Autism Spectrum Disorder Inflammatory Subtype: Biomarker Analysis

Short Title

Saint Peter's University Hospital

Project Description

This study is designed to assess utility of candidate biomarkers identified by our previous research for underlying innate immune abnormalities and their possible link to mitochondrial dysfunction.

  Many children diagnosed with autism spectrum disorder (ASD) have additional medical conditions that affect other organs, not just the brain. In these ASD children, symptoms involving multiple organs may serve as a marker that can hold the key to understanding the complex medical conditions found in these children.  If we focus on ASD subjects who display easily appreciable clinical symptoms, we will gain a better understanding of these ASD children. 

  Based on this concept, in our previous study funded by the Governor’s Council, we categorized ASD children with clinical features of noticeably fluctuating behavioral symptoms appears to be affected by each immune insult (typically viral/bacterial infection) along with ASD and non-ASD control subjects.  

 

  Our results revealed altered production of inflammatory and counter-regulatory (suppressive) cytokines in some but not all ASD subjects. Most notably changes were found in production of cytokines called IL-1ß, an inflammatory cytokine, and IL-10, a counter-regulatory cytokine.  These results are most easily observed if expressed as ratios of IL-1ß/IL-10 produced by peripheral blood monocytes (PB Mo) in cultures. ASD subjects with fluctuating IL-1ß/IL-10 ratios revealed a high IL-1ß/IL-10 ratios following microbial infection.  ASD subjects with fluctuating IL-1ß/IL-10 ratios produced by PB Mo had a tendency to have severe delayed type food allergy, and poor responses to the 1st line behavioral and pharmacological interventions. We also found that behavioral symptoms are affected by multiple environmental factors and it is hard to utilize behavioral symptoms for assessing underlying innate immune abnormalities.

 

  We then analyzed expression of microRNA (miRNA) by PB Mo obtained from all the ASD subjects and divided them into 3 groups, ASD cells with higher IL-1ß/IL-10 ratios, lower IL-1ß/IL-10 ratios, or equivalent IL-1ß/IL-10 ratios as compared normal control cells.  We found marked down-regulation of miRNAs in cells with lower IL-1ß/IL-10 ratios, which seems to be lost in cells with higher IL-1ß/IL-10 ratios.  These results indicate that activation of the innate immune system may cause loss of immune-regulation imposed by miRNAs in some ASD PB Mo.  Our preliminary results also indicate a positive association between IL-1ß production by PB Mo and mitochondrial function of peripheral blood mononuclear cells (PBMCs, a mixture of various immune cells). 

 

In this study, we hypothesize:

1) Altered monocyte functions detected by changes in cytokine production and miRNA expression can be biomarkers for ASD subjects suffering from underlying immune abnormalities.  We estimate that such subjects may be found in up to 30% of ASD subjects.  

2) These parameters are positively associated with mitochondrial functions of peripheral blood immune cells, i.e., PBMCs and possibly miRNA levels in the serum.  

 

The long term objective of this study is to assess how these biomarkers are helpful for assessing underlying immune abnormalities of monocytes in association with the onset and progress of ASD.

 

The expected outcome will be a better understanding of a possible link between variable immune abnormalities and mitochondrial dysfunction in ASD children, as well as obtainment of information on how the above described biomarkers are useful for assessing clinical outcomes and responses to 1st line interventions.  In addition, our results may also lead to new treatment measures, such as application of medications that reduce the effects of immune abnormalities found in such ASD children.

 

This study is conducted in collaboration with researchers at Institute of Genomic Medicine (IGM), Rutgers-NJMS and those at Arkansas Children's Hospital Research Institute (ACHRI).  Dr. James Dermody (IGM) and Dr. Richard Frye (ACHRI) serve as Co-Principal Investigators in this study. 


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Doctors Jyonouchi (standing) and Lee (seated)

Team Members

Harumi Jyonouchi
Principal Investigator
hjyonouchi@saintpetersuh.com

Lee Geng
Research Associate
leelgeng@yahoo.com

Marc Huguenin
IT/Data Management
marcandlisa.huguenin@gmail.com

Ryan Mendoza
Research Assistant
mendoza2275@gmail.com

Steve Buyske
Biostatistician
buyske@sta.rutgers.edu

Sharwani Kota
Research Assistant
Sharwani.kota@gmail.com

Lisa Huguenin
Research Assistant
marandlisa.huguenin@gmail.com

Pamela Kattouf
Research Assistant
pamelatk@aol.com

Contact Info

hjyonouchi@saintpetersuh.com
(732) 339-7780
254 Easton Avenue, 3rd Floor MOB
New Brunswick, NJ 08901

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