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University of Texas Southwestern, Children's Medical Center, USA
Konstantinos-Dionysios Alysandratos
Tufts University School of Medicine, USA
University of Texas Southwestern, Children's Medical Center, USA
Shahrzad Asadi
Tufts University School of Medicine, USA
Konstantinos Francis
University of Athens Medical School, Greece
Lefteris Lykouras
University of Athens Medical School, Greece
Dimitrios Kalogeromitros
University of Athens Medical School, Greece
*Address all correspondence to:
1. Introduction
He could fit in the palms of both hands, seemed to look at you beseechingly while you rushed to thread a vein and snake a tube down a tiny nostril of this 24 week preemie. Already exposed to the prenatal stress that culminated in premature delivery, he has been further exposed to the stress associated with the separation from his mother and multiple medical interventions. Like other premature babies, he is more vulnerable to invasive infections from bacteria and viruses; moreover, the delayed development of his gut-blood-brain barriers could expose him to potential neurotoxins.
Such infants are up to 4 times more likely to develop autism. If their mothers had allergies, mastocytosis or an autoimmune disease, this risk almost doubles.
Autism Spectrum Disorders (ASD) are pervasive developmental disorders that include Autistic Disorder and Asperger’s Disorder, although Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS) is frequently included (Johnson & Myers, 2007). ASD are characterized by variable deficits in social skills, stereotypic behaviors, and a wide range of behavioral and learning problems. ASD manifest during early childhood and at least 30% present with sudden clinical regression of development around 3 years of age (Matson J.L. & Kozlowski A.M., 2010; Zappella, 2010). Over the last 20 years, there has been an impressive rise in ASD with current prevalence estimates of 1/100 children (Fombonne, 2009; Kogan et al., 2009).
In the majority of cases, the cause of ASD is unknown (Levy et al., 2009). Some autism susceptibility genes have been identified (Weiss et al., 2009), but gene interactions with environmental factors are increasingly suspected (Deth et al., 2008; Herbert, 2010). Recent reviews have focused mostly on genomic screens that suggest there are multiple gene interactions in autism; however no gene abnormality alone can explain the apparent increase in ASD prevalence (Durkin et al., 2010; Herbert, 2010; Miles, 2011). Increasing evidence suggests that there are different ASD endophenotypes, even within the ASD spectrum (Palmieri & Persico, 2010).
Intrauterine conditions in combination with external environmental triggers or specific genotypes, may lead to developmental disturbances. Indeed, an epidemiologic study, nested within a cohort of 698 autistic children in Denmark, concluded that prenatal environmental factors and parental psychopathology are associated with the risk of autism and these factors seem to act independently (Larsson et al., 2005). It is also recognized that tuberous sclerosis, a neurocutaneous disorder, involves autistic symptoms in approximately 40-45% of cases (Smalley, 1998). It has been proposed that this partial penetrance may be the result of an interaction between gene mutations and environmental factors, such as gestational immune activation (Ehninger et al., 2010). An early environmental insult, such as prenatal infection could cause long-term changes in neural function by altering epigenetic programming. Studies on rodents suggest that during early development, environmental signals can activate intracellular pathways, leading to epigenetic changes and consequently changes in neural function (Zhang & Meaney, 2010). In fact, variations in early maternal care affect stress responses in the offspring by altering the methylation status of the glucocorticoid receptor gene promoter (Weaver et al., 2004).
Premature births (delivery prior to 37 weeks gestation) currently account for 12.7% of all births in the United States, a rise of approximately 20% in the past two decades (MacDorman et al., 2010). Although infants less than 28 weeks gestation are at the highest risk for long-term neurologic problems, infants born between 32 and 36 weeks are increasingly recognized to be at risk for neurologic injury, such as leukomalacia and grey matter damage (Adams-Chapman, 2006; Argyropoulou, 2010; Okumura et al., 2010; Volpe, 2009). Clinical, epidemiological and experimental studies have revealed that key factors, such as inflammation and oxidative stress contribute considerably to white- and grey-matter injury in premature infants, whose brains are particularly susceptible to damage (Kaindl et al., 2009). In infants surviving premature birth, cerebellar hemorrhagic injury is also associated with a high prevalence of neurodevelopmental disabilities (Limperopoulos et al., 2007). The resulting long-term neurologic complications may include learning difficulties, behavioral and socio-emotional concerns, and poor general health outcomes. These vulnerable near-term (late preterm) infants make up the greatest number of premature births and account for the significant increase in the rate of prematurity in the recent years (Martin, 2011). Although the etiology of premature delivery is often unknown, chronic in utero inflammation or infection are well-described conditions that lead to preterm labor and birth (Dubicke et al., 2010; Snegovskikh et al., 2009; Thaxton et al., 2010). Inflammation itself has been strongly associated with adverse neurodevelopmental outcomes in premature infants (Lin et al., 2010; Rovira et al., 2011). An additional 5-8% of deliveries are complicated by pre-eclampsia or gestational diabetes, which may lead to placental insufficiency, abnormal growth, and postnatal metabolic imbalance. Excessive production of cortocotropin releasing hormone (CRH) has also been linked to preterm labour (Campbell et al., 1987; Warren et al., 1992). A number of cytokines are known to cause in vitro secretion of CRH from cultured placental trophoblasts, including IL-1 and IL-6 (Petraglia et al., 1990). In turn, CRH stimulates release of IL-6 from peripheral blood mononuclear cells, which infiltrate the fetal membranes and the placenta in increasing numbers during intrauterine infection (Angioni et al., 1993).
Recent reports suggest a potential association between preterm birth and autism. In particular, one retrospective study investigated preterm children born in Atlanta, GA (1981-93) who survived to three years of age, and identified rates of autism through the Metropolitan Atlanta Developmental Disabilities Surveillance Program. Preterm birth prior to 33 weeks gestation was associated with a two-fold higher risk of autism in all infants (Limperopoulos et al., 2008). Interestingly, this study reported a gender-specific, four-fold increased risk for autism accompanied by mental retardation in preterm girls with low birth weight (LBW) (<2,500 g at birth). Another study performed a prospective follow-up assessment on 91 ex-preterm very low birth weight (VLBW) infants (<1,500 g at birth) at the mean age of 22 months and found 26% of these children to have a positive Modified Checklist for Autism in Toddlers (M-CHAT) test (Kinney et al., 2008). A more recent study found that 21% of infants (212/988) born before 28 weeks of gestation screened positive using M-CHAT (Kuban et al., 2009) as compared to 5.7% of healthy children 16-30 months old (Kleinman et al., 2008). Much higher rates of positive testing on M-CHAT were found in premature children with motor or sensory impairment (Kuban et al., 2009). It should be noted, however, that a positive CHAT test must be confirmed with more specific diagnostic tools, such as the Autism Diagnostic Observation Schedule-Generic (ADOS-G, a patient observational tool) or the Autism Diagnostic Interview-Revised (ADI-R, a parent interview tool) which provide a more reliable diagnosis for ASD. A prospective study of all births less than 26 weeks gestation in 1995 in the United Kingdom and Ireland concluded that ex-preterm children are at increased risk for ASD in middle childhood, compared with their term-born classmates, after psychiatric, clinical, IQ and SCQ (Social Communication Questionnaire) evaluations (Johnson et al., 2010).
A cohort of 164 families with autistic children (Brimacombe et al., 2007) concluded that the increased risk of autistic disorders related to prematurity is primarily attributed to perinatal complications that occur more commonly among preterm infants, results also confirmed in a Swedish population-based case-control study (Buchmayer et al., 2009). A meta-analysis on prenatal risk factors for autism argued that evidence is insufficient to implicate individual prenatal factors in autism etiology, because many of the studies examined all available prenatal data using designs with methodological weaknesses, so that significant associations may have been observed by chance after multiple testing (Gardener et al., 2009). Findings from population-based studies suggest that suboptimal birth conditions are not independent risk factors for infantile autism, but rather clusters of them increase the risk of ASD (Maimburg & Vaeth, 2006). Finally, a more recent cohort study on infants born in Canada between 1990-2002 concluded that perinatal risk factors including prenatal, obstetrical and neonatal complications, have a lesser overall effect on autistic outcomes among the genetically susceptible pediatric population, compared to children with low genetic susceptibility (Dodds et al., 2010). Reviews of studies evaluating neurobehavioral outcomes following preterm birth reveal a “preterm behavioral phenotype” characterized by symptoms of inattention, anxiety and social difficulties (Johnson & Marlow, 2011; Limperopoulos, 2009).
