Immune Contributions to Cause and Effect in Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that appears during the first 3 years of life and presents with a variable set of symptoms that include impairments in social communication, narrow and restricted interests, and repetitive behavior. ASD is the most rapidly increasing neurodevelopmental disorder and current estimates are alarming, indicating 1 in 68 children and 1 in 42 boys in the United States are on the spectrum (1). Despite this growing public health emergency, few effective treatments exist for ASD and more research is needed to identify new therapies and alleviate the enormous personal, social and economic costs of ASD to our society.Few therapies for ASD are currently available in large part because the field is still struggling to understand ASD and determine its underlying causes. The high rates of heritability of ASD strongly suggest a genetic component and recent research has identified a large number of genes associated with this disorder (2). In addition to genetic associations, there is a long list of diverse environmental factors that contribute to ASD (3) and it is currently thought that ASD is caused by a combination of genetic and environmental risk factors that either alone or together exceed a threshold for disease manifestation.One of the most exciting recent hypotheses in the field is that immune dysregulation contributes to, and may cause, ASD. Indeed, many of the genetic associations and most of the environmental factors linked to ASD converge on immune dysregulation through alterations in immune-related genes and/or immune responses to environmental stimuli (4). ASD is linked to aberrations on chromosome 6, which is densely packed with genes for immune molecules, (5) and specific haplotypes of immune genes-especially MHC and cytokines-correlate with ASD (4, 6). Moreover, the expression of many immune-related genes in the brain is altered in individuals with ASD (7). These genetic associations, either alone or in combination with environmental exposures, may contribute to ongoing immune dysregulation in ASD, which manifests as altered cytokine levels in the blood, brain, and cerebrospinal fluid (CSF) (8-14) and abnormalities in peripheral immune cells and their responsiveness that correlate with behavioral symptoms in ASD (4, 15, 16). The archival report by Careaga et al. in this special issue (17) provides further evidence for the association between immune cell responsiveness and ASD and suggests that ASD subtypes can be defined by distinct profiles of immune dysregulation. Children whose blood cells

Potential role for immune-related genes in autism spectrum disorders: Evidence from genome-wide association meta-analysis of autistic traits

“…Given the genetic correspondence between ASDs and ALTs, these results stress the importance to further investigate the relationship between immunogenetics and ASDs. Immune dysregulation, either in the form of ongoing inflammation or autoimmunity, is prevalent in ASDs (McAllister, 2017). ASDs are, in fact, associated with family history of autoimmune diseases, like celiac disease and rheumatoid arthritis (Atladóttir et al, 2009; Ludvigsson et al, 2013), and either increased or decreased levels of inflammatory markers have been found in the blood of ASD individuals (Goines & Ashwood, 2013).…”

New Developments in the Classification, Pathogenesis, Risk Factors, Natural History, and Treatment of Branch Retinal Vein Occlusion

“…The SCORE study ( n = 411) showed that the outcome of IVTA 1 mg groups is similar to IVTA 4 mg groups and can lower the rate of adverse events [131]. TA has numerous mechanisms of action, including anti-inflammatory effects, antiangiogenic properties and inhibition of VEGF, and other inflammatory cytokine expressions, such as IL-6, ICAM-1, and MCP-1 [132, 133]. Ozkiris et al evaluated the effect of TA injection on persistent CME in BRVO that failed to respond to previous laser photocoagulation.…”

MicroRNA expression changes in association with changes in interleukin-1ß/interleukin10 ratios produced by monocytes in autism spectrum disorders: their association with neuropsychiatric symptoms and comorbid conditions (observational study)

“…Since most inflammatory conditions are mediated by the immune system, such ASD patients as described above may have underlying immune-mediated inflammation, affecting both the brain and other organs. In fact, a role of immune-mediated inflammation has been implicated with the onset and progress of ASD by multiple researchers [ 5 , 6 ]. However, it has been difficult to elucidate how the immune system plays a role in ASD pathogenesis, since there are many immune abnormalities reported in ASD, affecting almost every arm of the immune system [ 6 , 7 ].…”