TNF Receptor-Associated Factor 5 Limits Function of Plasmacytoid Dendritic Cells by Controlling IFN Regulatory Factor 5 Expression.

The physiological functions of TNF receptor-associated factor 5 (TRAF5) in the skin inflammation and wound healing process are not well characterized. We found that Traf5 -/- mice exhibited an accelerated skin wound healing as compared with wild-type counterparts. The augmented wound closure in Traf5 -/- mice was associated with a massive accumulation of plasmacytoid dendritic cells (pDCs) into skin wounds and an enhanced expression of genes related to wound repair at skin sites. In accordance with this result, adoptive transfer of Traf5 -/- pDCs, but not wild-type pDCs, into the injured skin area in wild-type recipient mice significantly promoted skin wound healing. The expression of skin-tropic chemokine receptor CXCR3 was significantly upregulated in Traf5-/- pDCs, and treatment with a CXCR3 inhibitor cancelled the promoted wound healing in Traf5-/- mice, suggesting a pivotal role of CXCR3 in pDC-dependent wound healing. Traf5 -/- pDCs displayed significantly higher expression of IFN regulatory factor 5 (IRF5), which correlated with greater induction of proinflammatory cytokine genes and CXCR3 protein after stimulation with TLR ligands. Consistently, transduction of exogeneous TRAF5 in Traf5-/- pDCs normalized the levels of abnormally elevated proinflammatory molecules, including IRF5 and CXCR3. Furthermore, knockdown of IRF5 also rescued the abnormal phenotypes of Traf5-/- pDCs. Therefore, the higher expression and induction of IRF5 in Traf5-/- pDCs causes proinflammatory and skin-tropic characteristics of the pDCs, which may accelerate skin wound healing responses. Collectively, our results uncover a novel role of TRAF5 in skin wound healing that is mediated by IRF5-dependent function of pDCs.

TRAF5 promotes plasmacytoid dendritic cell development from bone marrow progenitors.

The conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs) originate from the same common dendritic cell precursor cells in the bone marrow. The pDCs produce large amounts of type 1 interferon in response to foreign nucleic acid and crucially contribute to host defense against viral infection. Tumor necrosis factor (TNF) receptor-associated factor 5 (TRAF5) is a pivotal component of various TNF receptor signaling pathways in the immune system. Although the functions of TRAF5 in T and B lymphocytes have been well studied, its roles in pDCs remains to be fully elucidated. In this study, we show that the expression of TRAF5 supports the generation of pDCs in the bone marrow and also critically contributes to the homeostasis of the pDC subset in the periphery in a cell-intrinsic manner. Furthermore, we provide evidence that TRAF5 promotes the commitment of DC precursor cells toward pDC versus cDC subsets, which is regulated by the balance of transcription factors TCF4 and ID2. Together our findings reveal that TRAF5 acts as a positive regulator of pDC differentiation from bone marrow progenitors.

Association of genetic variants with autism spectrum disorder in Japanese children revealed by targeted sequencing.

Introduction: Autism spectrum disorders (ASD) represent a heterogeneous group of neurodevelopmental disorders with strong genetic predispositions. Although an increasing number of genetic variants have been implicated in the pathogenesis of ASD, little is known about the relationship between ASD-associated genetic variants and individual ASD traits. Therefore, we aimed to investigate these relationships. Methods: Here, we report a case-control association study of 32 Japanese children with ASD (mainly with high-functioning autism [HFA]) and 36 with typical development (TD). We explored previously established ASD-associated genes using a next-generation sequencing panel and determined the association between Social Responsiveness Scale (SRS) T-scores and intelligence quotient (IQ) scores. Results: In the genotype-phenotype analyses, 40 variants of five genes (SCN1A, SHANK3, DYRK1A, CADPS, and SCN2A) were associated with ASD/TD phenotypes. In particular, 10 SCN1A variants passed permutation filtering (false discovery rate <0.05). In the quantitative association analyses, 49 variants of 12 genes (CHD8, SCN1A, SLC6A1, KMT5B, CNTNAP2, KCNQ3, SCN2A, ARID1B, SHANK3, DYRK1A, FOXP1, and GRIN2B) and 50 variants of 10 genes (DYRK1A, SCN2A, SLC6A1, ARID1B, CNTNAP2, SHANK3, FOXP1, PTEN, SCN1A, and CHD8) were associated with SRS T- and IQ-scores, respectively. Conclusion: Our data suggest that these identified variants are essential for the genetic architecture of HFA.

The influence of NRXN1 on systemizing and the brain structure in healthy adults.