The relationship between ASD and familial autoimmunity has long been recognized (Money et al., 1971), and has been supported by at least three large population-based studies discussed below; these studies utilized medical records and physician data to determine autoimmunity in families of ASD and typically-developing children.
One case-control study nested within a cohort of infants born in California between 1995-1999, examined the association of “immune-related conditions” with ASD using health records and reported that prevalence of maternal psoriasis, asthma, hay fever and atopic dermatitis during the second trimester of pregnancy correlated with over two-fold elevated risk of ASD in their children (Croen et al., 2005). The second cohort consisted of the pediatric population born in Denmark from 1993 through 2004 (n=689,196), in which 3,325 children were diagnosed with ASD including 1,089 cases of infantile autism. The study confirmed an association between family history of type 1 diabetes and infantile autism, as well as rheumatoid arthritis and ASD; it was also the first to show a significant association between maternal celiac disease and ASD (Atladottir et al., 2009). A significant association between parental rheumatic fever and ASD, as well as several significant correlations between maternal autoimmune diseases and ASD were investigated across 3 Swedish registries by means of a case-control study (n=1,227 ASD cases matched with 25 controls each) (Keil et al., 2010). Auto-antibodies against brain proteins have been reported in a number of mothers with children who developed autism (Croen et al., 2008). A possible explanation for the link between maternal immune dysregulation and ASD would be the transfer of maternal autoantibodies to the developing fetus during pregnancy (Braunschweig et al., 2008; Croen et al., 2008; Singer et al., 2008; Zimmerman et al., 2007), resulting in abnormal neurodevelopment. This phenomenon was manifested in the offsprings of pregnant mice after their transfection with human systemic lupus erythematosus autoantibodies (Lee et al., 2009). A preliminary report also indicated that mothers with a diagnosis of mastocytosis during pregnancy had a high chance of having one or more children with autism (Theoharides, 2009).
Results from animal modeling studies clearly indicate that maternal immune activation (MIA) can cause both acute and lasting changes in behavior and CNS structure and function in the offspring (Boksa, 2010). Administration of bacterial lipopolysaccharide (LPS), a cell wall component from Gram-negative bacteria, activates Toll-like receptor-4 (TLR-4) on immune cells leading to synthesis and release of TNF (Varadaradjalou et al., 2003), IL-1 and IL-6 (Supajatura et al., 2002). It was recently shown that IL-1 receptor antagonism prevented neurodevelopmental anomalies in pregnant rats after systemic end-of-gestation exposure to LPS (Girard et al., 2010). In addition to its direct detrimental effect on the placenta and fetal brain tissue, IL-1 induces selective release of IL-6 from mast cells (Kandere-Grzybowska et al., 2003). IL-6 appears critical for fetal brain development and social behavior development, as demonstrated in a poly(I:C) mouse model for MIA, where co-administration of anti-IL-6 antibody prevented the social deficits and associated gene expression changes in the brain of the offspring (Smith et al., 2007).
However, human studies investigating the role of prenatal infection in the pathogenesis of autism are limited, and mostly focused on viral infections (Chess, 1977; Libbey et al., 2005; Wilkerson et al., 2002). A recent nationwide study in Denmark including children born from 1980 through 2005 points to an increased risk for ASD after maternal viral infection in the first trimester of pregnancy (adjusted hazard ratio = 2.98; CI: 1.29-7.15) or maternal bacterial infection in the second trimester of pregnancy (adjusted hazard ratio = 1.42; CI: 1.08-1.87) (Atladottir et al., 2010). Moreover, a number of rotaviruses have been isolated from asymptomatic neonates (Dunn et al., 1993). Viral double-stranded RNA like poly(I:C) induces release of TNF and IL-6 without degranulation from mast cells through viral TLR-3 (Kulka et al., 2004).
A recent study implied the presence of an endophenotype with complex immune dysfunction both in autistic children and their non-autistic siblings (Saresella et al., 2009). Brain-specific auto-antibodies are present in the plasma of many ASD individuals (Cabanlit et al., 2007; Singh et al., 1997; Singh & Rivas, 2004). Such auto-antibodies suggest a loss of self-tolerance to neural antigens during early neurodevelopment, but their precise role in autism remains unknown (Enstrom et al., 2009; Mostafa et al., 2008; Mostafa & Kitchener, 2009; Wills et al., 2007). They may indicate disruption of the blood-brain barrier (BBB), at least in a subgroup of patients. The presence of an auto-inflammatory response is also supported by the detection of certain inflammation markers. For instance, TNF was high in the cerebrospinal fluid (CSF) (Chez et al., 2007), and IL-6 gene expression was increased in the brain (Li et al., 2009) of autistic patients. CSF and microglia of ASD patients had high levels of macrophage chemoattractant protein-1 (MCP-1) (Vargas et al., 2005), which is also a potent chemoattractant for mast cells (Conti et al., 1997). In contrast, ASD plasma levels of transforming growth factor-beta1 (TGF-β1) were low (Ashwood et al., 2008), which is important in view of the fact that TGF-β1 inhibits mast cell function (Gebhardt et al., 2005). Many children with ASD also report gastrointestinal symptoms (Buie et al., 2010). In a few studies, examination of intestinal biopsies from children with regressive autism reveals features of an autoimmune mucosal pathology, that is not seen in other conditions or inflammatory bowel diseases (Ashwood et al., 2003; Torrente et al., 2002).
Many of the epidemiologic, biochemical and pathologic findings could be explained through activation of mast cells, immune cells important in both innate and acquired immunity (Galli et al., 2005), as well as in inflammation (Theoharides & Kalogeromitros, 2006). Mast cells are well-known for their leading role in allergic reactions, during which they are stimulated by IgE binding to high-affinity receptors (FcεRI), aggregation of which leads to degranulation and secretion of numerous pre-stored and newly-synthesized mediators, including IL-6 and TNF (Blank & Rivera, 2004; Kraft & Kinet, 2007; Schroeder et al., 1995; Schwartz, 1987; Serafin & Austen, 1987; Stone et al., 2010; Torigoe et al., 1997). In addition to IgE, many substances originating in the environment, the intestine or the brain can trigger mast cell activation (Theoharides et al., 2011). These include non-allergic environmental, infectious, neurohormonal and oxidative stress-related triggers, involving release of mediators selectively, without degranulation (Theoharides et al., 2007b). For instance, LPS activates TLR-4 on mast cells and induces selective release of TNF (Varadaradjalou et al., 2003), while IL-1 induces selective release of IL-6 (Kandere-Grzybowska et al., 2003).
Environmental toxins have been implicated in developmental neurotoxicity (Grandjean & Landrigan, 2006) and also in mast cell activation. In particular, polychlorinated biphenyl (PCB) (Hertz-Picciotto et al., 2008) and mercury (Young et al., 2008) have been associated with ASD, and both also activate mast cells (Asadi et al., 2010; Kempuraj et al., 2010; Kwon et al., 2002). Other mast cell triggers include bacterial and viral antigens, as well as peptides such as neurotensin (NT), which we reported to be increased in serum of young children with autism (Angelidou et al., 2010), and to induce mast cell release of extracellular mitochondrial DNA, which was also increased in the serum of these ASD patients (Zhang et al., 2010). This finding may be in addition to mitochondrial dysfunction reported in ASD (Giulivi et al., 2010; Palmieri & Persico, 2010). Given the fact that NT activates mast cells (Theoharides et al., 2004) and abundant NT is located in the gut (Castagliuolo et al., 1996), its elevated levels might lead to gut dysfunction in a cohort of autistic patients. NT also augments the action of CRH, which stimulates selective release of vascular endothelial growth factor (VEGF) (Cao et al., 2005). In fact, CRH acts synergistically with NT to increase vascular permeability (Donelan et al., 2006).
