Detection of autoantibodies to neural cells of the cerebellum in the plasma of subjects with autism spectrum disorders.

Autism spectrum disorders (ASD) are a group of heterogeneous, behaviorally defined disorders characterized by disturbances in social interaction and communication, often with repetitive and stereotyped behavior. Previous studies have described the presence of antibodies to various neural proteins in autistic individuals as well as post-mortem evidence of neuropathology in the cerebellum. We examined plasma from children with ASD, as well as age-matched typically developing controls, for antibodies directed against human cerebellar protein extracts using Western blot analysis. In addition, the presence of cerebellar specific antibodies was assessed by immunohistochemical staining of sections from Macaca fascicularis monkey cerebellum. Western blot analysis revealed that 13/63 (21%) of subjects with ASD possessed antibodies that demonstrated specific reactivity to a cerebellar protein with an apparent molecular weight of approximately 52 kDa compared with only 1/63 (2%) of the typically developing controls (p=0.0010). Intense immunoreactivity, to what was determined morphologically to be the Golgi cell of the cerebellum, was noted for 7/34 (21%) of subjects with ASD, compared with 0/23 of the typically developing controls. Furthermore, there was a strong association between the presence of antibodies reactive to the 52 kDa protein by Western blot with positive immunohistochemical staining of cerebellar Golgi cells in the ASD group (r=0.76; p=0.001) but not controls. These studies suggest that when compared with age-matched typically developing controls, children with ASD exhibit a differential antibody response to specific cells located in the cerebellum and this response may be associated with a protein of approximately 52 kDa.

Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism.

Autism together with Asperger syndrome and pervasive developmental disorder not otherwise specified form a spectrum of conditions (autism spectrum disorders or ASD) that is characterized by disturbances in social behavior, impaired communication and the presence of stereotyped behaviors or circumscribed interests. Recent estimates indicate a prevalence of ASD of 1 per 150 (Kuehn, 2007). The cause(s) of most cases of ASD are unknown but there is an emerging consensus that ASD have multiple etiologies. One proposed cause of ASD is exposure of the fetal brain to maternal autoantibodies during pregnancy [Dalton, P., Deacon, R., Blamire, A., Pike, M., McKinlay, I., Stein, J., Styles, P., Vincent, A., 2003. Maternal neuronal antibodies associated with autism and a language disorder. Ann. Neurol. 53, 533-537]. To provide evidence for this hypothesis, four rhesus monkeys were exposed prenatally to human IgG collected from mothers of multiple children diagnosed with ASD. Four control rhesus monkeys were exposed to human IgG collected from mothers of multiple typically developing children. Five additional monkeys were untreated controls. Monkeys were observed in a variety of behavioral paradigms involving unique social situations. Behaviors were scored by trained observers and overall activity was monitored with actimeters. Rhesus monkeys gestationally exposed to IgG class antibodies from mothers of children with ASD consistently demonstrated increased whole-body stereotypies across multiple testing paradigms. These monkeys were also hyperactive compared to controls. Treatment with IgG purified from mothers of typically developing children did not induce stereotypical or hyperactive behaviors. These findings support the potential for an autoimmune etiology in a subgroup of patients with neurodevelopmental disorders. This research raises the prospect of prenatal evaluation for neurodevelopmental risk factors and the potential for preventative therapeutics.

Autoantibodies in autism spectrum disorders (ASD).

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders defined behaviorally by abnormalities in social, verbal, and nonverbal communication. The etiologies of ASD are unknown, likely to be the result of a variety of numerous genetic, neurological, environmental, and immunological interactions that lead to a general behavioral phenotype defined as ASD. This review will focus on the various immune system anomalies, in particular, autoantibodies, which have been reported in subjects with ASD. In addition, we will discuss recent studies performed by our group concerning the presence of autoantibodies directed against neural antigens, which are observed in patients with ASD.

Brain-specific autoantibodies in the plasma of subjects with autistic spectrum disorder.

Although autism spectrum disorder (ASD) is diagnosed on the basis of behavioral parameters, several studies have reported immune system abnormalities and suggest the possible role of autoimmunity in the pathogenesis of ASD. In this study we sought to assess the incidence of brain-specific autoantibodies in the plasma of children with autism (AU) compared to age-matched controls including, siblings without ASD, typically developing (TD) controls, and children with other developmental disabilities, but not autism (DD). Plasma from 172 individuals (AU, n = 63, median age: 43 months; TD controls, n = 63, median age: 48 months; siblings, n = 25, median age: 61 months; and DD controls, n = 21, median age: 38 months) was analyzed by Western blot for the presence of IgG antibodies against protein extracts from specific regions of the human adult brain including the hypothalamus and thalamus. The presence of a approximately 52 kDa MW band, in the plasma of subjects with AU, was detected with a significantly higher incidence when compared to plasma from TD controls (29% vs. 8%, P = 0.0027 and 30% vs. 11%, P = 0.01, in the thalamus and hypothalamus, respectively). Reactivity to three brain proteins (42-48 kDa MW), in particular in the hypothalamus, were observed with increased incidence in 37% of subjects with AU compared to 13% TD controls (P = 0.004). Multiple brain-specific autoantibodies are present at significantly higher frequency in children with AU. While the potential role of these autoantibodies in AU is currently unknown, their presence suggests a loss of self-tolerance to one or more neural antigens during early childhood.

Polyurethane shape-memory polymers demonstrate functional biocompatibility in vitro.

Shape memory polymers (SMPs) are a class of polymeric materials used in various medical interventions such as vascular stents. In this work, two SMPs, thermoplastic (TP) and thermoset (TS), have been measured in vitro for the degree of cellular and protein adhesion, their ability to stimulate inflammatory cytokine production, as well as the effects of the SMPs on the haemostatic system. The stimulatory properties of SMPs on neutrophils have also been directly addressed. Based on the studies of SMP biocompatibility as defined by inflammation, thrombogenesis, and the activation of both platelets and neutrophils, the TS and TP SMP materials are unlikely to stimulate an inflammatory response in vivo. [figure: see text]