IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation
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ORIGINAL ARTICLE
IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation Shiho Nishimura 1 & Yoshiyuki Kobayashi 1 & Hidenori Ohnishi 2 & Kunihiko Moriya 3,4 & Miyuki Tsumura 1 & Sonoko Sakata 1 & Yoko Mizoguchi 1 & Hidetoshi Takada 5 & Zenichiro Kato 2,6 & Vanessa Sancho-Shimizu 7 & Capucine Picard 8,9,10 & Sarosh R. Irani 11 & Osamu Ohara 12 & Jean-Laurent Casanova 3,10,13,14 & Anne Puel 3,10,13 & Nobutsune Ishikawa 1 & Satoshi Okada 1 & Masao Kobayashi 1,15 Received: 11 May 2020 / Accepted: 14 September 2020 # The Author(s) 2020
Abstract 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. Keywords anti-NMDAR encephalitis . autoimmunity . HHV6 . IRAK4
Introduction Toll-like receptors (TLRs) sense microbial products and play an important role in innate immunity [1]. Activation of the TLR response results in increased production of inflammatory cytokines such as IL-6 and type I interferons, a key component of the anti-viral state, and secretion of chemokines to attract innate immune cells [2]. Autosomal recessive (AR) interleukin-1 receptor (IL-1R)-associated kinase 4 (IRAK4) Shiho Nishimura and Yoshiyuki Kobayashi contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10875-020-00885-5) contains supplementary material, which is available to authorized users. * Satoshi Okada [email protected] Extended author information available on the last page of the article
deficiency, together with myeloid differentiation primary response gene 88 (MyD88) deficiency, is a primary immune deficiency that impairs IL-1R and TLR family signaling [3]. Pa
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