Mast cell-derived cytokines can also increase BBB permeability (Abbott, 2000; Theoharides & Konstantinidou, 2007). BBB disruption has been documented in brain inflammatory diseases, such as multiple sclerosis, where it precedes any pathological or clinical symptoms (Minagar & Alexander, 2003; Soon et al., 2007; Stone et al., 1995). We speculate that perinatal mast cell activation, in response to allergic or non-immune triggers, could disrupt the gut-blood-brain barriers (Theoharides & Doyle, 2008) and permit neurotoxic molecules to enter the brain and result in brain inflammation, thus contributing to ASD pathogenesis (Fig. 1) (Theoharides et al., 2008). It is intriguing that mast cell-derived IL-9 induces intestinal permeability and predisposes to oral antigen hypersensitivity in children (Forbes et al., 2008), while it also exacerbates newborn brain toxic lesions (Dommergues et al., 2000). Moreover, IL-33 can synergize with SP (Theoharides et al., 2010) and SCF (Drube et al., 2010) in stimulating mast cell TNF release, while it also activates glial cells to secrete pro-inflammatory cytokines (Yasuoka et al., 2011). The possible involvement of mast cells (Theoharides et al., 2011) in ASD is also supported by the fact that many children with ASD report “allergic-like” symptoms (Angelidou et al., 2011).
Mast cells have been implicated in inflammatory conditions that worsen by stress (Theoharides & Cochrane, 2004) and in regulating BBB permeability (Esposito et al., 2002). It was shown that early life stress due to maternal separation resulted in an altered brain-gut axis; it was sufficient to cause an increase in the blood concentrations of pro-inflammatory cytokines after a challenge with LPS, and also an increase in plasma corticosterone (O'Mahony et al., 2009). The timing of prenatal stressors was investigated in a case-control study, recording mothers’ reports on exposure to stressors during each 4-week block of pregnancy. A higher incidence of stressors at 21-32 weeks gestation was found in autism, in consistency with the embryological age at which pathological cerebellar changes in autism are seen (Beversdorf et al., 2005).
and mast cells (Kempuraj et al., 2004). In fact, CRH released from hair follicles can trigger mast cell proliferation (Ito et al., 2010). This form of tissue CRH sometimes called “immune CRH” may have an immunomodulatory role as an autocrine/paracrine mediator of inflammation during reproduction (Kalantaridou et al., 2007). One of the early effects of immune CRH is the activation of mast cells and the release of several pro-inflammatory cytokines (Theoharides et al., 2004). CRH was increased in the serum of mothers who delivered preterm babies and correlated with their level of anxiety during that period of pregnancy (Makrigiannakis et al., 2007). Maternal serum CRH can cross the placenta, and potentially high amounts of CRH could be produced by the placenta itself in response to external or intrauterine stress (Grammatopoulos, 2008; Torricelli et al., 2011). CRH can then disrupt the BBB (Theoharides & Konstantinidou, 2007), which appears to be compromised in ASD patients, as indicated by the presence of autoantibodies against encephalogenic peptides (Cabanlit et al., 2007; Goines & Van de Water J., 2010; Singer et al., 2006; Vojdani et al., 2002; Wills et al., 2008). BBB disruption due to stress is dependent on both CRH
Figure 1.
Diagrammatic depiction of how perinatal immune activation may contribute to brain inflammation and autism. CRH, corticotropin-releasing hormone; IL, interleukin; LPS, lipopolysaccharide; MCP-1, macrophage chemoattractant protein-1; mtDNA, mitochondrial DNA; NT, neurotensin; PCB, polychlorinated biphenyl; poly(IC),polyinosinic:polycytidylic acid; ROS, reactive oxygen species; SP, substance P; TGFβ1, transforming growth factor-beta1; TNF, tumor necrosis factor
The effect of CRH may be relevant to the behavioral manifestations of ASD. ASD patients had high anxiety levels and were unable to handle stress appropriately (Gillott & Standen, 2007). Evening cortisol levels positively correlated to daily stressors in children with autism (Corbett et al., 2009). Moreover, increase in age of autistic children correlated with increased cortisol levels during social interaction stress (Corbett et al., 2010). CRH has also been shown to increase intestinal permeability of human colonic biopsies, while maternal separation stress and CRH are associated with a dysfunctional mucosal barrier in rodents (Soderholm et al., 2002). A short period of restraint (Chandler et al., 2002) or maternal deprivation stress (Teunis et al., 2002) also increased the severity of experimental autoimmune encephalomyelitis.
The presence of maternal stress may explain why children born within a year of the first child that developed autism had a much higher chance of developing autism than if they were born two years later (Cheslack-Postava et al., 2011). Increased circulating CRH, directly or through immune cell release of other inflammatory and vasoactive molecules, can disrupt the gut-blood-brain barriers during gestation and/or infancy and permit absorption of intestinal-derived inflammatory and neurosensitizing mediators.
High weight gain in pregnancy has been considered an independent risk factor for autism in the offspring (Stein et al., 2006). Even though a clear mechanism is lacking, leptin is suspected to play a major role. Obese subjects have higher leptin levels than normal weight subjects (Considine et al., 1996; Dardeno et al., 2010). Additionally, it has been suggested that elevated plasma leptin levels during pregnancy are indicative of placental dysfunction (Hauguel-de et al., 2006). Placental insufficiency, possibly associated with anoxia, may also contribute to autism in the offspring (Glasson et al., 2004).
Elevated plasma leptin levels were reported in children with regressive autism (n=37), compared with typically-developing controls (n=50) (Ashwood et al., 2007). One group also measured the variation of circulating leptin at baseline and after one year of follow-up in 35 patients with “classic autism” (according to DSM-IV criteria) aged 14.1±5.4 years old. The authors reported significantly higher leptin values in the patients versus the controls (24.1±17.8 ng/ml vs 9.8±3.2 ng/ml at baseline; 33.5±21.4 ng/ml vs 11.1±3.9 ng/ml at one year), and leptin concentrations were not associated with obesity or pubertal status (Blardi et al., 2010). It is still unclear, however, if the alteration of leptin levels in autism is a primary event or a finding attributable to the disease. Plasma levels of leptin have also been investigated in patients with Rett syndrome (n=16), where it was found that leptin was significantly increased compared to healthy controls (n=16), but also did not correlate with obesity (Blardi et al., 2008), suggesting that there may be more to the actions of leptin in neurodevelopment than weight balance.
The immunomodulatory properties of leptin were first reported on a mouse model, in which obese mice were found to have impaired cell-mediated and humoral immunity, attributed to possible lack of leptin (Chandra, 1980). The epigenetic status in adulthood was shown to be directionally dependent on prenatal nutritional status (Gluckman et al., 2007) and neonatal leptin administration late in the phase of developmental plasticity was able to reverse the developmental programming in rats (Vickers et al., 2005). Mast cells also express leptin and leptin receptors, a finding implicating paracrine or autocrine immunomodulatory effects of leptin on mast cells (Taildeman et al., 2009). Locally released leptin from T lymphocytes doesn’t seem to play a major role in immunoregulation in mouse models of intestinal inflammation, suggesting other sources of leptin as critical in modulation of the inflammatory response (Fantuzzi et al., 2005). Despite evidence supporting the role of leptin in immune processes (Lago et al., 2008; Matarese et al., 2005), its precise role in inflammation remains incompletely understood.
A variety of events associated with poor fetal growth or preterm birth are also associated with oxidative stress. These include maternal infection and inflammation that lead to increased lipid peroxidation, but more importantly to alterations in the expression of many genes associated with adverse perinatal outcomes (Ingelfinger, 2007).
Considerable evidence indicates that oxidative stress may be increased in patients with ASD, possibly due to their decreased ability to neutralize free radicals. An earlier study showed increased levels of plasma malondialdehyde, a marker of oxidative stress, (p<0.05) in the blood of mothers who delivered preterm and in the cord blood of their preterm neonates, compared to the levels in samples from term deliveries (Joshi et al., 2008). Preterm birth is associated with increased generation of reactive oxygen species (ROS), which places these infants in high risk for injury (Davis & Auten, 2010). In fact, a recent study identified an increase in the oxidative stress marker non-protein bound iron (NPBI) in the cord blood of 168 preterm newborns of gestational age 24-32 weeks (Perrone et al., 2010), suggesting that early identification of neonates at-risk is possible.
