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• Replication study confirms immunogenetic association of HLA-G with ASD. • HLA-G alleles are significantly skewed in Sardinian ASD children. • Skewed HLA-G alleles seen in ASD might play a pathogenic role. Recent results show that in mainland Italian children with Autism spectrum disorder (ASD), HLA-G coding alleles distribution is skewed and an association between HLA- G*01:05N and ASD is present. Herein, in an independent cohort of Sardinian ASD (sASD) children and their relatives, we verify whether HLA-G allele association with ASD could be confirmed in this genetically peculiar insular population. One hundred children with a diagnosis of ASD, born in Sardinia and of Sardinian descent, 91 of their mothers, and 40 of their healthy siblings were enrolled. DNA sequencing analysis of HLA-G exon 2, 3 and 4 was used to obtain HLA-G allelic frequencies. Alleles distribution was compared with that of continental ASD children and with a control group of Caucasoid couples of multiparous women and their partners from Brazil and Denmark. Skewing of HLA-G allele distribution was replicated in sASD children; in particular, the HLA-G*01:03 allele, associated with reduced fetal tolerogenicity and development of myeloid leukemia, was more common in both ASD groups compared to controls (p c = 1 × 10−3; OR:3.5, 95%CI: 1.8–6.8). However, given the lack of data on HLA-G *01:03 allelic distribution among Sardinian healthy subjects, we cannot exclude a population effect. These data confirm an association of HLA-G locus with ASD development, particularly with those alleles linked to a lower expression of tolerogenic HLA-G protein, thus warranting further studies on HLA-G polymorphism distribution in different ASD populations. [ABSTRACT FROM AUTHOR]

Different isoforms of HLA-G protein are endowed with a differential ability to induce allogenic tolerance during pregnancy. As prenatal immune activation is suggested to play a role in the onset of autistic spectrum disorders (ASD), we evaluated HLA G*01:01-*01:06 allelic polymorphism in a cohort of Italian children affected by ASD (N = 111) their mothers (N = 81), and their healthy siblings (N = 39). DNA sequencing analysis of HLA-G exon 2, 3 and 4 was used to obtain HLA-G allelic frequencies; alleles distribution was compared with that of two control groups of Caucasoid couples of multiparous women and their partners from Brazil and Denmark. HLA-G distribution was significantly different in ASD children compared to both control groups (Brazilian p c = 1 × 10 −4 ; Danish p c = 1 × 10 −3 ). Since HLA-G distribution was similar in the two control groups, their data were pooled. Results indicated that HLA-G*01:01 was significantly less frequent (p c = 1 × 10 −4 ; OR:0.5, 95%CI: 0.3–0.7) whereas HLA-G*01:05N was significantly more frequent (p c = 2 × 10 −3 ; OR:7.3, 95%CI: 2.4–26.6) in ASD children compared to combined controls. Finally, no clear pattern emerged when HLA-G allelic distribution was analyzed in healthy sibs. Notably, HLA-G allelic distribution found in ASD mothers was similar to that observed in the control subgroup of women with recurrent miscarriages, whilst it was significantly different compared to women without miscarriages (p c = 6 × 10 −4 df = 12). Since HLA-G*01:01 is associated with the elicitation of KIR-mediated tolerogenic responses and HLA-G*01:05N correlates with NK cells activation, results herein indicate that an immune activating milieu during pregnancy is more likely observed in association with the development of ASD, similarly to what occurs in women with recurrent miscarriages. [ABSTRACT FROM AUTHOR]

Background Inflammasomes are multimeric protein platforms involved in the regulation of inflammatory responses whose activity results in the production of proinflammatory cytokines. Because neuroinflammation is observed in autistic spectrum disorders (ASD), a neurologic condition of childhood resulting in a complex behavioural impairment, we analyzed the inflammasomes activity in ASD. Additionally we verified whether alterations of the gastrointestinal (GI) barriers might play a role in inflammasomes activation. Methods The activity of the inflammasomes, the concentration of the inflammasomes-derived proinflammatory cytokines interleukin (IL)-1β and IL-18, and serum parameters of GI damage were analyzed in 25 ASD children, 23 healthy siblings (HS) and 30 unrelated age-matched healthy controls (HC). Results A significant upregulation of the AIM2 and the NLRP3 inflammasomes and an increased production of IL-1β and IL-18 that was associated with a consistent reduction of IL-33, an anti inflammation cytokine were observed in ASD alone. Notably, in a possible immune-mediated attempt to dampen inflammation, IL-37, a suppressor of innate inflammatory responses, was significantly augmented in these same children. Finally, intestinal fatty acid binding protein (IFABP), an index of altered GI permeability, was significantly increased in serum of ASD and HS. Conclusions These results show that the inflammasomes are activated in ASD and shed light on the molecular mechanisms responsible for ASD-associated neuroinflammation. The observation that GI alterations could be present as well in ASD offers a possible link between such alterations and neuroinflammation. Therapeutic strategies targeting inflammasome activation could be useful in ASD. [ABSTRACT FROM AUTHOR]