Certain behavioral characteristics of autism spectrum disorder can be found in otherwise healthy people. Individuals with difficulties in social adaptation may have subclinical autistic traits; however, effective biomarkers of these traits have not yet been established. There is a dire need for objective indices of these traits that combine behavior, brain images, and genetic information. In this study, we examined the association among a single nucleotide polymorphism of NRXN1 (rs858932; C/G), autistic traits, and brain structure in 311 healthy adults. We found that carriers of minor alleles (carriers of the G-allele) had significantly higher systemizing scores than major-allele (C-allele) homozygotes. Furthermore, the regional white matter volume in the right anterior limb of the internal capsule was significantly greater in carriers of the G-allele than in C-allele homozygotes. To the best of our knowledge, this is the first report of NRXN1 rs858932 being involved in systemizing and the brain structure of healthy adults. Our findings provide insight into the effects of genetics on autistic traits and their respective neural substrates.

Alterations in brain networks in children with sub-threshold autism spectrum disorder: A magnetoencephalography study.

Individuals with sub-threshold autism spectrum disorder (ASD) are those who have social communication difficulties but do not meet the full ASD diagnostic criteria. ASD is associated with an atypical brain network; however, no studies have focused on sub-threshold ASD. Here, we used the graph approach to investigate alterations in the brain networks of children with sub-threshold ASD, independent of a clinical diagnosis. Graph theory is an effective approach for characterizing the properties of complex networks on a large scale. Forty-six children with ASD and 31 typically developing children were divided into three groups (i.e., ASD-Unlikely, ASD-Possible, and ASD-Probable groups) according to their Social Responsiveness Scale scores. We quantified magnetoencephalographic signals using a graph-theoretic index, the phase lag index, for every frequency band. Resultantly, the ASD-Probable group had significantly lower small-worldness (SW) in the delta, theta, and beta bands than the ASD-Unlikely group. Notably, the ASD-Possible group exhibited significantly higher SW than the ASD-Probable group and significantly lower SW than the ASD-Unlikely group in the delta band only. To our knowledge, this was the first report of the atypical brain network associated with sub-threshold ASD. Our findings indicate that magnetoencephalographic signals using graph theory may be useful in detecting sub-threshold ASD.

Effect of CNTNAP2 polymorphism on receptive language in children with autism spectrum disorder without language developmental delay.

AIM: The receptive language ability of individuals with autism spectrum disorder (ASD) seems to lag behind expressive language ability. Several autism-related genes may influence this developmental delay. Polymorphism of one such gene, namely, the contactin-associated protein-like 2 gene (CNTNAP2), affects receptive language in individuals with language delay. However, the association between CNTNAP2 polymorphism and receptive language in individuals with no language delay remains unclear. METHODS: We included 59 children with ASD and 57 children with typical development in this study and investigated this association using coarse-grained exact matching. RESULTS: We present the first evidence of an association between CNTNAP2 rs2710102 (A-allele carrier) and reduced receptive language ability in children with ASD whose language development was not delayed. Similarly, among children with typical development, A-allele carriers had lower receptive language ability, but the difference was non-significant. CONCLUSIONS: It is possible that the effect of rs2710102 on receptive language ability is larger in the presence of autism-related genes. Consequently, we speculate that the effect of rs2710102 on receptive language ability would be exerted in combination with other genes. These findings provide new insights into the genetic interactions between mutations associated with common language disorders and ASD and identify molecular mechanisms and risk alleles that contribute to receptive vocabulary. These findings also provide practical guidance in terms of providing candidate genetic markers that may provide opportunities for targeted early intervention to stratify risk and improve prognosis for poor receptive language development in children with ASD.

Mercury levels in hair are associated with reduced neurobehavioral performance and altered brain structures in young adults.

The detrimental effects of high-level mercury exposure on the central nervous system as well as effects of low-level exposure during early development have been established. However, no previous studies have investigated the effects of mercury level on brain morphometry using advance imaging techniques in young adults. Here, utilizing hair analysis which has been advocated as a method for biological monitoring, data of regional gray matter volume (rGMV), regional white matter volume (rWMV), fractional anisotropy (FA) and mean diffusivity (MD), cognitive functions, and depression among 920 healthy young adults in Japan, we showed that greater hair mercury levels were weakly but significantly associated with diminished cognitive performance, particularly on tasks requiring rapid processing (speed measures), lower depressive tendency, lower rGMV in areas of the thalamus and hippocampus, lower rWMV in widespread areas, greater FA in bilaterally distributed white matter areas overlapping with areas of significant rWMV reductions and lower MD of the widely distributed gray and white matter areas particularly in the bilateral frontal lobe and the right basal ganglia. These results suggest that even normal mercury exposure levels in Japan are weakly associated with differences of brain structures and lower neurobehavioral performance and altered mood among young adults.

A common variant of CNTNAP2 is associated with sub-threshold autistic traits and intellectual disability.