The impact of environmental oxidants in the etiology of autism is associated with brain region-specific changes in oxidative stress markers, such as 3-nitrotyrosine (3-NT) and neurotrophin-3 (NT-3), in ASD (Sajdel-Sulkowska et al., 2008; Sajdel-Sulkowska et al., 2011). Deficiencies in anti-oxidant enzymes might, in certain cases, be associated with mercury toxicity, which was shown to be tightly bound to and inactivate thioredoxin (Carvalho et al., 2008). In fact, cytosolic and mitochondrial redox imbalance was found in lymphoblastoid cells of ASD children compared to controls, an event exaggerated by exposure to thimerosal (James et al., 2009).
Several studies have suggested a link between oxidative stress and the immune response (Viora et al., 2001). Because immune cell functions are specially linked to ROS generation, their normal functioning is largely dependent on the oxidant/antioxidant balance. A strong association between oxidative stress and autoimmunity was shown in a group of 44 Egyptian autistic children, 88.64% of whom had elevated plasma F2-isoprostane (a marker of lipid peroxidation) and/or reduced glutathione peroxidase (an anti-oxidant enzyme), compared to 44 age-matched controls. Anti-neuronal antibodies were found in 54.5% of the same cohort, implying immunomodulation (Mostafa et al., 2010). Several groups have hypothesized that oxidative stress is the mechanism by which prenatal LPS affects offspring neurodevelopment (Lante et al., 2008; Paintlia et al., 2008). Potential therapies for oxidative stress and ROS-induced morbidities in the preterm infant include both enzymatic and nonenzymatic antioxidant preparations (Lee & Davis, 2011), such as the naturally-occuring flavonoids quercetin and luteolin (Cotelle, 2001; Middleton, Jr. et al., 2000). Quercetin inhibits mast cells (Kandere-Grzybowska et al., 2006), and also inhibited and reversed acute stress-induced autistic-like behavior and the associated reduced brain glutathione levels in mice (Kumar & Goyal, 2008). Luteolin can also block mast cell activation and superstimulation of activated T-cells (Kempuraj et al., 2008; Theoharides et al., 2007a). Luteolin and its structural analog diosmin prevented MIA-induced behavioral deficits in the mouse offspring by blocking the IL-6-induced JAK2/STAT3 (Janus tyrosine kinase-2/signal transducer and activator of transcription-3) signaling pathway, both in vivo and in vitro (Parker-Athill et al., 2009). A luteolin-containing dietary supplement, Neuroprotek® was recently made available to help the body reduce brain inflammation.
A number of findings suggest the presence of different biological endophenotypes in ASD (Persico et al., 2008), as well as between early-onset and regressive autism, with the latter being associated with poorer outcomes in social reciprocity, verbal IQ and more gastrointestinal symptoms, according to caregiver interviews (Richler et al., 2006).
Increasing evidence indicates that perinatal immune activation, in the mother and/or the fetus, could adversely affect neurodevelopment. Moreover, mast cell activation during this period by environmental, infectious, neurohormonal and immune triggers appears to be involved in gut-blood-brain barrier disruption and subsequent brain inflammation. Reduction of stress during gestation and infancy, potential use of specific CRH receptor antagonists, as well as drugs that could prevent BBB disruption, or block brain inflammation may prove useful in at least a subgroup of infants at high risk for developing autism. These goals may be at least partly achieved by the use of mast cell blockers. Unfortunately, there are no clinically effective mast cell inhibitors, and the available disodium cromoglycate (cromolyn) has proven a weak inhibitor of human mast cells (Theoharides & Kalogeromitros, 2006). Instead, flavonoids such as luteolin are anti-inflammatory and neuroprotective (Dirscherl et al., 2010), and can inhibit mast cell activation (Asadi et al., 2010).
Aspects of research mentioned here were funded by Safe Minds, the National Autism Association, the Autism Research Collaborative, as well as Theta Biomedical Consulting and Development Co., Inc. (Brookline, MA). Asimenia Angelidou and Konstantinos-Dionysios Alysandratos are recipients of scholarships for postgraduate studies from the Hellenic State Scholarships Foundation (Athens, Greece). The authors declare that they have no competing interests. TCT is the inventor of patent application US 12/534,571; US 12/861,152; US 13/009,282 covering the diagnosis and treatment of ASD.
References
1.AbbottN. J.2000 Inflammatory mediators and modulation of blood-brain barrier permeability. Cell Mol Neurobiol, 20131147
2.Adams-ChapmanI.2006 Neurodevelopmental outcome of the late preterm infant. Clin Perinatol., 33, 4, 947964
3.AngelidouA.FrancisK.VasiadiM.Alysandratos-DK.ZhangB.TheoharidesA.LykourasL.KalogeromitrosD.TheoharidesT. C.2010 Neurotensin is increased in serum of young children with autistic disorder. J Neuroinflammation, 7, 48 EOF
4.AngelidouA.AlysandratosK. D.AsadiS.ZhangB.FrancisK.VasiadiM.KalogeromitrosD.TheoharidesT. C.2011 Brief Report: "Allergic Symptoms" in Children with Autism Spectrum Disorders. More than Meets the Eye? J Autism Dev.Disord., (Jan 6) [Ahead of print].
5.AngioniS.PetragliaF.GallinelliA.CossarizzaA.FranceschiC.MuscettolaM.GenazzaniA. D.SuricoN.GenazzaniA. R.1993 Corticotropin-releasing hormone modulates cytokines release in cultured human peripheral blood mononuclear cells. Life Sci, 5317351742
6.ArgyropoulouM. I.2010 Brain lesions in preterm infants: initial diagnosis and follow-up. Pediatr Radiol., 40, 6, 811818
7.AsadiS.ZhangB.WengZ.AngelidouA.KempurajD.AlysandratosK. D.TheoharidesT. C.2010 Luteolin and thiosalicylate inhibit HgCl2 and thimerosal-induced VEGF release from human mast cells. Int J Immunopathol.Pharmacol, 23, 4, 10151020
8.AshwoodP.AnthonyA.PellicerA. A.TorrenteF.Walker-SmithJ. A.WakefieldA. J.2003 Intestinal lymphocyte populations in children with regressive autism: evidence for extensive mucosal immunopathology. J Clin Immunol., 23, 6, 504517
9.AshwoodP.EnstromA.KrakowiakP.Hertz-PicciottoI.HansenR. L.CroenL. A.OzonoffS.PessahI. N.de WaterJ. V.2008 Decreased transforming growth factor beta1 in autism: A potential link between immune dysregulation and impairment in clinical behavioral outcomes. J Neuroimmunol., 204149153
10.AshwoodP.KwongC.HansenR.Hertz-PicciottoI.CroenL.KrakowiakP.WalkerW.PessahI. N.Van de WaterJ.2007 Brief Report: Plasma leptin levels are elevated in autism: Association with early onset phenotype? J.Autism Dev.Disord., 38, 1, 169175
11.AtladottirH. O.PedersenM. G.ThorsenP.MortensenP. B.DeleuranB.EatonW. W.ParnerE. T.2009 Association of family history of autoimmune diseases and autism spectrum disorders. Pediatrics, 124, 2, 687694
12.AtladottirH. O.ThorsenP.OstergaardL.SchendelD. E.LemckeS.AbdallahM.ParnerE. T.2010 Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. J Autism Dev.Disord., 40, 12, 14231430
