Autism spectrum disorder (ASD) is a neurodevelopmental disorder with hallmark symptoms including social deficits, communication deficits and repetitive behaviors. Accumulating evidence suggests a potential role of the immune system in the pathophysiology of ASD. The complement system represents one of the major effector mechanisms of the innate immune system, and regulates inflammation, and orchestrates defense against pathogens. However, the role of CNS complement system in ASD is not well understood. In the present study, we found a significant increase in C2, C5, and MASP1, but a decrease in C1q, C3, and C4 mRNA levels in the middle frontal gyrus of ASD subjects compared to controls. Significant decreases in the mRNA levels of 2 key proinflammatory cytokines, IL-17 and IL-23 were observed in ASD subjects. Our study further demonstrated a strong association of complement genes with IL-17 and IL-23, suggesting a possible role of the complement system in immune dysregulation in ASD. We observed significant associations between complement components and abnormality of development scores in subjects with ASD. In rodents, C3 knockdown in the prefrontal cortex induced social interaction deficits and repetitive behavior in mice. Together, these studies suggest a potential role of C3 in the pathophysiology of ASD.

Impaired social interaction is a key feature of several major psychiatric disorders including depression, autism, and schizophrenia. While, anatomically, the prefrontal cortex (PFC) is known as a key regulator of social behavior, little is known about the cellular mechanisms that underlie impairments of social interaction. One etiological mechanism implicated in the pathophysiology of the aforementioned psychiatric disorders is cellular stress and consequent adaptive responses in the endoplasmic reticulum (ER) that can result from a variety of environmental and physical factors. The ER is an organelle that serves essential roles in protein modification, folding, and maturation of proteins; however, the specific role of ER stress in altered social behavior is unknown. In this study, treatment with tunicamycin, an ER stress inducer, enhanced the phosphorylation level of inositol-requiring ER-to-nucleus signal kinase 1 (IRE1) and increased X-box-binding protein 1 (XBP1) mRNA splicing activity in the mouse PFC, whereas inhibition of IRE1/XBP1 pathway in PFC by a viral particle approach attenuated social behavioral deficits caused by tunicamycin treatment. Reduced estrogen receptor beta (ERβ) protein levels were found in the PFC of male mice following tunicamycin treatment. Pretreatment with an ERβ specific agonist, ERB-041 significantly attenuated tunicamycin-induced deficits in social behavior, and activation of IRE1/XBP1 pathway in mouse PFC. Moreover, ERB-041 inhibited tunicamycin-induced increases in functional connectivity between PFC and hippocampus in male mice. Together, these results show that ERβ agonist attenuates ER stress-induced deficits in social behavior through the IRE-1/XBP1 pathway.

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Papuloerythroderma of Ofuji (PEO) is a rare skin disorder characterized by a distinctive pattern of pruritic, flat-topped, erythematous papules which coalesce into an erythroderma-like eruption with classic sparing of the skin folds. Although the pathogenesis of this condition is incompletely understood, previous reports have suggested a notable link between PEO and various forms of malignancy and immunocompromised states. Here, we report a case of a healthy young male with no comorbidities who presented with the classical features of PEO that responded well to combination therapy comprised of topical corticosteroids and phototherapy.

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