Browsing by Subject "Immunodeficiency"

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    Bone marrow mesenchymal stromal cells supportregeneration of intestinal damage in a colitis mouse model,independent of their CXCR4 expression
    (Wiley-Blackwell Publishing, Inc., 2024-05-14) Pervin, B.; Gizer, M.; Seker, M.E.; Erol, Ö.D.; Gür, S.N.; Polat, E.G.; Değirmenci Uzun, Bahar; Korkusuz, P.; Aerts-Kaya, F.
    Inflammatory bowel disease (IBD) is characterized by a chronically dysregulated immune response in the gastrointestinal tract. Bone marrow multipotent mesenchymal stromal cells have an important immunomodulatory function and support regeneration of inflamed tissue by secretion of soluble factors as well as through direct local differentiation. CXCR4 is the receptor for CXCL12 (SDF-1, stromal-derived factor-1) and has been shown to be the main chemokine receptor, required for homing of MSCs. Increased expression of CXCL12 by inflamed intestinal tissue causes constitutive inflammation by attracting lymphocytes but can also be used to direct MSCs to sites of injury/inflammation. Trypsin is typically used to dissociate MSCs into single-cell suspensions but has also been shown to digest surface CXCR4. Here, we assessed the regenerative effects of $CXCR4^{high}$ and $CXCR4^{low}$ MSCs in an immune-deficient mouse model of DSS-induced colitis. We found that transplantation of MSCs resulted in clinical improvement and histological recovery of intestinal epithelium. In contrary to our expectations, the levels of CXCR4 on transplanted MSCs did not affect their regenerative supporting potential, indicating that paracrine effects of MSCs may be largely responsible for their regenerative/protective effects.
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    Characterization of inherited IRAK-4 deficiency in a patient with acute HHV-6 encephalitis
    (2023-07) Demir, Zeynep Güneş Tepe
    Human herpesvirus-6 (HHV-6), a ubiquitous virus among humans, typically causes acute febrile illness in children, whereas the majority remain asymptomatic. HHV-6 infection can rarely cause encephalitis, with unknown pathogenesis. We hypothesized that inborn single-gene defects may underlie susceptibility to HHV-6 encephalitis in otherwise healthy children. We performed whole-exome sequencing on genomic DNA of a male child diagnosed with acute HHV-6 encephalitis and found a novel homozygous missense variation (NM_016123.4:c.G236A:p.C79Y) in Interleukin-1 receptor-associated kinase 4 (IRAK4), which is involved in the Toll-Interleukin-1 receptor signaling pathway. Sanger sequencing confirmed that both parents and the sibling were heterozygotes. The p.C79Y that affected an evolutionary conserved residue was predicted to be damaging by in silico algorithms. We found that IRAK-4 expression was severely reduced in patient’s leukocytes. There were similar levels of wild-type (WT) and mutant IRAK-4 when transiently over-expressed in HEK293 cells, however mutant IRAK-4 expression was dramatically decreased upon cycloheximide treatment, compared to the WT. This indicated that the p.C79Y might impair IRAK-4 stability. We found that patient’s leukocytes had diminished innate immune responses to various stimuli inducing different Toll-like receptors and cytosolic nucleic acid sensors, compared to the healthy controls. We also generated IRAK4 knockout HEK293 cells by CRISPR-Cas9 genome editing. Transient expression of mutant IRAK-4 had significantly reduced NFκB-dependent luciferase activity, compared to the WT in IRAK4 knockout cells treated with IL-18. Collectively, the p.C79Y impaired both the expression and function of IRAK-4, leading to diminished immune responses against bacterial and viral stimuli in patient’s leukocytes. Overall, this was the first study demonstrating that inborn errors of immunity could underlie isolated acute HHV-6 encephalitis. Our findings also widened the known genotypic and phenotypic spectrum of inherited IRAK-4 deficiency in humans.
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    Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children
    (Rockefeller University Press, 2024-01-04) Bastard, Paul; Gervais, Adrian; Taniguchi, Maki; Saare, Liisa; Särekannu, Karita; Voyer, Tom le; Philippot, Quentin; Rosain, Jeremie; Bizien, Lucy; Asano, Takaki; Garcia-Prat, Marina; Parra-Martínez, Alba; Migaud, Mélanie; Tsumura, Miyuki; Conti, Francesca; Belot, Alexandre; Rivière, Jacques G.; Morio, Tomohiro; Tanaka, Junko; Javouhey, Etienne; Haerynck, Filomeen; Duvlis, Sotirija; Özçelik, Tayfun; Keles, Sevgi; Redondo, yacine tandjaoui-lambiotte; Escoda, Simon; Husain, Maya; Pan-Hammarström, Qiang; Hammarström, Lennart; Gloria, Ahlijah; Haidar, Anthony ABI; Soudee, Camille; Abolhassani, Hassan; Sahanic, Sabina; Tancevski, Ivan; Nukui, Yoko; Hayakawa, Seiichi; Chrousos, George P.; Michos, Athanasios; Tatsi, Elizabeth; Filippatos, Filippos; Rodriguez-Palmero, Agusti; García, Jesús Troya; Tipu, Imran; Meyts, Isabelle; Roussel, Lucie; Ostrowski, Sisse Rye; Schidlowski, Laire; Prando, Carolina; Condino-Neto, Antonio; Cheikh, Nathalie; Bousfiha, Ahmed Aziz; Bakkouri, Jalila EL; Peterson, Pärt; Pujol, Aurora; Lévy, Romain; Quartier, Pierre; Vinh, Donald C.; Boisson, Bertrand; Béziat, Vivien; Zhang, Shen-Ying; Borghesi, Alessandro; Pession, Andrea; Andreakos, Evangelos; Marr, Nico; Mentis, Alexios-Fotios; Mogensen, Trine Hyrup; Rodríguez-Gallego, Carlos; Soler-Palacín, Pere; Colobran, Roger; Tillmann, Vallo; Neven, Benedicte; Trouillet-Assant, Sophie; Brodin, Petter; Abel, Laurent; Jouanguy, Emmanuelle; Zhang, Qian; Martinon-Torres, Federico; Salas, Antonio; Gómez-Carballa, Alberto; Gonzalez-Granado, Luis Ignacio; Kisand, Kai; Okada, Satoshi; Puel, Anne; Cobat, Aurélie; Casanova, Jean-Laurent
    We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2.