14.BlankU.RiveraJ.2004 The ins and outs of IgE-dependent mast-cell exocytosis. Trends Immunol, 25266273
15.BlardiP.de LallaA.CeccatelliL.VanessaG.AuteriA.HayekJ.2010 Variations of plasma leptin and adiponectin levels in autistic patients. Neurosci.Lett., 479, 1, 5457
16.deBlardiP. LallaA.D’AmbrogioT. G. V. L. C. A. A.J. H.2008 Long-term plasma levels of leptin and adiponectin in Rett Syndrome. Clin Endocrinol. (Oxf), 70, 5, 706709
17.BoksaP.2010 Effects of prenatal infection on brain development and behavior: a review of findings from animal models. Brain Behav.Immun., 24, 6, 881897
18.BraunschweigD.AshwoodP.KrakowiakP.Hertz-PicciottoI.HansenR.CroenL. A.PessahI. N.Van de WaterJ.2008 Autism: maternally derived antibodies specific for fetal brain proteins. NeuroToxicology, 29, 2, 226231
19.BrimacombeM.MingX.LamendolaM.2007 Prenatal and birth complications in autism. Matern.Child Health J, 11, 1, 7379
20.BuchmayerS.JohanssonS.JohanssonA.HultmanC. M.SparenP.CnattingiusS.2009 Can association between preterm birth and autism be explained by maternal or neonatal morbidity? Pediatrics, 124, 5, e817e825
21.BuieT.CampbellD. B.FuchsG. J.IIIFurutaG. T.LevyJ.VandewaterJ.WhitakerA. H.AtkinsD.BaumanM. L.BeaudetA. L.CarrE. G.GershonM. D.HymanS. L.JirapinyoP.JyonouchiH.KoorosK.KushakR.LevittP.LevyS. E.LewisJ. D.MurrayK. F.NatowiczM. R.SabraA.WershilB. K.WestonS. C.ZeltzerL.WinterH.2010 Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics, 125, Suppl 1:S118
22.CabanlitM.WillsS.GoinesP.AshwoodP.Van de WaterJ.2007 Brain-specific autoantibodies in the plasma of subjects with autistic spectrum disorder. Ann.N Y.Acad.Sci., 110792103
24.CaoJ.PapadopoulouN.KempurajD.BoucherW. S.SugimotoK.CetruloC. L.TheoharidesT. C.2005 Human mast cells express corticotropin-releasing hormone (CRH) receptors and CRH leads to selective secretion of vascular endothelial growth factor. J Immunol, 17476657675
25.CarvalhoC. M.ChewE. H.HashemyS. I.LuJ.HolmgrenA.2008 Inhibition of the human thioredoxin system. A molecular mechanism of mercury toxicity. J Biol.Chem., 283, 18, 1191311923
26.CastagliuoloI.LeemanS. E.Bartolac-SukiE.NikulassonS.QiuB.CarrawayR. E.PothoulakisC.1996 A neurotensin antagonist, SR 48692, inhibits colonic responses to immobilization stress in rats. Proc Natl Acad Sci USA, 931261112615
27.ChandlerN.JacobsonS.ConnollyR.EspositoP.TheoharidesT. C.2002 Acute stress shortens the time of onset of experimental allergic encephalomyelitis (EAE) in SJL/J mice. Brain Behav Immun, 16757763
29.Cheslack-PostavaK.LiuK.BearmanP. S.2011 Closely Spaced Pregnancies Are Associated With Increased Odds of Autism in California Sibling Births. Pediatrics,
30.ChessS.1977 Follow-up report on autism in congenital rubella. J Autism Child Schizophr., 127, 2, 246253
31.ChezM. G.DowlingT.PatelP. B.KhannaP.KominskyM.2007 Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr.Neurol., 36, 6, 361365
32.ChrousosG. P.1995 The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med, 33213511362
33.ConsidineR. V.SinhaM. K.HeimanM. L.KriauciunasA.StephensT. W.NyceM. R.OhannesianJ. P.MarcoC. C.Mc KeeL. J.BauerT. L.1996 Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N.Engl.J Med., 334, 5, 292295
34.ContiP.PangX.BoucherW.LetourneauR.RealeM.BarbacaneR. C.ThibaultJ.TheoharidesT. C.1997 Impact of Rantes and MCP-1 chemokines on in vivo basophilic mast cell recruitment in rat skin injection model and their role in modifying the protein and mRNA levels for histidine decarboxylase. Blood, 8941204127
35.CorbettB. A.SchuppC. W.LevineS.MendozaS.2009 Comparing cortisol, stress, and sensory sensitivity in children with autism. Autism Res., 2, 1, 3949
36.CorbettB. A.SchuppC. W.SimonD.RyanN.MendozaS.2010 Elevated cortisol during play is associated with age and social engagement in children with autism. Mol.Autism, 1, 1, 13
37.CotelleN.2001 Role of flavonoids in oxidative stress. Curr.Top.Med.Chem., 1, 6, 569590
38.CroenL. A.BraunschweigD.HaapanenL.YoshidaC. K.FiremanB.GretherJ. K.KharraziM.HansenR. L.AshwoodP.Van de WaterJ.2008 Maternal mid-pregnancy autoantibodies to fetal brain protein: the early markers for autism study. Biological Psychiatry, 64, 7, 583588
39.CroenL. A.GretherJ. K.YoshidaC. K.OdouliR.Van de WaterJ.2005 Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case-control study. Arch.Pediatr.Adolesc.Med., 159, 2, 151157
40.DardenoT. A.ChouS. H.MoonH. S.ChamberlandJ. P.FiorenzaC. G.MantzorosC. S.2010 Leptin in human physiology and therapeutics. Front Neuroendocrinol., 31, 3, 377393
41.DavisJ. M.AutenR. L.2010 Maturation of the antioxidant system and the effects on preterm birth. Semin.Fetal Neonatal Med., 15, 4, 191195
42.DethR.MuratoreC.BenzecryJ.Power-CharnitskyV. A.WalyM.2008 How environmental and genetic factors combine to cause autism: A redox/methylation hypothesis. NeuroToxicology, 29, 1, 190201
43.DirscherlK.KarlstetterM.EbertS.KrausD.HlawatschJ.WalczakY.MoehleC.FuchshoferR.LangmannT.2010 Luteolin triggers global changes in the microglial transcriptome leading to a unique anti-inflammatory and neuroprotective phenotype. J Neuroinflammation., 7, 1, 3
44.DoddsL.FellD. B.SheaS.ArmsonB. A.AllenA. C.BrysonS.2011 The Role of Prenatal, Obstetric and Neonatal Factors in the Development of Autism. J Autism Dev.Disord., 41, 7, 891902
45.DommerguesM. A.PatkaiJ.RenauldJ. C.EvrardP.GressensP.2000 Proinflammatory cytokines and interleukin-9 exacerbate excitotoxic lesions of the newborn murine neopallium. Ann.Neurol., 47, 1, 5463
46.DonelanJ.BoucherW.PapadopoulouN.LytinasM.PapaliodisD.TheoharidesT. C.2006 Corticotropin-releasing hormone induces skin vascular permeability through a neurotensin-dependent process. Proc Natl Acad Sci USA, 10377597764
47.DrubeS.HeinkS.WalterS.LohnT.GrusserM.GerbauletA.BerodL.SchonsJ.DudeckA.FreitagJ.GrothaS.ReichD.RudeschkoO.NorgauerJ.HartmannK.RoersA.KamradtT.2010 The receptor tyrosine kinase c-Kit controls IL-33 receptor signaling in mast cells. Blood, 115, 19, 38993906
48.DubickeA.FranssonE.CentiniG.AnderssonE.BystromB.MalmstromA.PetragliaF.Sverremark-EkstromE.Ekman-OrdebergG.2010 Pro-inflammatory and anti-inflammatory cytokines in human preterm and term cervical ripening. J Reprod.Immunol, 84, 2, 176185
49.DunnS. J.GreenbergH. B.WardR. L.NakagomiO.BurnsJ. W.VoP. T.PaxK. A.DasM.GowdaK.RaoC. D.1993 Serotypic and genotypic characterization of human serotype 10 rotaviruses from asymptomatic neonates. J Clin Microbiol., 31, 1, 165169
50.DurkinM. S.MaennerM. J.MeaneyF. J.LevyS. E.Di GuiseppiC.NicholasJ. S.KirbyR. S.Pinto-MartinJ. A.SchieveL. A.2010 Socioeconomic inequality in the prevalence of autism spectrum disorder: evidence from a U.S. cross-sectional study. PLoS.ONE., 5, 7, e11551
51.EhningerD.SanoY.de VriesP. J.DiesK.FranzD.GeschwindD. H.KaurM.LeeY. S.LiW.LoweJ. K.NakagawaJ. A.SahinM.SmithK.WhittemoreV.SilvaA. J.2010 Gestational immune activation and Tsc2 haploinsufficiency cooperate to disrupt fetal survival and may perturb social behavior in adult mice. Mol.Psychiatry, (Nov 16) [Ahead of print].
