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Autism: A Developmental Disorder Influenced by Autoimmunity

Autism is a prototypic pervasive childhood developmental disorder.  It is usually apparent by age 3 year and characterized by the triad: limited or absent verbal communication, social interaction or responsiveness, and restricted, stereotypic, or ritualized patterns of interests and behavior.  Autism spectrum disorder (ASD) is a broader term that encompasses several less severe disorders. The prevalence of childhood autism and ASD, and the resultant life-long developmental disabilities, increased 20- to 30-fold in epidemiological studies leading up to 2000, estimating a rise in prevalence from 1 in 2500 children (0.04%) in the late 1960s, to 2 in 100 vaccination-eligible age children. 

The Centers for Disease Control and Prevention (CDC) has been tracking the prevalence of ASD noting a 29% higher overall prevalence of 11.3 per 1000 in 2008 to 14.7 per 1000 in 2010, without a clear explanation. Using a prediction analysis to calculate how broadening diagnostic criteria such as younger age at diagnosis and improved efficiency of case ascertainment could produce temporal trends in the incidence and prevalence of autistic disorders, resulted in an estimated 11.0-fold increase over a 13-year period. The more recent estimates of the global burden of ASD amount to 52 million cases, equating to an estimated prevalence of 7.6 per 1000, or 1 in 132 persons. 

Children with ASD in the Norwegian Mother and Child Cohort Study were at significantly increased odds of maternally reported gastrointestinal (GI) disturbances including constipation, food allergies, food intolerance, diarrhea, and constipation. Evidence of alterations of the intestinal barrier of children with ASD included immune cell infiltrates in the small and large intestine, and increased T-cell activation in the intestinal mucosa compared to controls.  It is suggested that alterations in bowel microflora and associated inflammatory changes may contribute to the development of ASD, analogous to other chronic and degenerative diseases.  In a model of autoimmune uveitis, intestinal microbiota provide a source of antigen that stimulates autoreactive T-cells that cross-react with a retinal antigen through specific antigenic receptors in the gut.  The expression of ASD in a given individual may be similarly influenced by brain-related autoimmunity stemming from dysregulation and altered immunity of intestinal microbiota.  

Apart from the impact of infection and autoimmunity, autism has been associated with increased maternal age (>35 years), maternal use of medications during pregnancy, low birth weight, congenital malformations, increased paternal age, underlying genetic factors, obstetric complications, maternal exposure to drugs, substance abuse, pesticides, air pollution, and vitamin deficiencies. The Autism Birth Cohort (ABC) was established to address the natural history of ASD and to explore genetic and pre- or perinatal environmental factors inherent in causation. It is hoped that this cohort will illuminate the interplay between genes and environment; and facilitate the discovery of biomarkers with the potential to enable early recognition and treatment.  Current thinking of the causation of ASD also includes the contribution of inflammatory-autoimmune insults that triggers aberrant neuronal development.  Future directions have already included the empiric use of immunomodulatory therapy in affected children with abnormal serum titers of autoantibodies autoreactive to the brain, and inherently disturbed cell-mediated or humoral immunity, and concurrent autoimmune disorders.