دورية أكاديمية
Human MD2 deficiency – an inborn error of immunity with pleiotropic features
| العنوان: | Human MD2 deficiency – an inborn error of immunity with pleiotropic features |
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| المؤلفون: | Li, Y, Yu, Z, Schenk, M, Lagovsky, I, Illig, D, Walz, C, Rohlfs, M, Conca, R, Muise, AM, Snapper, SB, Uhlig, HH, Zion Garty, B, Klein, C, Kotlarz, D |
| بيانات النشر: | Elsevier |
| سنة النشر: | 2023 |
| المجموعة: | Oxford University Research Archive (ORA) |
| الوصف: | Background: Toll-like receptors (TLRs) are important pattern recognition receptors that sense microbes and control host defense. Myeloid differentiation protein 2 (MD2) is the indispensable coreceptor for TLR4, facilitating the binding to the gram-negative bacterial cell wall component LPS and activation of downstream signaling. Objective: We sought to provide phenotypic and mechanistic insights into human MD2 deficiency. Methods: To elucidate the genetic cause in a patient with very early onset inflammatory bowel disease, we performed whole-exome sequencing and studied the functional consequences of the identified mutation in LY96 (encoding for MD2) in genetically engineered induced pluripotent stem cell-derived macrophages with knockout of MD2 or knockin of the patient-specific mutation, including TLR4-mediated signaling, cytokine production, and bacterial handling. Results: Whole-exome sequencing identified a homozygous in-frame deletion in the LY96 gene (c.347_349delCAA; p.Thr116del) in a patient with very early onset inflammatory bowel disease and a sibling presenting with pneumonia and otitis media. Induced pluripotent stem cell-derived macrophages with knockout of MD2 or expression of the Thr116del mutation showed impaired activation of nuclear factor kappa B and mitogen-activated protein kinase signaling as well as TLR4 endocytosis on challenge with LPS or bacteria. In addition, MD2-deficient macrophages showed decreased cytokine expression (eg, IL-6, TNF, and IL-10) in response to LPS or gram-negative but not gram-positive bacteria. Conclusions: Human MD2 deficiency causes defective TLR4 signaling in response to LPS or gram-negative bacteria. The clinical manifestations and expressivity might be variable due to unknown secondary risk factors. Because TLR4 represents a therapeutic target for multiple inflammatory conditions, our study may provide insights into potential side effects of pharmacological TLR4 targeting. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | https://ora.ox.ac.uk/objects/uuid:521f632d-d05b-44d0-a57d-b6a0c373b399Test; https://doi.org/10.1016/j.jaci.2022.09.033Test |
| DOI: | 10.1016/j.jaci.2022.09.033 |
| الإتاحة: | https://doi.org/10.1016/j.jaci.2022.09.033Test https://ora.ox.ac.uk/objects/uuid:521f632d-d05b-44d0-a57d-b6a0c373b399Test |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.670E4B7E |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.jaci.2022.09.033 |
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