52.EnstromA. M.Van de WaterJ. A.AshwoodP.2009 Autoimmunity in autism. Curr.Opin.Investig.Drugs, 10, 5, 463473
54.EspositoP.GheorgheD.KandereK.PangX.ConallyR.JacobsonS.TheoharidesT. C.2001 Acute stress increases permeability of the blood-brain-barrier through activation of brain mast cells. Brain Res, 888117127
55.FantuzziG.SennelloJ. A.BatraA.FedkeI.LehrH. A.ZeitzM.SiegmundB.2005 Defining the role of T cell-derived leptin in the modulation of hepatic or intestinal inflammation in mice. Clin Exp.Immunol, 142, 1, 3138
60.GebhardtT.LorentzA.DetmerF.TrautweinC.BektasH.MannsM. P.BischoffS. C.2005 Growth, phenotype, and function of human intestinal mast cells are tightly regulated by transforming growth factor beta1. Gut, 54, 7, 928934
61.GillottA.StandenP. J.2007 Levels of anxiety and sources of stress in adults with autism. J.Intellect.Disabil., 11, 4, 359370
62.GirardS.TremblayL.LepageM.SebireG.2010 IL-1 receptor antagonist protects against placental and neurodevelopmental defects induced by maternal inflammation. J Immunol, 184, 7, 39974005
64.GlassonE. J.BowerC.PettersonB.de KlerkN.ChaneyG.HallmayerJ. F.2004 Perinatal factors and the development of autism: a population study. Arch.Gen.Psychiatry, 61, 6, 618627
65.GluckmanP. D.LillycropK. A.VickersM. H.PleasantsA. B.PhillipsE. S.BeedleA. S.BurdgeG. C.HansonM. A.2007 Metabolic plasticity during mammalian development is directionally dependent on early nutritional status. Proc Natl Acad Sci U S A, 104, 31, 1279612800
66.GoinesP.Van de WaterJ.2010 The immune system’s role in the biology of autism. Curr.Opin.Neurol., 23, 2, 111117
67.GrammatopoulosD. K.2008 Placental corticotrophin-releasing hormone and its receptors in human pregnancy and labour: still a scientific enigma. Journal of Neuroendocrinology, 20, 4, 432438
69.Hauguel-deMouzon. S.LepercqJ.CatalanoP.2006 The known and unknown of leptin in pregnancy. Am.J Obstet.Gynecol., 194, 6, 15371545
70.HerbertM. R.2010 Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders. Curr.Opin.Neurol., 23, 2, 103110
71.Hertz-PicciottoI.ParkH. Y.DostalM.KocanA.TrnovecT.SramR.2008 Prenatal exposures to persistent and non-persistent organic compounds and effects on immune system development. Basic Clin.Pharmacol.Toxicol., 102, 2, 146154
72.IngelfingerJ. R.2007 Prematurity and the legacy of intrauterine stress. N.Engl.J Med., 356, 20, 20932095
73.ItoN.SugawaraK.BodoE.TakigawaM.van BeekN.ItoT.PausR.2010 Corticotropin-releasing hormone stimulates the in situ generation of mast cells from precursors in the human hair follicle mesenchyme. J Invest Dermatol., 130, 4, 9951004
74.JamesS. J.RoseS.MelnykS.JerniganS.BlossomS.PavlivO.GsylorD. W.2009 Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism. FASEB, 23(8) 23742383
75.JohnsonC. P.MyersS. M.2007 Identification and evaluation of children with autism spectrum disorders. Pediatrics, 120, 5, 11831215
77.JohnsonS.MarlowN.2011 Preterm Birth and Childhood Psychiatric Disorders. Pediatric Research, (May) [Ahead of print]., 69, 5 Pt 2, 11R18R
78.JoshiS. R.MehendaleS. S.DangatK. D.KilariA. S.YadavH. R.TaralekarV. S.2008 High maternal plasma antioxidant concentrations associated with preterm delivery. Ann.Nutr.Metab, 53, 3-4, 276282
79.KaindlA. M.FavraisG.GressensP.2009 Molecular mechanisms involved in injury to the preterm brain. J Child Neurol., 24, 9, 11121118
80.KalantaridouS.MakrigiannakisA.ZoumakisE.ChrousosG. P.2007 Peripheral corticotropin-releasing hormone is produced in the immune and reproductive systems: actions, potential roles and clinical implications. Front Biosci., 12572580
81.Kandere-GrzybowskaK.LetourneauR.KempurajD.DonelanJ.PoplawskiS.BoucherW.AthanassiouA.TheoharidesT. C.2003 IL-1 induces vesicular secretion of IL-6 without degranulation from human mast cells. J Immunol, 171, 9, 48304836
82.Kandere-GrzybowskaK.KempurajD.CaoJ.CetruloC. L.TheoharidesT. C.2006 Regulation of IL-1-induced selective IL-6 release from human mast cells and inhibition by quercetin. Br J Pharmacol, 148208215
83.KaralisK.LouisJ. M.BaeD.HilderbrandH.MajzoubJ. A.1997 CRH and the immune system. J Neuroimmunol, 72131136
84.KeilA.DanielsJ. L.ForssenU.HultmanC.CnattingiusS.SoderbergK. C.FeychtingM.SparenP.2010 Parental autoimmune diseases associated with autism spectrum disorders in offspring. Epidemiology, 21, 6, 805808
85.KempurajD.AsadiS.ZhangB.ManolaA.HoganJ.PetersonE.TheoharidesT. C.2010 Mercury induces inflammatory mediator release from human mast cells. J Neuroinflammation, 7, 1, 20
86.KempurajD.PapadopoulouN. G.LytinasM.HuangM.Kandere-GrzybowskaK.MadhappanB.BoucherW.ChristodoulouS.AthanassiouA.TheoharidesT. C.2004 Corticotropin-releasing hormone and its structurally related urocortin are synthesized and secreted by human mast cells. Endocrinology, 1454348
87.KempurajD.TagenM.IliopoulouB. P.ClemonsA.VasiadiM.BoucherW.HouseM.WolfergA.TheoharidesT. C.2008 Luteolin inhibits myelin basic protein-induced human mast cell activation and mast cell dependent stimulation of Jurkat T cells. Br J Pharmacol, 15510761084
88.KinneyD. K.MunirK. M.CrowleyD. J.MillerA. M.2008 Prenatal stress and risk for autism. Neurosci.Biobehav.Rev., 32, 8, 15191532
89.KleinmanJ. M.RobinsD. L.VentolaP. E.PandeyJ.BoorsteinH. C.EsserE. L.WilsonL. B.RosenthalM. A.SuteraS.VerbalisA. D.BartonM.HodgsonS.GreenJ.Dumont-MathieuT.VolkmarF.ChawarskaK.KlinA.FeinD.2008 The modified checklist for autism in toddlers: a follow-up study investigating the early detection of autism spectrum disorders. J Autism Dev.Disord., 38, 5, 827839
90.KoganM. D.BlumbergS. J.SchieveL. A.BoyleC. A.PerrinJ. M.GhandourR. M.SinghG. K.StricklandB. B.TrevathanE.van DyckP. C.2009 Prevalence of parent-reported diagnosis of autism spectrum disorder among children in the US, 2007. Pediatrics, 5, 124, 13951403
91.KraftS.KinetJ. P.2007 New developments in FcepsilonRI regulation, function and inhibition. Nat Rev.Immunol, 7, 5, 365378
92.KubanK. C.O’SheaT. M.AllredE. N.Tager-FlusbergH.GoldsteinD. J.LevitonA.2009 Positive screening on the Modified Checklist for Autism in Toddlers (M-CHAT) in extremely low gestational age newborns. Journal of Pediatrics, 154, 4, 535540
93.KulkaM.AlexopoulouL.FlavellR. A.MetcalfeD. D.2004 Activation of mast cells by double-stranded RNA: evidence for activation through Toll-like receptor 3. J Allergy Clin.Immunol, 114, 1, 174182
94.KumarA.GoyalR.2008 Quercetin protects against acute immobilization stress-induced behaviors and biochemical alterations in mice. J Med Food, 11, 3, 469473
95.KwonO.LeeE.MoonT. C.JungH.LinC. X.NamK. S.BaekS. H.MinH. K.ChangH. W.2002 Expression of cyclooxygenase-2 and pro-inflammatory cytokines induced by 2,2’,4,4’,5,5’-hexachlorobiphenyl (PCB 153) in human mast cells requires NF-kappa B activation. Biol.Pharm.Bull., 25, 9, 11651168
96.LagoR.GomezR.LagoF.Gomez-ReinoJ.GualilloO.2008 Leptin beyond body weight regulation--current concepts concerning its role in immune function and inflammation. Cell Immunol, 252, 1-2, 139145
97.LanteF.MeunierJ.GuiramandJ.De JesusFerreira. M. C.CambonieG.AimarR.Cohen-SolalC.MauriceT.VignesM.BarbanelG.2008 Late N-acetylcysteine treatment prevents the deficits induced in the offspring of dams exposed to an immune stress during gestation. Hippocampus, 18, 6, 602609
104.LimperopoulosC.2009 Autism spectrum disorders in survivors of extreme prematurity. Clin Perinatol., 36, 4, 791805vi.
