Elsevier

Cytokine

Volume 61, Issue 2, February 2013, Pages 370-376
Cytokine

Neonatal chemokine levels and risk of autism spectrum disorders: Findings from a Danish historic birth cohort follow-up study

https://doi.org/10.1016/j.cyto.2012.11.015Get rights and content

Abstract

A potential role of chemokines in the pathophysiology of Autism Spectrum Disorders (ASDs) has been previously suggested. In a recent study we examined levels of three inflammatory chemokines (MCP-1, MIP-1α and RANTES) in samples of amniotic fluid of children diagnosed later in life with ASD and controls frequency-matched to cases on gender and year of birth. In this follow-up study, levels of the same chemokines were analyzed postnatally in dried blood spot samples from the same subjects utilizing the Danish Newborn Screening Biobank. Crude estimates showed decreased levels of RANTES. In the adjusted estimates, no differences were found in levels of the three examined chemokines in ASD cases compared to controls. Our findings may cautiously suggest an altered cell-mediated immunity during the early neonatal period in ASD. Further research is needed to examine the relationship between maternal/fetal and neonatal chemokine levels and their role in ASD.

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

References (44)

  • Y.S. Kim et al.

    Prevalence of autism spectrum disorders in a total population sample

    Am J Psychiatr

    (2011)
  • Rice C. Prevalence of Autism Spectrum Disorders: Autism and Developmental Disabilities Monitoring Network, Six Sites,...
  • Jon Baio. Prevalence of Autism Spectrum Disorders – Autism and Developmental Disabilities Monitoring Network, 14 Sites,...
  • E.T. Parner et al.

    Autism prevalence trends over time in Denmark: changes in prevalence and age at diagnosis

    Arch Pediatr Adolescent Med

    (2008)
  • B.S. Abrahams et al.

    Advances in autism genetics: on the threshold of a new neurobiology

    Nat Rev Genet

    (2008)
  • J. Hallmayer et al.

    Genetic heritability and shared environmental factors among twin pairs with autism

    Arch Gen Psychiatr

    (2011)
  • C. Onore et al.

    The role of immune dysfunction in the pathophysiology of autism

    Brain, Behav, Immun

    (2011)
  • I. Comerford et al.

    Mini-review series: focus on chemokines

    Immunol Cell Biol

    (2011)
  • M.W. Abdallah et al.

    Psychiatric comorbidities in autism spectrum disorders: findings from a Danish Historic Birth Cohort

    Eur Child Adolescence Psychiatr

    (2011)
  • P. Munk-Jorgensen et al.

    The Danish Psychiatric Central Register

    Danish Med Bull

    (1997)
  • T.F. Andersen et al.

    The Danish National Hospital Register. a valuable source of data for modern health sciences

    Danish Med Bull

    (1999)
  • L. Knudsen et al.

    The Danish Medical Birth Registry

    Danish Med Bull

    (1998)
  • Cited by (49)

    • Maternal Immune Activation Hypotheses for Human Neurodevelopment: Some Outstanding Questions

      2022, Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
    • Maternal immune dysregulation and autism spectrum disorder

      2022, Neural Engineering Techniques for Autism Spectrum Disorder: Volume 2: Diagnosis and Clinical Analysis
    • The progress of chemokines and chemokine receptors in autism spectrum disorders

      2021, Brain Research Bulletin
      Citation Excerpt :

      The higher level of CCL5 in peripheral blood and plasma might be linked to neuroinflammation and aberrations in the complement system while the conflicting results of the relationship between the CCL5 level and behavior patterns in ASD might be related to the different assessment methods adopted by these studies. The study by Abdallah et al. also revealed that based on the crude estimates, the decreased neonatal level of CCL5 was correlated to a higher risk of ASD, which might be a consequence of the low activities of immune cells during the neonatal time in ASD (Abdallah et al., 2013). Moreover, Abdallah et al. found that there was no significant difference in the CSF level of CCL5 in ASD groups compared to controls (Abdallah et al., 2012), indicating little connection between CCL5 and maternal infection relevant to ASD.

    • Methylmercury chloride exposure aggravates proinflammatory mediators and Notch-1 signaling in CD14<sup>+</sup> and CD40<sup>+</sup> cells and is associated with imbalance of neuroimmune function in BTBR T<sup>+</sup> Itpr3tf/J mice

      2021, NeuroToxicology
      Citation Excerpt :

      For example, studies have found that immune anomalies, including increased production of proinflammatory factors have been widely observed in the brain and periphery of individuals with ASD (Ashwood et al., 2006; Korvatska et al., 2002). In addition, elevated levels of chemokines and cytokines are involved in behavioral outcomes in ASD (Li et al., 2009; Abdallah et al., 2013). Previously, we observed that alterations of Th1, Th2, Th17, and regulatory T cell-related transcription factor signaling plays a critical role in autistic children and BTBR mice (Ahmad et al., 2017a; Bakheet et al., 2017).

    View all citing articles on Scopus
    View full text