Neonatal chemokine levels and risk of autism spectrum disorders: Findings from a Danish historic birth cohort follow-up study
Highlights
► Neonatal levels of three inflammatory chemokines (MCP-1, MIP-1α and RANTES) were analyzed in ASD and controls. ► Non-adjusted estimates showed decreased levels of RANTES in ASD. ► Adjusted estimates showed no differences in levels of MCP-1, MIP-1α or RANTES in ASD and controls. ► Dysfunctional cell-mediated immunity may be present during neonatal period in ASD. ► Chemokines may play a timing-specific role in ASD.
Introduction
Autism spectrum disorders (ASDs) are complex group of neurodevelopmental disorders, behaviorally defined and characterized by qualitative impairments in social interaction, communication and stereotyped behavior [1]. Several epidemiological studies have indicated a distinct trend of increasing ASD prevalence rates [2], [3], [4]. Whilst some recent reports showed strikingly high prevalence estimates up to 2.6% [3], the most recent estimate is calculated to be around 1.1% [5]. The numbers from Denmark show a parallel trend as well, with recent estimates ranging from 62 to 82 per 10,000 [6].
The pathophysiology of ASD is complex with both genetic and environmental components [1]. Currently, the most optimistic estimates of identified genetic causes for ASD are at about 30% of the total ASD cases [7]. While these causes can be grouped into cytogenetically visible chromosomal abnormalities, copy number variants, and single-gene disorders, surprisingly, none of the individual causes accounts for more than 1–2% of ASD cases [8]. Furthermore, a recent large-scale twin study suggested that although genetic factors may play an important role in the etiology of ASD, their magnitude may be lower than the earlier estimates, what emphasizes the importance of environmental factors [9].
Mounting evidence has suggested a pivotal role of immune dysfunction in ASD [10]. Both neuroinflammatory changes and dysfunctional peripheral immune responses have been repeatedly reported in individuals with ASD [10]. However, convergence toward a unified immunologic pathway is still lacking.
Current evidence suggests an important role of cytokines on the neurodevelopmental trajectory in autistic offspring [11]. However, identifying which specific cytokines may play the pivotal role in the development of ASD is not an easy task [12]. According to Dammann and O’Shea [12], the complexity in identifying specific cytokines in charge of perinatal brain damage is mainly due to the biology of the cytokines themselves, where there is a high degree of overlap in their functions, their target cells and their sources of secretion.
Chemokines represent a family of cytokines with a diverse range of physiological and pathological functions including immune system development, inflammation and cancer metastasis [13]. A potential role of chemokines in ASD has been suggested and discrepant levels of chemokines (from different biologic samples like brain tissue, cerebrospinal fluid, plasma and amniotic fluid) were also found associated with the disease and several behavioral impairments in individuals diagnosed with ASD [14], [15].
The aim of this study was to examine levels of chemokines during early neonatal period through utilizing biologic materials from a national screening program in Denmark along with data retrieved from nation-wide health registers.
Section snippets
Materials and methods
In this study, levels of three selected inflammatory chemokines (Monocyte Chemotactic Protein-1 [MCP-1], Macrophage Inflammatory Protein-1α [MIP-1α] and Regulated upon Activation Normal T-Cell Expressed and Secreted [RANTES]) were examined in neonatal dried blood spot samples (n-DBSS). For this purpose, a 1:2 case control study design was adopted. Both cases and controls were retrieved from a historic birth cohort based on second trimester amniotic fluid sample collection (mostly around the
Results
A total of 359 ASD cases and 741 frequency-matched controls in the HBC had a corresponding n-DBSS in the DNSB, and therefore were included in the study. ASD cases encompassed 82 cases of infantile autism, 105 cases of Asperger Syndrome, 14 cases of Atypical Autism and 158 other ASD cases; median age of ASD diagnosis (defined by the first admission date registered in the Danish Psychiatric Central Register) ranged from 6.37 years in infantile autism cases to 10.94 years in atypical autism. ASD
Discussion
Differential levels of chemokines have been previously reported in ASD individuals which may indicate a potential role of this group of cytokines in the pathophysiology of ASD [10]. In this study we examined levels of three inflammatory chemokines (MCP-1, MIP1-α, and RANTES) measured in neonatal dried blood spot samples. Our unadjusted findings suggested that decreased levels of RANTES were associated developing ASD later in life. In our adjusted estimates, no significant differences were found
Acknowledgements
The authors thank Lasse S. Jønsson and Jørn Riis from Statens Serum Institute (SSI) and Maria Pryds for their assistance in data retrieval and also Vibeke Munk from University of Copenhagen for her administrative assistance. We also thank Dr. Poul Thorsen for his input and SSI Luminex Lab technical staff for their time and efforts. The Danish Historic Birth Cohort was established at Statens Serum Institute in Copenhagen with a grant from The Danish Medical Research Foundation and The Danish
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