105.LimperopoulosC.BassanH.GauvreauK.RobertsonR. L.JrSullivanN. R.BensonC. B.AveryL.StewartJ.SoulJ. S.RingerS. A.VolpeJ. J.du PlessisA. J.2007 Does cerebellar injury in premature infants contribute to the high prevalence of long-term cognitive, learning, and behavioral disability in survivors? Pediatrics, 120, 3, 584593
106.LimperopoulosC.BassanH.SullivanN. R.SoulJ. S.RobertsonR. L.JrMooreM.RingerS. A.VolpeJ. J.duPlessis. A. J.2008 Positive screening for autism in ex-preterm infants: prevalence and risk factors. Pediatrics, 121, 4, 758765
107.LinC. Y.ChangY. C.WangS. T.LeeT. Y.LinC. F.HuangC. C.2010 Altered inflammatory responses in preterm children with cerebral palsy. Ann.Neurol., 68, 2, 204212
108.MacDorman. M. F.DeclercqE.ZhangJ.2010 Obstetrical intervention and the singleton preterm birth rate in the United States from 1991-2006. Am J Public Health, 100, 11, 22412247
112.MatareseG.MoschosS.MantzorosC. S.2005 Leptin in immunology. J Immunol, 174, 6, 31373142
113.MatsonJ. L.KozlowskiA. M.2010 Autistic regression. Res Autism Spectr Disord, 4340345
114.MiddletonE.JrKandaswamiC.TheoharidesT. C.2000 The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease and cancer. Pharmacol Rev, 52673751
120.MostafaG. A.KitchenerN.2009 Serum anti-nuclear antibodies as a marker of autoimmunity in Egyptian autistic children. Pediatr Neurol, 40, 2, 107112
121.O’MahonyS. M.MarchesiJ. R.ScullyP.CodlingC.CeolhoA. M.QuigleyE. M.CryanJ. F.DinanT. G.2009 Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biological Psychiatry, 65, 3, 263267
122.OkumuraA.YamamotoT.KidokoroH.KatoT.KubotaT.ShojiH.SatoH.ShimojimaK.ShimizuT.2010 Altered gene expression in umbilical cord mononuclear cells in preterm infants with periventricular leukomalacia. Early Hum.Dev., 86, 10, 665667
124.PalmieriL.PersicoA. M.2010 Mitochondrial dysfunction in autism spectrum disorders: Cause or effect? Biochim.Biophys.Acta, 1797, 6-7, 11301137
125.Parker-AthillE.LuoD.BaileyA.GiuntaB.TianJ.ShytleR. D.MurphyT.LegradiG.TanJ.2009 Flavonoids, a prenatal prophylaxis via targeting JAK2/STAT3 signaling to oppose IL-6/MIA associated autism. J Neuroimmunol., 217, 1-2, 2027
126.PerroneS.TatarannoM. L.NegroS.LonginiM.MarzocchiB.ProiettiF.IacoponiF.CapitaniS.BuonocoreG.2010 Early identification of the risk for free radical-related diseases in preterm newborns. Early Hum.Dev., 86, 4, 241244
127.PersicoA. M.SaccoR.CuratoloP.ManziB.LentiC.SaccaniM.MiliterniR.BravaccioC.EliaA.2008 Isolation of principal components in autistic disorder symptomatology and their association with biological endophenotypes. Proc.Society for Neuroscience, Washington DC, Abstract #446.20.
128.PetragliaF.GarutiG. C.De RamundoB.AngioniS.GenazzaniA. R.BilezikjianL. M.1990 Mechanism of action of interleukin-1 beta in increasing corticotropin-releasing factor and adrenocorticotropin hormone release from cultured human placental cells. Am.J Obstet.Gynecol., 163, 4 Pt 1, 13071312
129.RichlerJ.LuysterR.RisiS.HsuW. L.DawsonG.BernierR.DunnM.HepburnS.HymanS. L.Mc MahonW. M.Goudie-NiceJ.MinshewN.RogersS.SigmanM.SpenceM. A.GoldbergW. A.Tager-FlusbergH.VolkmarF. R.LordC.2006 Is there a ‘regressive phenotype’ of Autism Spectrum Disorder associated with the measles-mumps-rubella vaccine? A CPEA Study. J Autism Dev.Disord., 36, 3, 299316
130.RoviraN.AlarconA.IriondoM.IbanezM.PooP.CusiV.AgutT.PertierraA.KrauelX.2011 Impact of histological chorioamnionitis, funisitis and clinical chorioamnionitis on neurodevelopmental outcome of preterm infants. Early Hum.Dev, 84253257
131.Sajdel-SulkowskaE. M.LipinskiB.WindomH.AudhyaT.Mc GinnisW.2008 Oxidative stress in autism: elevated cerebellar 3-nitrotyrosine levels. AM J Biochem Biotechnol, 47384
132.Sajdel-SulkowskaE. M.XuM.Mc GinnisW.KoibuchiN.2011 Brain region-specific changes in oxidative stress and neurotrophin levels in autism spectrum disorders (ASD). Cerebellum, 10, 1, 4348
133.SaresellaM.MarventanoI.GueriniF. R.MancusoR.CeresaL.ZanzotteraM.RusconiB.MaggioniE.TinelliC.ClericiM.2009 An autistic endophenotype results in complex immune dysfunction in healthy siblings of autistic children. Biological Psychiatry, 66, 10, 978984
134.SchroederJ. T.Kagey-SobotkaA.MacGlashan. D. W.LichtensteinL. M.1995 The interaction of cytokines with human basophils and mast cells. International Archives of Allergy and Immunology, 1077981
135.SchwartzL. B.1987 Mediators of human mast cells and human mast cell subsets. Ann Allergy, 58226235
136.SerafinW. E.AustenK. F.1987 Mediators of immediate hypersensitivity reactions. N Engl J Med, 3173034
137.SingerH. S.MorrisC. M.GauseC. D.GillinP. K.CrawfordS.ZimmermanA. W.2008 Antibodies against fetal brain in sera of mothers with autistic children. J Neuroimmunol., 194, 1-2, 165172
138.SingerH. S.MorrisC. M.WilliamsP. N.YoonD. Y.HongJ. J.ZimmermanA. W.2006 Antibrain antibodies in children with autism and their unaffected siblings. J Neuroimmunol., 178, 1-2, 149155
139.SinghV. K.RivasW. H.2004 Prevalence of serum antibodies to caudate nucleus in autistic children. Neurosci.Lett., 355, 1-2, 5356
140.SinghV. K.WarrenR.AverettR.GhaziuddinM.1997 Circulating autoantibodies to neuronal and glial filament proteins in autism. Pediatr.Neurol., 17, 1, 8890
141.SkofitschG.ZamirN.HelkeC. J.SavittJ. M.JacobowitzD. M.1985 Corticotropin-releasing factor-like immunoreactivity in sensory ganglia and capsaicin sensitive neurons of the rat central nervous system: colocalization with other neuropeptides. Peptides, 6307318
142.SlominskiA.WortsmanJ.PisarchikA.ZbytekB.LintonE. A.MazurkiewiczJ. E.WeiE. T.2001 Cutaneous expression of corticotropin-releasing hormone (CRH), urocortin, and CRH receptors. FASEB J, 1516781693
143.SlominskiA.ZbytekB.ZmijewskiM.SlominskiR. M.KauserS.WortsmanJ.TobinD. J.2006 Corticotropin releasing hormone and the skin. Front Biosci, 1122302248
147.SoderholmJ. D.YatesD. A.GareauM. G.YangP. C.MacQueen. G.PerdueM. H.2002 Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress. Am.J Physiol Gastrointest.Liver Physiol, 283, 6, G1257G1263
148.SoonD.AltmannD. R.FernandoK. T.GiovannoniG.BarkhofF.PolmanC. H.O’ConnorP.GrayB.PanzaraM.MillerD. H.2007 A study of subtle blood brain barrier disruption in a placebo-controlled trial of natalizumab in relapsing remitting multiple sclerosis. J Neurol., 254, 3, 306314
149.SteinD.WeizmanA.RingA.BarakY.2006 Obstetric complications in individuals diagnosed with autism and in healthy controls. Comprehensive Psychiatry, 47, 1, 6975
150.StoneK. D.PrussinC.MetcalfeD. D.2010 IgE, mast cells, basophils, and eosinophils. The Journal of Allergy and Clinical Immunology, 125, 2 Suppl 2, S73S80
151.StoneL. A.SmithM. E.AlbertP. S.BashC. N.MaloniH.FrankJ. A.Mc FarlandH. F.1995 Blood-brain barrier disruption on contrast-enhanced MRI in patients with mild relapsing-remitting multiple sclerosis: Relationship to course, gender, and age. Neurology, 4511221126
152.SupajaturaV.UshioH.NakaoA.AkiraS.OkumuraK.RaC.OgawaH.2002 Differential responses of mast cell Toll-like receptors 2 and 4 in allergy and innate immunity. J Clin Invest, 10913511359
153.TaildemanJ.Perez-NovoC. A.RottiersI.FerdinandeL.WaeytensA.De ColvenaerV.BachertC.DemetterP.WaelputW.BraetK.CuvelierC. A.2009 Human mast cells express leptin and leptin receptors. Histochem.Cell Biol., 131, 6, 703711
154.TeunisM. A.HeijnenC. J.SluyterF.BakkerJ. M.Van DamA. M.HofM.CoolsA. R.KavelaarsA.2002 Maternal deprivation of rat pups increases clinical symptoms of experimental autoimmune encephalomyelitis at adult age. J.Neuroimmunol., 133, 1-2, 3038
155.ThaxtonJ. E.NeversT. A.SharmaS.2010 TLR-mediated preterm birth in response to pathogenic agents. Infect.Dis.Obstet.Gynecol., 2010, pii: 378472.