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    Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance
    (Rockefeller University Press, 2021-06-17) Asano, T.; Khourieh, J.; Zhang, P.; Rapaport, F.; Spaan, A. N.; Li, J.; Lei, W. T.; Pelham, S. J.; Hum, D.; Chrabieh, M.; Han, J. E.; Guérin, A.; Mackie, J.; Gupta, S.; Saikia, B.; Baghdadi, J. E. I.; Fadil, I.; Bousfiha, A.; Habib, T.; Marr, N.; Ganeshanandan, L.; Peake, J.; Droney, L.; Williams, A.; Celmeli, F.; Hatipoglu, N.; Özçelik, Tayfun; Picard, C.
    Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been recently suggested that eight out-of-frame variants operate by haploinsufficiency. We experimentally tested these 143 variants, 7 novel out-of-frame variants found in HIES patients, and other STAT3 variants from the general population. Strikingly, all 15 out-of-frame variants were DN via their encoded (1) truncated proteins, (2) neoproteins generated from a translation reinitiation codon, and (3) isoforms from alternative transcripts or a combination thereof. Moreover, 128 of the 135 in-frame variants (95%) were also DN. The patients carrying the seven non-DN STAT3 in-frame variants have not been studied for other genetic etiologies. Finally, none of the variants from the general population tested, including an out-of-frame variant, were DN. Overall, our findings show that heterozygous STAT3 variants, whether in or out of frame, underlie AD-HIES through negative dominance rather than haploinsufficiency.
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    SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency
    (Rockefeller University Press, 2024-07-18) Yi-Hao Chan; Lundberg, Vanja; Pen, Jérémie Le; Yuan, Jiayi; Lee, Danyel; Pinci, Francesca; Volpi, Stefano; Nakajima, Koji; Bondet, Vincent; Linnéa Åkesson, Sanna Emmy; Khobrekar, Noopur; Bodansky, Aaron; Du, Likun; Melander, Tina; Mariaggi, Alice-Andrée; Seeleuthner, Yoann; Saleh, Tariq Shikh; Chakravarty, Debanjana; Marits, Per; Dobbs, Kerry; Vonlanthen, Sofie; Hennings, Viktoria; Thörn, Karolina; Rinchai, Darawan; Bizien, Lucy; Chaldebas, Matthieu; Sobh, Ali; Özçelik, Tayfun; Keles, Sevgi; AlKhater, Suzan; Prando, Carolina; Meyts, Isabelle; Wilson, Michael; Rosain, Jeremie; Jouanguy, Emmanuelle; Aubart, Melodie; Abel, Laurent; Mogensen, Trine Hyrup; Pan-Hammarström, Qiang; Gao, Daxing; Duffy, Darragh; Cobat, Aurélie; Berg, Stefan; Notarangelo, Luigi; Harschnitz, Oliver; Rice, Charles M.; Studer, Lorenz; Casanova, Jean-Laurent; Ekwall, Olov; Zhang, Shen-Ying
    Inherited deficiency of the RNA lariat–debranching enzyme 1 (DBR1) is a rare etiology of brainstem viral encephalitis. The cellular basis of disease and the range of viral predisposition are unclear. We report inherited DBR1 deficiency in a 14-year-old boy who suffered from isolated SARS-CoV-2 brainstem encephalitis. The patient is homozygous for a previously reported hypomorphic and pathogenic DBR1 variant (I120T). Consistently, DBR1 I120T/I120T fibroblasts from affected individuals from this and another unrelated kindred have similarly low levels of DBR1 protein and high levels of RNA lariats. DBR1 I120T/I120T human pluripotent stem cell (hPSC)–derived hindbrain neurons are highly susceptible to SARS-CoV-2 infection. Exogenous WT DBR1 expression in DBR1 I120T/I120T fibroblasts and hindbrain neurons rescued the RNA lariat accumulation phenotype. Moreover, expression of exogenous RNA lariats, mimicking DBR1 deficiency, increased the susceptibility of WT hindbrain neurons to SARS-CoV-2 infection. Inborn errors of DBR1 impair hindbrain neuron–intrinsic antiviral immunity, predisposing to viral infections of the brainstem, including that by SARS-CoV-2.