Neuro-immunopathogenesis in autism

Abstract

Abstract Autism is an idiopathic brain disorder of unknown cause and etiology. It causes severe deficits of higher mental functions, as well as behavioral manifestations. Based on our ongoing research of a reciprocal relationship between nervous system and immune system, we studied autism as a neuro-immune dysfunction syndrome (NIDS) in which autoimmunity to brain was strongly implicated. Because myelination is one of the most important postnatal developmental events, we specifically focused on autoimmunity to brain myelin. We conducted laboratory evaluation of brain autoantibodies and virus serology in approximately 250 autistic children and 150 controls (healthy and non-autistic disease controls). The brain autoantibody study included detection of antibodies to neuron-axon filament proteins (NAFP) and three main myelin components: myelin basic protein (MBP), galactocerebrosides (GC) and 2,3-cyclic nucleotide 3′-phosphohydrolase (CNP). The virus serology included measurement of IgG antibodies to measles virus, human herpesvirus-6, cytomegalovirus and rubella virus. We found that autoantibodies to MBP were selectively present in up to 80% of the autistic children, but they were only rarely detected in the controls. Autoantibodies to NAFP and GC were also detected, but they were found non-specifically in control subjects also. Autoantibodies to CNP were absent in both groups of children. Thus MBP is potentially a candidate autoantigen in autism. Regarding virus serology, autistic children had a significantly higher level of measles virus antibodies as compared to controls; however, the antibody level of other three viruses did not significantly differ between the two groups. This suggested a temporal link of measles virus with autoimmunity in autism. The examination of brain autoantibody and virus serology data revealed that there was a serological association between measles virus and MBP autoantibodies, i.e., the higher the measles virus antibody level the greater the chance of MBP autoantibody. Collectively, these observations led us to speculate that an autoimmune response, presumably secondary to an atypical measles virus infection, may cause autism. The idea that autism is an autoimmune disorder is further strengthened by the fact that many autistic children respond well to treatment with immune moduating drugs. Considering MBP autoantibodies as an index of autoimmunity to myelin, an open-label trial of oral Sphingolin (myelin containing autoantigen) is under assessment-preliminary results are encouraging with significant improvement of behavioral characteristics in the autistic people. In conclusion, autism involves a neuroautoimmune response that occurs at the neuro-immune biology interface. Clinically, therefore, there is enormous potential for restoring brain function in autistic people through immunology.