156.TheoharidesT. C.2009 Autism spectrum disorders and mastocytosis. Int J Immunopathol Pharmacol, 22, 4, 859865
157.TheoharidesT. C.AngelidouA.AlysandratosK. D.ZhangB.AsadiS.FrancisK.ToniatoE.KalogeromitrosD.2011 Mast cell activation and autism. Biochim.Biophys.Acta, (Dec 23) [Ahead of print].
158.TheoharidesT. C.CochraneD. E.2004 Critical role of mast cells in inflammatory diseases and the effect of acute stress. J Neuroimmunol, 146112
159.TheoharidesT. C.DonelanJ. M.PapadopoulouN.CaoJ.KempurajD.ContiP.2004 Mast cells as targets of corticotropin-releasing factor and related peptides. Trends Pharmacol Sci, 25563568
162.TheoharidesT. C.KalogeromitrosD.2006 The critical role of mast cell in allergy and inflammation. Ann NY Acad Sci, 10887899
163.TheoharidesT. C.KempurajD.IliopoulouB. P.2007a Mast cells, T cells, and inhibition by luteolin: implications for the pathogenesis and treatment of multiple sclerosis. Advances in Experimental Medicine and Biology, 601423430
164.TheoharidesT. C.KempurajD.TagenM.ContiP.KalogeromitrosD.2007b Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol Rev, 2176578
165.TheoharidesT. C.KonstantinidouA.2007 Corticotropin-releasing hormone and the blood-brain-barrier. Front Biosci, 1216151628
166.TheoharidesT. C.ZhangB.KempurajD.TagenM.VasiadiM.AngelidouA.AlysandratosK. D.KalogeromitrosD.AsadiS.StavrianeasN.PetersonE.LeemanS.ContiP.2010 IL-33 augments substance P-induced VEGFsecretion from human mast cells and is increased in psoriatic skin. Proc Natl Acad Sci U S A, 107, 9, 44484453
167.TorigoeC.GoldsteinB.WofsyC.MetzgerH.1997 Shuttling of initiating kinase between discrete aggregates of the high affinity receptor for IgE regulates the cellular response. Proc.Natl.Acad.Sci.U.S.A, 94, 4, 13721377
168.TorrenteF.AshwoodP.DayR.MachadoN.FurlanoR. I.AnthonyA.DaviesS. E.WakefieldA. J.ThomsonM. A.Walker-SmithJ. A.MurchS. H.2002 Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism. Mol.Psychiatry, 7, 4, 375382
169.TorricelliM.NovembriR.BloiseE.De BonisM.ChallisJ. R.PetragliaF.2011 Changes in placental CRH, urocortins, and CRH-receptor mRNA expression associated with preterm delivery and chorioamnionitis. J Clin Endocrinol.Metab, 96, 2, 534540
170.VaradaradjalouS.FegerF.ThieblemontN.HamoudaN. B.PleauJ. M.DyM.ArockM.2003 Toll-like receptor 2 (TLR2) and TLR4 differentially activate human mast cells. Eur J Immunol, 33899906
171.VargasD. L.NascimbeneC.KrishnanC.ZimmermanA. W.PardoC. A.2005 Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann.Neurol., 57, 1, 6781
173.VioraM.QuarantaM. G.StrafaceE.VariR.MasellaR.MalorniW.2001 Redox imbalance and immune functions: opposite effects of oxidized low-density lipoproteins and N-acetylcysteine. Immunology, 104, 4, 431438
174.VojdaniA.CampbellA. W.AnyanwuE.KashanianA.BockK.VojdaniE.2002 Antibodies to neuron-specific antigens in children with autism: possible cross-reaction with encephalitogenic proteins from milk, Chlamydia pneumoniae and Streptococcus group A. J Neuroimmunol., 129, 1-2, 168177
175.VolpeJ. J.2009 The encephalopathy of prematurity--brain injury and impaired brain development inextricably intertwined. Semin.Pediatr Neurol, 16, 4, 167178
176.WarrenW. B.PatrickS. L.GolandR. S.1992 Elevated maternal plasma corticotropin-releasing hormone levels in pregnancies complicated by preterm labor. Am J Obstet Gynecol, 1661198204
178.WeissL. A.ArkingD. E.DalyM. J.ChakravartiA.2009 A genome-wide linkage and association scan reveals novel loci for autism. Nature, 461, 7265, 802808
179.WilkersonD. S.VolpeA. G.DeanR. S.TitusJ. B.2002 Perinatal complications as predictors of infantile autism. Int J Neurosci., 112, 9, 10851098
180.WillsS.CabanlitM.BennettJ.AshwoodP.AmaralD.Van de WaterJ.2007 Autoantibodies in autism spectrum disorders (ASD). Ann.N.Y.Acad.Sci., 11077991
181.WillsS.CabanlitM.BennettJ.AshwoodP.AmaralD. G.Van de WaterJ.2008 Detection of autoantibodies to neural cells of the cerebellum in the plasma of subjects with autism spectrum disorders. Brain Behav.Immun., 236474
182.YasuokaS.KawanokuchiJ.ParajuliB.JinS.DoiY.NodaM.SonobeY.TakeuchiH.MizunoT.SuzumuraA.2011 Production and functions of IL-33 in the central nervous system. Brain Res, 1385, 817
183.YoungH. A.GeierD. A.GeierM. R.2008 Thimerosal exposure in infants and neurodevelopmental disorders: an assessment of computerized medical records in the Vaccine Safety Datalink. J Neurol Sci, 271, 1-2, 110118
184.ZappellaM.2010 Autistic regression with and without EEG abnormalities followed by favourable outcome. Brain Dev., 32, 9, 739745
185.ZhangB.AngelidouA.AlysandratosK. D.VasiadiM.FrancisK.AsadiS.TheoharidesA.Siderik.LykourasL.KalogeromitrosD.TheoharidesT. C.2010 Mitochondrial DNA and anti-mitochondrial antibodies in serum of autistic children. J Neuroinflammation, 7, 1, 80
186.ZhangT. Y.MeaneyM. J.2010 Epigenetics and the environmental regulation of the genome and its function. Annu.Rev Psychol., 614393
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