Invited MinireviewThe role of immune dysfunction in the pathophysiology of autism
Introduction
Autism spectrum disorders (ASD) are a series of pervasive development disorders which include autistic disorder, Rett’s disorder, childhood disintegrative disorder, Asperger’s syndrome or pervasive developmental disorder not otherwise specified (PDD-NOS). Autism spectrum disorders are characterized by severe and pervasive impairment in several areas of development: reciprocal social interaction skills, communication skills, or the presence of stereotyped behavior, interests and activities (APA, 2000). According to the most recent estimates calculated by the US Center of Disease Control, ASD affects 1 in 110 children under the age of eight (MMWR, 2009). Although current research suggests there may be no single genetic cause for ASD, there are several lines of evidence to suggest that the disorder is highly heritable. There is a concordance rate for ASD of 0–37% reported for dizygotic twins, while concordance rates of 44–91% are reported for monozygotic twins (Bailey et al., 1995, Constantino and Todd, 2000, Kates et al., 2004, Steffenburg et al., 1989), suggesting that genetic composition may contribute to increased risk of developing ASD. In addition to the heritability observed in twin-pairs, the risk of developing ASD in non-twin siblings is increased 25-fold in comparison to the general population (Jorde et al., 1991). While the heritability of ASD suggests a genetic component in the disorders etiology, the genes involved vary greatly among individuals and family clusters.
Whole-genome linkage studies, gene association studies, copy number variation screening and SNP analyses have uncovered a large number of ASD candidate genes (Abrahams and Geschwind, 2008). Associations with ASD have been demonstrated for genes involved in a diverse range of functions including RELN (Skaar et al., 2005), SHANK3 (Moessner et al., 2007), NLGN3, NLGN4X (Jamain et al., 2003), MET (Campbell et al., 2006), GABRB3 (Buxbaum et al., 2002), OXTR (Wu et al., 2005), and SLC6A4 (Wu et al., 2005). Furthermore, in several syndromic disorders with single gene mutations, including Rett’s syndrome (MeCP2) (Nagarajan et al., 2008), Fragile X (FMR1) (Belmonte and Bourgeron, 2006), tuberous sclerosis (either TSC1 or TSC2) (Wiznitzer, 2004), Timothy syndrome (CACNA1C), Cowden’s syndrome (PTEN), and Angelman’s syndrome (UBE3A) the occurrence of ASD is higher than the general population. Among these potential candidate genes several play important roles in immune function. Proteins within the phosphoinositide-3-kinase (PI3K) pathway, including those coded by MET, PTEN, TSC1 and TSC2, have a major role in regulating interleukin (IL)-12 production from myeloid cells and are involved in shifting macrophage phenotypes from inflammatory (M1) to alternative activated (M2) subsets (Fukao et al., 2002). Additional candidate genes including the major histocompatibility complex type 2 (MHC-II) haplotypes (Lee et al., 2006, Torres et al., 2002), as well as complement 4B (C4B) (Odell et al., 2005), and macrophage inhibitory factor (MIF) (Grigorenko et al., 2008) are important in directing and controlling immune responses. Even with the recent advancements in identifying candidate genes involved in ASD, all identified genetic risk factors combined account for only 10–20% of the total ASD population (Abrahams and Geschwind, 2008). A number of these genetic risk factors can also be present in individuals without ASD, suggesting that many of these mutations may increase the risk of developing ASD, but additional risk factors are also necessary.
The absence of a known genetic cause in the majority of cases, and the incomplete penetrance of known genetic risk factors, suggests that environmental factors are linked with the causation of ASD. Growing research has highlighted maternal immune activation (MIA), especially during the first or second trimesters of pregnancy, as one potential environmental factor that increases the risk for ASD (Patterson, 2009). In 1964 a rubella epidemic in the US which affected many pregnant mothers resulted in a large increase in the number of children who developed ASD (Chess et al., 1978, Swisher and Swisher, 1975). Moreover, using medical information obtained in a large Danish database, increased risk for ASD is associated with mothers that required hospitalization for a viral infection in the first trimester of pregnancy, or mothers hospitalized for a bacterial infection in the second trimester of pregnancy (Atladottir et al., 2010), suggesting that bacterial and viral infections may confer different risks depending on gestational age. Further data suggest that season of birth is important, with increased rates of ASD associated with experiencing the first trimester of pregnancy during the winter months, timing which coincided with the influenza season (Zerbo et al., 2011). Increased psoriasis, asthma and allergies during pregnancy have also been suggested as risk factors for the development of ASD (Croen et al., 2005).