HLA-G expressed by the trophoblast ligates KIR molecules expressed by maternal NK cells at the uterine fetal/maternal interface: this interaction is involved in generating immune tolerance during pregnancy. A 14-bp insertion in the HLA-G 3′-UTR associates with significantly reduced levels of both HLA-G mRNA and soluble HLA-G, thus hampering the efficacy of HLA-G-mediated immune tolerance during pregnancy. Because prenatal immune activation is suggested to play an important role in the onset of autistic spectrum disorders (ASD) we performed an in-depth evaluation of HLA-G polymorphisms in a well-characterized cohort of Italian families of ASD children. Results showed that frequency of both homozygous 14bp+/14bp+ genotype and 14bp+ allele was significantly higher in ASD children and their mothers compared to controls ( p < 0.05 in all cases); analysis of the frequency of transmission of the 14bp+ allele from parents to ASD children and their non-ASD siblings showed that the 14bp+ allele was more frequently transmitted (T) to ASD children, whereas it was preferentially not transmitted (NT) to the non-ASD siblings (overall discrepancy: p = 0.02; OR: 2.6, 95% CI: 1.1–6.4). Results herein suggest that HLA-G polymorphisms are associated with ASD development, possibly as a consequence of prenatal immune activation. These data infer that the immune alterations seen in ASD are associated with the maternal-fetal interaction alone, and reinforce the observation that different genetic backgrounds characterize ASD children and their non-ASD siblings. [ABSTRACT FROM AUTHOR]

Highlight: [•] HLA/KIR complexes are skewed toward activation in ASD children and their mothers; this could play a role in the aetiology of ASD. [Copyright &y& Elsevier]

Abstract: Synaptosomal-associated protein of 25kD (SNAP-25), a protein participating in the regulation of synaptic vesicle exocytosis and in calcium homeostasis, was recently involved in neuropsychiatric conditions. Because alterations affecting the homeostasis of calcium are described in patients affected by autism spectrum disorders (ASD) we investigated a possible involvement of SNAP-25 in ASD by evaluating five SNAP-25 gene polymorphisms in a cohort of 67 ASD children. Data analyzed in relationship with clinical outcomes and compared to those of 205 healthy sex-matched children did not reveal significant differences. Further analyses nevertheless showed the presence of highly significant associations of the rs363043 (CT) genotype, localized in the intron 1 region that affects the transcription factor binding sites of the SNAP-25 gene, with both increasing CARS (p =0.001) and hyperactivity scores (p =0.006). The finding that polymorphisms of the SNAP-25 gene, a gene involved in neurotransmission and regulation of calcium homeostasis, are associated with the degree of hyperactivity in children with ASD, reinforces the hypothesis that alterations of these mechanisms play a pivotal role in the events leading to ASD-associated behavioral impairment. Modulation of these processes could result in novel therapeutic strategies. [Copyright &y& Elsevier]

Abstract: One hundred fifty-six children and adolescents with epilepsy from six Italian rehabilitation units were retrospectively enrolled to define the proportion of patients with epileptogenic developmental disorders who benefit from comprehensive rehabilitation programs and to identify factors predicting treatment response. The rehabilitation programs were classified as neuromotor, psychomotor, and speech and language. For each program, the response was coded as present or absent according to the caring physician''s judgment. Selected demographic and clinical variables were correlated to treatment response. Neuromotor rehabilitation was performed in 86 cases (55%), psychomotor rehabilitation in 54 cases (34%), and speech and language rehabilitation in 40 cases (26%). Response rates were 58, 74, and 90%, respectively. Independent negative predictors of treatment response included severity of functional impairment (odds ratio=0.02, 95% confidence interval=0.01–0.14) and daily seizures (odds ratio=0.22, 95% confidence interval=0.08–0.58). [Copyright &y& Elsevier]