer cells. Conclusions Taken together, our data indicate that hydrogen can serve as a therapeutic target for endometrial cancer via TNF/NF-κB pathway and apoptosis induction.

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Disseminated Mycobacterium malmoense and Salmonella Infections Associated with a Novel Variant in NFKBIA

Cited by 14 publications

References 12 publications

Outcome of Hematopoietic Stem Cell Transplantation in patients with Mendelian Susceptibility to Mycobacterial Diseases

Outcome of Hematopoietic Stem Cell Transplantation in patients with Mendelian Susceptibility to Mycobacterial Diseases

Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency

RNA sequencing analysis reveals apoptosis induction by hydrogen treatment in endometrial cancer via TNF and NF-κB pathways

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