Decreased transforming growth factor beta1 in autism: A potential link between immune dysregulation and impairment in clinical behavioral outcomes

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Abstract

Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. There is evidence of both immune dysregulation and autoimmune phenomena in autism. We examined the regulatory cytokine transforming growth factor beta-1 (TGFβ1) because of its role in controlling immune responses. Plasma levels of active TGFβ1 were evaluated in 75 children with ASD compared with 68 controls. Children with ASD had significantly lower plasma TGFβ1 levels compared with typically developing controls (p = 0.0017) and compared with children with developmental disabilities other than ASD (p = 0.0037), after adjusting for age and gender. In addition, there were significant correlations between psychological measures and TGFβ1 levels, such that lower TGFβ1 levels were associated with lower adaptive behaviors and worse behavioral symptoms. The data suggest that immune responses in autism may be inappropriately regulated due to reductions in TGFβ1. Such immune dysregulation may predispose to the development of possible autoimmune responses and/or adverse neuroimmune interactions during critical windows in development.

Introduction

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders that are distinguished by qualitative impairments in social interaction, deficits in verbal and non-verbal communication, and restricted repetitive and stereotyped patterns of behavior and interests (Filipek et al., 2000, Lord et al., 2000). There is growing evidence that an abnormal immune response may exert a negative influence on neurodevelopment, potentially contributing to the etiology of some cases of ASD. Alterations in appropriate regulation of the immune response may result in chronic inflammation, autoimmunity, or an inappropriate response to immune challenge in children with ASD (reviewed in Ashwood et al., 2006a). Furthermore, abnormally regulated immune responses could potentially cause inflammation of the CNS or brain leading to altered neurodevelopment.

Systemic immunologic aberrations in autism have often been associated with immune dysregulation, in particular, the generation of antibodies reactive against brain and CNS proteins (Ashwood et al., 2004, Cabanlit et al., 2007, Connolly et al., 1999, Connolly et al., 2006, Kozlovskaia et al., 2000, Singh et al., 1993, Singh et al., 1997a, Singh et al., 1997b, Singh et al., 2002, Singh and Rivas, 2004, Todd et al., 1988, Wills et al., 2007). Indeed, autoantibodies to critical neuronal components have been reported in as many as 25–70% of individuals with autism (Connolly et al., 1999, Connolly et al., 2006, Singh et al., 2002, Singh and Rivas, 2004, Todd et al., 1988). However, it must be noted that it is not currently known whether these antibodies are a cause of autism or generated as a result of inflammation in the brain and CNS. Many genetic studies have indicated a link between autism and genes that have immune functions, including complement C4 alleles, MHC haplotypes B44-SC30-DR4, human leukocyte antigen (HLA)-DRB1, and DR13 (Ferrante et al., 2003, Torres et al., 2001, Warren et al., 1991, Warren et al., 1996). Moreover, several studies have shown immune abnormalities in patients with autism including abnormal or skewed T helper cell cytokine profiles, decreased lymphocyte numbers, decreased T cell mitogen response, and an imbalance of serum immunoglobulin levels (reviewed in Ashwood et al., 2006a). Of particular note, Vargas et al., recently described increased neuroinflammation in brain and CNS specimens obtained from subjects with ASD (Vargas et al., 2005). In addition, gene expression profiles in the temporal cortex of autistic subjects show increased transcript levels of many immune system-related genes when compared with matched controls (Garbett et al., 2008). Taken together these data are suggestive of the presence of ongoing neuroinflammatory processes in the brain and CSF, as well as indicative of widespread changes in the peripheral immune response of at least a significant proportion of children with ASD. We propose that the disturbances in immune function that have been reported in autism stem from deficits and defects in the regulatory immune system controlling the overall immune response.

