Autism Spectrum Disorders (ASDs) represent a group of neurodevelopmental disorders associated with social and behavioral impairments. Although dysfunctions in several signaling pathways have been associated with ASDs, very few molecules have been identified as potentially effective drug targets in the clinic. Classically, research in the ASD field has focused on the characterization of pathways involved in neural development and synaptic plasticity, which support the pathogenesis of this group of diseases. More recently, immune system dysfunctions have been observed in ASD. In addition, high levels of reactive oxygen species (ROS), which cause oxidative stress, are present in ASD patients. In this review, we will describe the major alterations in the expression of genes coding for enzymes involved in the ROS scavenging system, in both ASD patients and ASD mouse models. In addition, we will discuss, in the context of the most recent literature, the possibility that oxidative stress, inflammation and immune system dysfunction may be connected to, and altogether support, the pathogenesis and/or severity of ASD. Finally, we will discuss the possibility of novel treatments aimed at counteracting the interplay between ROS and inflammation in people with ASD.

After repeated antigen exposure, both memory and terminally differentiated cells can be generated within CD8⁺ T cells. Although, during their differentiation, activated CD8⁺ T cells may first lose CD28, and CD28⁻ cells may eventually express CD57 as a subsequent step, a population of CD28⁺CD57⁺(DP) CD8⁺ T cells can be identified in the peripheral blood. How this population is distinct from CD28⁻CD57⁻(DN) CD8⁺ T cells, and from the better characterized non‐activated/early‐activated CD28⁺CD57⁻ and senescent‐like CD28⁻CD57⁺ CD8⁺ T cell subsets is currently unknown. Here, RNA expression of the four CD8⁺ T cell subsets isolated from human PBMCs was analyzed using microarrays. DN cells were more similar to “early” highly differentiated cells, with decreased TNF and IFN‐γ production, impaired DNA damage response and apoptosis. Conversely, increased apoptosis and expression of cytokines, co‐inhibitory, and chemokine receptors were found in DP cells. Higher levels of DP CD8⁺ T cells were observed 7 days after Hepatitis B vaccination, and decreased levels of DP cells were found in rheumatoid arthritis patients. More DP and DN CD8⁺ T cells were present in the bone marrow, in comparison with PBMCs. In summary, our results indicate that DP and DN cells are distinct CD8⁺ T cell subsets displaying defined properties.

Autism spectrum disorders (ASD) are a group of neurodevelopmental syndromes with both genetic and environmental origins. Several recent studies have shown that inflammation and oxidative stress may play a key role in supporting the pathogenesis and the severity of ASD. Thus, the administration of anti-inflammatory and antioxidant molecules may represent a promising strategy to counteract pathological behaviors in ASD patients. In the current review, results from recent literature showing how natural antioxidants may be beneficial in the context of ASD will be discussed. Interestingly, many antioxidant molecules available in nature show anti-inflammatory activity. Thus, after introducing ASD and the role of the vitamin E/vitamin C/glutathione network in scavenging intracellular reactive oxygen species (ROS) and the impairments observed with ASD, we discuss the concept of functional food and nutraceutical compounds. Furthermore, the effects of well-known nutraceutical compounds on ASD individuals and animal models of ASD are summarized. Finally, the importance of nutraceutical compounds as support therapy useful in reducing the symptoms in autistic people is discussed.

Abnormal tactile response is an integral feature of Autism Spectrum Disorders (ASDs), and hypo-responsiveness to tactile stimuli is often associated with the severity of ASDs core symptoms. Patients with Phelan-McDermid syndrome (PMS), caused by mutations in the SHANK3 gene, show ASD-like symptoms associated with aberrant tactile responses. The neural underpinnings of these abnormalities are still poorly understood. Here we investigated, in Shank3b^−/− adult mice, the neural substrates of whisker-guided behaviors, a key component of rodents’ interaction with the surrounding environment. We assessed whisker-dependent behaviors in Shank3b^−/− adult mice and age-matched controls, using the textured novel object recognition (tNORT) and whisker nuisance (WN) test. Shank3b^−/− mice showed deficits in whisker-dependent texture discrimination in tNORT and behavioral hypo-responsiveness to repetitive whisker stimulation in WN. Sensory hypo-responsiveness was accompanied by a significantly reduced activation of the primary somatosensory cortex (S1) and hippocampus, as measured by c-fos mRNA induction, a proxy of neuronal activity following whisker stimulation. Moreover, resting-state fMRI showed a significantly reduced S1-hippocampal connectivity in Shank3b mutants, in the absence of altered connectivity between S1 and other somatosensory areas. Impaired crosstalk between hippocampus and S1 might underlie Shank3b^−/− hypo-reactivity to whisker-dependent cues, highlighting a potentially generalizable somatosensory dysfunction in ASD.

The expression of CD4 and CD8 co-receptors defines two distinct T cell populations with specialized functions. While CD4⁺ T cells support and modulate immune responses through different T-helper (Th) and regulatory subtypes, CD8⁺ T cells eliminate cells that might threaten the organism, for example, virus-infected or tumor cells. However, a paradoxical population of CD4⁺CD8⁺ double-positive (DP) T cells challenging this paradigm has been found in the peripheral blood. This subset has been observed in healthy as well as pathological conditions, suggesting unique and well-defined functions. Furthermore, DP T cells express activation markers and exhibit memory-like features, displaying an effector memory (EM) and central memory (CM) phenotype. A subset expressing high CD4 (CD4^bright+) and intermediate CD8 (CD8^dim+) levels and a population of CD8^bright+CD4^dim+ T cells have been identified within DP T cells, suggesting that this small subpopulation may be heterogeneous. This review summarizes the current literature on DP T cells in humans in health and diseases. In addition, we point out that strategies to better characterize this minor T cell subset’s role in regulating immune responses are necessary.

CD4⁺ regulatory T cells have been intensively studied during aging, but little is still known about age-related changes of other regulatory T cell subsets. It was, therefore, the goal of the present study to analyze CD8⁺human leukocyte antigen–antigen D related (HLADR)⁺ T cells in old age, a cell population reported to have suppressive activity and to be connected to specific genetic variants. We demonstrate a strong increase in the number of CD8⁺HLADR⁺ T cells with age in a cohort of female Sardinians as well as in elderly male and female persons from Austria. We also show that CD8⁺HLADR⁺ T cells lack classical activation molecules, such as CD69 and CD25, but contain increased numbers of checkpoint inhibitory molecules, such as cytotoxic T lymphocyte-associated antigen 4, T cell immunoglobulin and mucin protein-3, LAG-3, and PD-1, when compared with their HLADR⁻ counterparts. They also have the capacity to inhibit the proliferation of autologous peripheral blood mononuclear cells. This suppressive activity is, however, decreased when CD8⁺HLADR⁺ T cells from elderly persons are analyzed. In accordance with this finding, CD8⁺HLADR⁺ T cells from persons of old age contain lower percentages of checkpoint inhibitory molecules than young controls. We conclude that in spite of high abundance of a CD8⁺ regulatory T cell subset in old age its expression of checkpoint inhibitory molecules and its suppressive function on a per cell basis are reduced. Reduction of suppressive capacity may support uncontrolled subclinical inflammatory processes referred to as “inflamm-aging.”