IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation

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.

Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia

“…Consistently, critical COVID-19 pneumonia is both much less common and much less well understood in children than in adults. There are 15 known inborn errors of type I IFN that are recessively inherited and biochemically complete ( Meyts and Casanova, 2021 ): mutations of TLR3 ( Guo et al, 2011 ; Zhang et al, 2007 ), TICAM1 ( Sancho-Shimizu et al, 2011 ), UNC93B1 ( Casrouge et al, 2006 ), TLR7 ( Asano et al, 2021 ), IRAK4 ( Nishimura et al, 2021 ; Picard et al, 2003 ), MYD88 ( Giardino et al, 2016 ; von Bernuth et al, 2008 ), IFIH1 ( Asgari et al, 2017 ; Chen et al, 2021 ; Lamborn et al, 2017 ), TBK1 ( Schmidt et al, 2021 ; Taft et al, 2021 ), IRF7 ( Ciancanelli et al, 2015 ; Zhang et al, 2020b ), IFNAR1 ( Abolhassani et al, 2022 ; Bastard et al, 2021c ; Hernandez et al, 2019 ), IFNAR2 ( Bastard et al, 2021d ; Duncan et al, 2015 ), TYK2 ( Minegishi et al, 2006 ; Sarrafzadeh et al, 2020 ), STAT1 ( Dupuis et al, 2003 ; Le Voyer et al, 2021 ), STAT2 ( Freij et al, 2020 ; Hambleton et al, 2013 ), and IRF9 ( Bravo Garcia-Morato et al, 2019 ; Hernandez et al, 2018 ). Deficiencies of TLR3 and TRIF (encoded by TICAM1 ) disrupt the TLR3 pathway, whereas deficiencies of TLR7, MYD88, and IRAK4 affect the TLR7 pathway.…”

“…These disorders (or, by inference from their milder, dominant form, for autosomal disorders, underlined) are associated with severe viral diseases, including influenza pneumonia ( TLR3 , IRF7, IRF9, STAT1, STAT2; Alosaimi et al, 2019 ; Ciancanelli et al, 2015 ; Hernandez et al, 2018 ; Le Voyer et al, 2021 ), COVID-19 pneumonia ( TLR3 , UNC93B1 , TBK1 , TRIF , IRF3 , IRF7, IFNAR1, IFNAR2 , TLR7; Abolhassani et al, 2022 ; Asano et al, 2021 ; Schmidt et al, 2021 ; Solanich et al, 2021 ; van der Made et al, 2020 ; Zhang et al, 2020b ), rhinovirus or respiratory syncytial virus pneumonia (MDA5, encoded by IFIH1 ; Asgari et al, 2017 ; Lamborn et al, 2017 ), herpes simplex virus encephalitis (IFNAR1, STAT1, TLR3, TRIF, TYK2, UNC93B1; Bastard et al, 2021c ; Casrouge et al, 2006 ; Dupuis et al, 2003 ; Guo et al, 2011 ; Kreins et al, 2015 ; Minegishi et al, 2006 ; Sancho-Shimizu et al, 2011 ), adverse reactions to measles, mumps, and rubella (MMR) or yellow fever virus (YFV) vaccines (IFNAR1, IFNAR2, STAT1, STAT2; Bastard et al, 2022 ; Burns et al, 2016 ; Duncan et al, 2015 ; Duncan et al, 2022 ; Hambleton et al, 2013 ; Hernandez et al, 2019 ; Moens et al, 2017 ), enterovirus encephalitis ( TLR3 , MDA5; Chen et al, 2021 ), EBV viremia (MYD88; Chiriaco et al, 2019 ), and human herpesvirus-6 (HHV6) infection (IRAK4; Nishimura et al, 2021 ). Over the last two decades, 105 children with these disorders have been reported, and many more were probably diagnosed.…”

Inherited IRAK-4 Deficiency in Acute Human Herpesvirus-6 Encephalitis

“…Next, we prioritized candidate genes based on their expression pattern and function related to viral encephalitis and on the rarity and predicted deleteriousness of variations (Table S4 and S5 ). IRAK4 , encoding the interleukin-1 receptor-associated kinase 4, was the most plausible disease-causing gene, as (i) it encodes a kinase that is involved in TLR/IL-1R signaling, regulating most innate immune responses, and deficiency of which causes recurrent life-threatening bacterial infections in early childhood [ 11 , 12 , 23 – 26 ], and (ii) its deficiency was recently reported in anti-NMDAR encephalitis and HHV-6 reactivation in a male infant [ 10 ]. Moreover, the IRAK4 variant (NM_016123.4: c.G236A; NP_057207.2: p.C79Y) was not found in any public databases, such as 1000 Genomes, the Single Nucleotide Polymorphism Database (dbSNP), gnomAD, Bravo or the Greater Middle East (GME) Variome Project.…”

“…We assessed expression levels of IRAK-4 in PBMCs from three healthy donors, the patient and his healthy sibling and parents by flow cytometry as previously described [ 10 ]. We found that IRAK-4 expression was drastically reduced in CD3 + CD4 + T cells, CD3 + CD8 + T cells, and CD19 + B cells, but to a lesser extent in CD14 + monocytes of the patient compared to healthy donors and family members (Fig.…”

“…Interestingly, there is not yet any known inherited immunodeficiency associated with encephalitis upon infection with HHV-6 [ 9 ]. Recently, one IRAK-4 (interleukin-1 receptor (IL-1R)-associated kinase 4)-deficient patient presenting with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and HHV-6 reactivation was reported [ 10 ]. Human IRAK-4 deficiency impairs the Toll-like receptor (TLR)/IL-1R-mediated immunity, rendering affected individuals predominantly susceptible to recurrent life-threatening bacterial infections [ 11 – 13 ].…”