The potential role of a heightened or activated maternal immune response in the risk for ASD is further strengthened by epidemiological data from large population based studies that show increased rates of autoimmune disorders in the families of individuals with ASD (Atladottir et al., 2009, Croen et al., 2005). Separately or coincidentally, the presence of specific anti-fetal brain antibodies in approximately 12% of mothers of children with ASD, which are absent in mothers of children who are typically developing or mothers of children with developmental delays, suggests a potential inflammatory process that leads to the production of antibodies directed to the developing brain (Braunschweig et al., 2008, Croen et al., 2008, Singer et al., 2009). Such fetal brain-specific antibodies could alter neurodevelopment as is seen in systemic lupus erythematosis (SLE) (DeGiorgio et al., 2001, Lee et al., 2009). In experiments using IgG collected from mothers of children with ASD, administration of these antibodies to pregnant rhesus macaques, induced stereotypic behavior and hyperactivity in the offspring, symptoms that share homology to ASD (Martin et al., 2008). Similarly, anti-brain protein reactive antibodies from mothers who have children with ASD mediate behavioral changes and neuro-pathology in the offspring of pregnant dams that are injected with these antibodies (Singer et al., 2009). These data suggest a potential pathogenic/pathological effect of anti-fetal brain antibodies in some mothers who have children that develop ASD.
In rodent models of MIA, several abnormal behavioral features are exhibited in the offspring that may have face validity to some autistic features, including decreased prepulse inhibition and latent inhibition, as well as impaired sociability (reviewed in Patterson, 2009). These models are becoming more established and can be induced by congenital exposure to bacteria, the bacterial compound LPS, influenza virus or, the viral mimic and toll-like receptor (TLR)3 ligand polyinosinic:polycytidylic acid [poly(I:C)]. In all four versions of the model, IL-6 appears to play an essential role and exposure to IL-6 alone during gestation is sufficient to elicit behavioral changes in the offspring (Hsiao and Patterson, 2011, Smith et al., 2007). The similarities between the behaviors seen in models of MIA and the symptoms of ASD have spurred further investigation into the physiological features of the offspring. For example, an increase in IL-6 is present up to 24 weeks postnatally in brains of offspring of dams exposed to poly(I:C) (Samuelsson et al., 2006). While elevated numbers of splenic TH17 cells have been observed in offspring after maternal poly(I:C) exposure (Mandal et al., 2011). This evidence suggests that in the MIA model, there are prolonged inflammatory responses that persist in adult offspring and are likely maintained by alterations in the immune system of the affected offspring. These data bear more than passing resemblance to features of dysfunctional immune activity frequently observed in children and adults with ASD.
Section snippets
Neuroinflammation
A key finding in ASD research has been the observations of marked ongoing neuroinflammation in postmortem brain specimens from individuals with ASD over a wide range of ages (4–45 years of age) (Li et al., 2009, Morgan et al., 2010, Vargas et al., 2005). These findings include prominent microglia activation and, increased inflammatory cytokine and chemokine production, including interferon (IFN)-γ, IL-1β, IL-6, IL-12p40, tumor necrosis factor (TNF)-α and chemokine C–C motif ligand (CCL)-2 in the
Potential impact of immune dysfunction in ASD on CNS activity and behavior
Although a singular pathology of ASD remains elusive, a wealth of evidence suggests that ASD symptoms may be related to immune dysfunction (Careaga et al., 2010, Enstrom et al., 2009c, Korade and Mirnics, 2011). Further detailed investigations are needed to concretely identify whether the immunological findings in ASD converge to a single immunopathology. However, in the following section we will try and identify potential mechanisms of action in which the observed immune dysfunction in ASD
Conclusion
The collective findings of immune aberration in ASD, and the effects of immune dysfunction in normal neurodevelopment, are difficult to ignore. Despite several early challenges the evidence of immune cell dysfunction in ASD has continued to grow. In conjunction, recent basic research has provided further evidence of how the immune system can profoundly impact neurodevelopment, cognitive function, and behavior. The dysfunctional immune activity observed in ASD spans both innate and adaptive arms
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