Immunological characterization and transcription profiling of peripheral blood (PB) monocytes in children with autism spectrum disorders (ASD) and specific polysaccharide antibody deficiency (SPAD): case study.
BACKGROUND
There exists a small subset of children with autism spectrum disorders (ASD) characterized by fluctuating behavioral symptoms and cognitive skills following immune insults. Some of these children also exhibit specific polysaccharide antibody deficiency (SPAD), resulting in frequent infection caused by encapsulated organisms, and they often require supplemental intravenous immunoglobulin (IVIG) (ASD/SPAD). This study assessed whether these ASD/SPAD children have distinct immunological findings in comparison with ASD/non-SPAD or non-ASD/SPAD children.


METHODS
We describe 8 ASD/SPAD children with worsening behavioral symptoms/cognitive skills that are triggered by immune insults. These ASD/SPAD children exhibited delayed type food allergy (5/8), treatment-resistant seizure disorders (4/8), and chronic gastrointestinal (GI) symptoms (5/8) at high frequencies. Control subjects included ASD children without SPAD (N = 39), normal controls (N = 37), and non-ASD children with SPAD (N = 12).


RESULTS
We assessed their innate and adaptive immune responses, by measuring the production of pro-inflammatory and counter-regulatory cytokines by peripheral blood mononuclear cells (PBMCs) in responses to agonists of toll like receptors (TLR), stimuli of innate immunity, and T cell stimulants. Transcription profiling of PB monocytes was also assessed. ASD/SPAD PBMCs produced less proinflammatory cytokines with agonists of TLR7/8 (IL-6, IL-23), TLR2/6 (IL-6), TLR4 (IL-12p40), and without stimuli (IL-1ß, IL-6, and TNF-α) than normal controls. In addition, cytokine production of ASD/SPAD PBMCs in response to T cell mitogens (IFN-γ, IL-17, and IL-12p40) and candida antigen (Ag) (IL-10, IL-12p40) were less than normal controls. ASD/non-SPAD PBMDs revealed similar results as normal controls, while non-ASD/SPAD PBMCs revealed lower production of IL-6, IL-10 and IL-23 with a TLR4 agonist. Only common features observed between ASD/SPAD and non-ASD/SPAD children is lower IL-10 production in the absence of stimuli. Transcription profiling of PB monocytes revealed over a 2-fold up (830 and 1250) and down (653 and 1235) regulation of genes in ASD/SPAD children, as compared to normal (N = 26) and ASD/non-SPAD (N = 29) controls, respectively. Enriched gene expression of TGFBR (p < 0.005), Notch (p < 0.01), and EGFR1 (p < 0.02) pathways was found in the ASD/SPAD monocytes as compared to ASD/non-SPAD controls.


CONCLUSIONS
The Immunological findings in the ASD/SPAD children who exhibit fluctuating behavioral symptoms and cognitive skills cannot be solely attributed to SPAD. Instead, these findings may be more specific for ASD/SPAD children with the above-described clinical characteristics, indicating a possible role of these immune abnormalities in their neuropsychiatric symptoms.
Division of Allergy/Immunology and Infectious Diseases, Department of pediatrics, UMDN-NJMS, 185 South Orange Ave, Newark, NJ 07101-1709, USA. jyanouha@umdnj.edu
Harumi
H
Jyonouchi
Lee
L
Geng
Deanna L
DL
Streck
Gokce A
GA
Toruner
D000293:Adolescent; D000906:Antibodies / Q000097:blood*; D002478:Cells, Cultured; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000097:blood* / Q000276:immunology*; D002675:Child, Preschool; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology; D011134:Polysaccharides / Q000276:immunology*; D011569:Psychiatric Status Rating Scales; D011804:Quinolines / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015054:Zymosan / Q000494:pharmacology
D000906:Antibodies; C547051:CL097 compound; D016207:Cytokines; D007093:Imidazoles; D008070:Lipopolysaccharides; D011134:Polysaccharides; D011804:Quinolines; D014157:Transcription Factors; C036757:lipopolysaccharide B; D003208:Concanavalin A; D015054:Zymosan; D011070:Poly I-C