Sub-threshold autistic traits are common in the general population. Children with sub-threshold autistic traits have difficulties with social adaptation. Contactin-associated protein-like 2 (CNTNAP2) is associated with the development of Autism spectrum disorder (ASD) and the single-nucleotide polymorphism rs2710102 (G/A) of CNTNAP2 is suggested to contribute to sub-threshold social impairments and intellectual disabilities. We recruited 67 children with Autistic disorder (AD) (49 boys, 18 girls, aged 38-98 months) and 57 typically developing (TD) children (34 boys, 23 girls, aged 53-90 months). We assessed the participants' intelligence and social reciprocity using the Kaufman Assessment Battery for Children (K-ABC) and the Social Responsiveness Scale (SRS), respectively. Genomic DNA was extracted from the buccal mucosa and genotyped for rs2710102. A chi-square test revealed a significant association between genotype and group [χ2(2) = 6.56, p = 0.038]. When a co-dominant model was assumed, the results from linear regression models demonstrated that TD children with A-carriers (AA + AG) presented higher SRS T-scores [t(55) = 2.11, p = 0.039] and lower simultaneous processing scale scores of K-ABC [t(55) = -2.19, p = 0.032] than those with GG homozygotes. These associations were not significant in children with ASD. TD children with the rs2710102 A-allele may have more sub-threshold autistic traits than those with GG homozygotes, reflected in higher SRS scores and lower simultaneous processing scale scores. These results support the use of genetic evidence to detect sub-threshold autistic traits.

Atypical Resting State Functional Neural Network in Children With Autism Spectrum Disorder: Graph Theory Approach.

Measuring whole brain networks is a promising approach to extract features of autism spectrum disorder (ASD), a brain disorder of widespread regions. Objectives of this study were to evaluate properties of resting-state functional brain networks in children with and without ASD and to evaluate their relation with social impairment severity. Magnetoencephalographic (MEG) data were recorded for 21 children with ASD (7 girls, 60-89 months old) and for 25 typically developing (TD) control children (10 girls, 60-91 months old) in a resting state while gazing at a fixation cross. After signal sources were localized onto the Desikan-Killiany brain atlas, statistical relations between localized activities were found and evaluated in terms of the phase lag index. After brain networks were constructed and after matching with intelligence using a coarsened exact matching algorithm, ASD and TD graph theoretical measures were compared. We measured autism symptoms severity using the Social Responsiveness Scale and investigated its relation with altered small-worldness using linear regression models. Children with ASD were found to have significantly lower small-worldness in the beta band (p = 0.007) than TD children had. Lower small-worldness in the beta band of children with ASD was associated with higher Social Responsiveness Scale total t-scores (p = 0.047). Significant relations were also inferred for the Social Awareness (p = 0.008) and Social Cognition (p = 0.015) sub-scales. Results obtained using graph theory demonstrate a difference between children with and without ASD in MEG-derived resting-state functional brain networks, and the relation of that difference with social impairment. Combining graph theory and MEG might be a promising approach to establish a biological marker for ASD.

Epileptiform discharges relate to altered functional brain networks in autism spectrum disorders.

Many individuals with autism spectrum disorders have comorbid epilepsy. Even in the absence of observable seizures, interictal epileptiform discharges are common in individuals with autism spectrum disorders. However, how these interictal epileptiform discharges are related to autistic symptomatology remains unclear. This study used magnetoencephalography to investigate the relation between interictal epileptiform discharges and altered functional brain networks in children with autism spectrum disorders. Instead of particularly addressing individual brain regions, we specifically examine network properties. For this case-control study, we analysed 70 children with autism spectrum disorders (52 boys, 18 girls, 38-92 months old) and 19 typically developing children (16 boys, 3 girls, 48-88 months old). After assessing the participants' social reciprocity using the Social Responsiveness Scale, we constructed graphs of functional brain networks from frequency band separated task-free magnetoencephalography recordings. Nodes corresponded to Desikan-Killiany atlas-based 68 brain regions. Edges corresponded to phase lag index values between pairs of brain regions. To elucidate the effects of the existence of interictal epileptiform discharges on graph metrics, we matched each of three pairs from three groups (typically developing children, children with autism spectrum disorders who had interictal epileptiform discharges and those who did not) in terms of age and sex. We used a coarsened exact matching algorithm and applied adjusted regression analysis. We also investigated the relation between social reciprocity and the graph metric. Results show that, in children with autism spectrum disorders, the average clustering coefficient in the theta band was significantly higher in children who had interictal epileptiform discharges. Moreover, children with autism spectrum disorders who had no interictal epileptiform discharges had a significantly lower average clustering coefficient in the theta band than typically developing children had. However, the difference between typically developing children and children with autism spectrum disorder who had interictal epileptiform discharges was not significant. Furthermore, the higher average clustering coefficient in the theta band corresponded to severe autistic symptoms in children with autism spectrum disorder who had interictal epileptiform discharges. However, the association was not significant in children with autism spectrum disorders who had no interictal epileptiform discharge. In conclusion, results demonstrate that alteration of functional brain networks in children with autism spectrum disorders depends on the existence of interictal epileptiform discharges. Interictal epileptiform discharges might 'normalize' the deviation of altered brain networks in autism spectrum disorders, increasing the clustering coefficient. However, when the effect exceeds tolerance, it actually exacerbates autistic symptoms.