Therefore, it seems that proteasome inhibitors could be used to rapidly reduce autoantibody titers, without compromising the humoral immune system[50]. possible future medical interventions. == 1. Introduction == Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by deficits in interpersonal communication and conversation, and restricted repetitive behaviors, interests, and activities[1]. The estimates of ASD prevalence have been steadily rising for the last several years, and this increase in frequency cannot be fully attributed to diagnostic changes and improvements in detection[2]. Moreover, the etiology of ASD is not well understood, but is usually thought to involve a complex interplay between both genetics and environment[2,3]. Specifically, maternal antibodies transferred to the developing fetus during pregnancy are gaining interest in the field as a viable environmental exposure for autism risk [4]. The placental transfer of maternal immunoglobulin to the developing fetus is usually a specific adaptive mechanism that confers short-term immunity in the neonate by providing the immunologically nave fetus with a subset of the maternal humoral immune system[5,6]. Immunoglobulin G (IgG) crosses the placenta in part mediated by the neonatal Fc receptor (FcRn), an IgG transport protein[7,8]. Most antibodies are acquired during the third trimester and IgG levels in full-term infants often exceed those in the maternal circulation[9,10]. Additionally, maternal IgG is usually ingested by the newborn in its mothers milk and colostrum, which enables maternal IgG to persist and provide protection to the newborn through early infancy[8]. However, maternal antibodies are exceeded into the fetal compartment without regard to their specificity, and pathologically significant maternal autoantibodies might be delivered in addition to protective antibodies[11]. Several studies by our laboratory and others revealed a significant correlation between the presence of maternal autoantibodies reactive to fetal brain proteins and diagnosis of ASD in the child[6,7,12-18]. Recognizing that identification of the target antigens for maternal autoantibody related (MAR) autism was a critical step towards advancing this area of research, our laboratory recently decided the identity of seven candidate autoantigens, including lactate dehydrogenase (LDH) A and B, stress-induced phosphoprotein 1 (STIP1), collapsin response mediator proteins (CRMPs) 1 and 2, cypin, and Y-box binding protein (YBX1)[17]. Each of these autoantigens is known to be present in abundance in the fetal brain, and all play an important role in neurodevelopment, which further supports maternal autoantibodies interfering with crucial processes in neurogenesis[17]. Currently, it is unclear how these maternal autoantibodies arise, but several potential mechanisms are possible. In addition to the protective antibodies needed to overcome infection, the generation of pathologically significant autoantibodies can result if loss of self-tolerance is usually facilitated by excessive immune activation[19]. Additionally, molecular mimicry is usually thought to lead to a misguided immune response to self-antigens due to cross-reactivity between the infectious agent and self-proteins[19]. Some individuals have a genetic predisposition toward autoimmunity, which is often attributed to specific major histocompatibility complex (MHC) haplotypes and polymorphisms in genes involved in establishing self-tolerance and immune regulation[20]. Interestingly, several ETP-46464 studies have found an increased association between a family history of certain autoimmune diseases and ASD[21]. Lastly, there is evidence that this generation of particular anti-brain autoantibodies can be induced by systemic malignancies that express onconeural antigens, such as occurs with paraneoplastic disorders [22]. While this seems like the least likely cause of autoantibody generation, a couple of recent studies have found correlations between having a child with ASD and cancer; One study found a statistically significant increase in the incidence in endocrine-related (ovarian and uterine) cancers, tumors, or growths in mothers of children with ASD compared to mothers of typically developing children ETP-46464 and women with ASD, while another found evidence of increased malignancy mortality in mothers of children with ASD[23,24]. Further, one of the identified antigens in MAR autism, YB-1, is a marker for aggressive breast carcinomas[25]. Thus, while we have no information regarding the generation ETP-46464 of the antibodies associated with MAR autism, it remains an area of active study. Prior to designing a therapeutic intervention, one TRADD must first demonstrate that the specific autoantibodies have pathological significance. Thus, while many studies have shown that the mere presence of autoantibodies with brain reactivity does not necessarily correlate with CNS disease or pathogenicity for several antibody-mediated diseases, this concept is usually convincingly established when passive transfer of autoantibodies associated with a particular autoimmune disorder induces disease in an animal model [26,27]. Presently, we do not know if maternal autoantibodies, regardless of their.