Regulatory responses by the immune system are essential for the maintenance of tolerance to self-antigen and to innocuous non-harmful substances such as food nutrients. The regulatory immune response is also critical in the down-regulation of the inflammatory immune response following infection, thus limiting potential tissue damage. Immunosuppressive cytokines such as transforming growth factor beta1 (TGFβ1) are critical for immune homeostasis, and are important in the induction of unresponsiveness in activated T cells (den Haan et al., 2007, Marra et al., 2004, Sonoda et al., 2001). Although, published findings support widespread changes in the immune systems of at least a significant proportion of children with autism, the exact nature of this immune dysfunction is not yet fully characterized. Reports of increased expression of TH1 cytokines (Croonenberghs et al., 2002, Molloy et al., 2006, Singh, 1996, Vargas et al., 2005), acute inflammatory cytokines (Croonenberghs et al., 2002, Singh, 1996, Vargas et al., 2005, Zimmerman et al., 2005), and TH2 cytokines (Molloy et al., 2006, Gupta et al., 1998) in autism do not implicate a specific inflammatory profile but instead suggest that a loss of regulation in the immune response may have occurred.

One of the most important immune regulators that can effectively control diverse aspects of the immune response is TGFβ1. In the autism literature, there are several studies that demonstrate an alteration or dysregulation of immune responses in autism compared with matched controls (Ashwood et al., 2004, Ashwood and Wakefield, 2006b, Cohly and Panja, 2005, Jyonouchi et al., 2005). In addition, altered TGFβ1 levels have been observed in brain specimens of subjects with autism (Vargas et al., 2005). Although one recent study revealed decreased plasma TGFβ1 in adults with autism (Okada et al., 2007), thus far we are unaware of any studies addressing the levels of TGFβ1 in children with autism, close to the time of their diagnosis, and compared with age-matched control children. To better define the immune status of children with ASD, we utilized a large population based study of well-characterized children with confirmed ASD and age-matched controls, with and without developmental disabilities, to examine whether circulating active TGFβ1 differed between groups. If a defect in the immune regulatory function were confirmed, such a finding would contribute to the understanding of the role of the immune system in autism, and could potentially offer a new diagnostic or treatment target.

Section snippets

Subjects

Participants in the study were recruited from the case-control population based CHARGE (Childhood Autism Risk from Genetics and Environment) study conducted at the UC Davis M.I.N.D. Institute (Hertz-Picciotto et al., 2006). One hundred and forty-three (143) children were investigated in this study. Participants met one of the following 3 criteria: 1) diagnosed with an autism spectrum disorder (ASD); 2) diagnosed with developmental disability but not ASD; or 3) controls from the general

Results

Plasma TGFβ1 levels were significantly lower in children with ASD compared with typically developing general population controls (median = 11.54, interquartile range (6.73–17.84) ng/ml versus 16.16 (11.97–22.32) ng/ml, p = 0.0017) or compared with children having other developmental disabilities (15.34 (11.41–25.71) ng/ml, p = 0.0037). Individual results are represented in Fig. 1. Indeed, the combined group of non-ASD controls (i.e. children with developmental disabilities or typical controls, 15.43

Discussion

The current study describes a significant decrease in plasma TGFβ1 levels in children with ASD when compared with typically developing controls and children with developmental disabilities in cognitive or adaptive function but who do not have ASD. Low TGFβ1 levels may lead to an inappropriate control of the immune response in these children. While Okada et al., recently published a similar finding of reduced TGFβ1 in a small cohort of 19 adults with autism compared with 21 healthy male controls

Acknowledgements

This study was funded by the NIEHS Children's Center grant (2 P01 ES011269), US EPA STAR program grant (R833292 and R829388), NIEHS CHARGE study (R01ES015359) Cure Autism Now, the Ted Lindsay Foundation, Visceral, Peter Emch Foundation and a generous gift from the Johnson Family. We would like to thank the staff of both the UC Davis M.I.N.D Institute and the CHARGE study for their technical support. The commitment of the families who took part in these studies, at both the M.I.N.D. Institute

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