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IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation
IRAK4 deficiency is an inborn error of immunity predisposing patients to invasive pyogenic infections. Currently, there is no established simple assay that enables precise characterization of IRAK4 mutant alleles in isolation. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846526/ https://www.ncbi.nlm.nih.gov/pubmed/33083971 http://dx.doi.org/10.1007/s10875-020-00885-5 |
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author | Nishimura, Shiho Kobayashi, Yoshiyuki Ohnishi, Hidenori Moriya, Kunihiko Tsumura, Miyuki Sakata, Sonoko Mizoguchi, Yoko Takada, Hidetoshi Kato, Zenichiro Sancho-Shimizu, Vanessa Picard, Capucine Irani, Sarosh R. Ohara, Osamu Casanova, Jean-Laurent Puel, Anne Ishikawa, Nobutsune Okada, Satoshi Kobayashi, Masao |
author_facet | Nishimura, Shiho Kobayashi, Yoshiyuki Ohnishi, Hidenori Moriya, Kunihiko Tsumura, Miyuki Sakata, Sonoko Mizoguchi, Yoko Takada, Hidetoshi Kato, Zenichiro Sancho-Shimizu, Vanessa Picard, Capucine Irani, Sarosh R. Ohara, Osamu Casanova, Jean-Laurent Puel, Anne Ishikawa, Nobutsune Okada, Satoshi Kobayashi, Masao |
author_sort | Nishimura, Shiho |
collection | PubMed |
description | IRAK4 deficiency is an inborn error of immunity predisposing patients to invasive pyogenic infections. Currently, there is no established simple assay that enables precise characterization of IRAK4 mutant alleles in isolation. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune condition that is characterized by psychiatric symptoms, involuntary movement, seizures, autonomic dysfunction, and central hypoventilation. It typically occurs in adult females associated with tumors. Only a few infantile cases with anti-NMDAR encephalitis have been so far reported. We identified a 10-month-old boy with IRAK4 deficiency presenting with anti-NMDAR encephalitis and human herpes virus 6 (HHV6) reactivation. The diagnosis of IRAK4 deficiency was confirmed by the identification of compound heterozygous mutations c.29_30delAT (p.Y10Cfs*9) and c.35G>C (p.R12P) in the IRAK4 gene, low levels of IRAK4 protein expression in peripheral blood, and defective fibroblastic cell responses to TLR and IL-1 (TIR) agonist. We established a novel NF-κB reporter assay using IRAK4-null HEK293T, which enabled the precise evaluation of IRAK4 mutations. Using this system, we confirmed that both novel mutations identified in the patient are deleterious. Our study provides a new simple and reliable method to analyze IRAK4 mutant alleles. It also suggests the possible link between inborn errors of immunity and early onset anti-NMDAR encephalitis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10875-020-00885-5) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-7846526 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-78465262021-02-11 IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation Nishimura, Shiho Kobayashi, Yoshiyuki Ohnishi, Hidenori Moriya, Kunihiko Tsumura, Miyuki Sakata, Sonoko Mizoguchi, Yoko Takada, Hidetoshi Kato, Zenichiro Sancho-Shimizu, Vanessa Picard, Capucine Irani, Sarosh R. Ohara, Osamu Casanova, Jean-Laurent Puel, Anne Ishikawa, Nobutsune Okada, Satoshi Kobayashi, Masao J Clin Immunol Original Article IRAK4 deficiency is an inborn error of immunity predisposing patients to invasive pyogenic infections. Currently, there is no established simple assay that enables precise characterization of IRAK4 mutant alleles in isolation. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune condition that is characterized by psychiatric symptoms, involuntary movement, seizures, autonomic dysfunction, and central hypoventilation. It typically occurs in adult females associated with tumors. Only a few infantile cases with anti-NMDAR encephalitis have been so far reported. We identified a 10-month-old boy with IRAK4 deficiency presenting with anti-NMDAR encephalitis and human herpes virus 6 (HHV6) reactivation. The diagnosis of IRAK4 deficiency was confirmed by the identification of compound heterozygous mutations c.29_30delAT (p.Y10Cfs*9) and c.35G>C (p.R12P) in the IRAK4 gene, low levels of IRAK4 protein expression in peripheral blood, and defective fibroblastic cell responses to TLR and IL-1 (TIR) agonist. We established a novel NF-κB reporter assay using IRAK4-null HEK293T, which enabled the precise evaluation of IRAK4 mutations. Using this system, we confirmed that both novel mutations identified in the patient are deleterious. Our study provides a new simple and reliable method to analyze IRAK4 mutant alleles. It also suggests the possible link between inborn errors of immunity and early onset anti-NMDAR encephalitis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10875-020-00885-5) contains supplementary material, which is available to authorized users. Springer US 2020-10-20 2021 /pmc/articles/PMC7846526/ /pubmed/33083971 http://dx.doi.org/10.1007/s10875-020-00885-5 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Original Article Nishimura, Shiho Kobayashi, Yoshiyuki Ohnishi, Hidenori Moriya, Kunihiko Tsumura, Miyuki Sakata, Sonoko Mizoguchi, Yoko Takada, Hidetoshi Kato, Zenichiro Sancho-Shimizu, Vanessa Picard, Capucine Irani, Sarosh R. Ohara, Osamu Casanova, Jean-Laurent Puel, Anne Ishikawa, Nobutsune Okada, Satoshi Kobayashi, Masao IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation |
title | IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation |
title_full | IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation |
title_fullStr | IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation |
title_full_unstemmed | IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation |
title_short | IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation |
title_sort | irak4 deficiency presenting with anti-nmdar encephalitis and hhv6 reactivation |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846526/ https://www.ncbi.nlm.nih.gov/pubmed/33083971 http://dx.doi.org/10.1007/s10875-020-00885-5 |
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