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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.

Jyonouchi H, Geng L, Streck DL, Toruner GA - J Neuroinflammation (2012)

Bottom Line: 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).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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Allergy/Immunology and Infectious Diseases, Department of pediatrics, UMDN-NJMS, 185 South Orange Ave, Newark, NJ 07101-1709, USA. jyanouha@umdnj.edu

ABSTRACT

Introduction: 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.

Case description: 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).

Discussion and evaluation: 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.

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Cytokine production by PBMCs from ASD/SPAD, normal control, ASD/non-SPAD and non-ASD/SPAD children when stimulated by TLR agonists. IL-12p40/IL-10 production with TLR4 agonist (LPS) (Panel A), IL-6 production with TLR2/6 and 7/8 agonists or without a stimulus (Panel B), spontaneous production of TNF-α, IL-1ß, and IL-10 as well as IL-23 production with TLR4 and 7/8 agonists (Panel C), and IL-6 production with TLR4 agonist (Panel D) was shown. PBMCs (106 cells/ml) were incubated with TLR agonists as indicated overnight and cytokine levels in the culture supernatant were measured by ELISA. In Figs 1-2, the results of cytokine production with stimuli shown were those corrected by subtracting the levels of cytokines produced without a stimulus. *; lower than all the study groups (p < 0.05).
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Figure 1: Cytokine production by PBMCs from ASD/SPAD, normal control, ASD/non-SPAD and non-ASD/SPAD children when stimulated by TLR agonists. IL-12p40/IL-10 production with TLR4 agonist (LPS) (Panel A), IL-6 production with TLR2/6 and 7/8 agonists or without a stimulus (Panel B), spontaneous production of TNF-α, IL-1ß, and IL-10 as well as IL-23 production with TLR4 and 7/8 agonists (Panel C), and IL-6 production with TLR4 agonist (Panel D) was shown. PBMCs (106 cells/ml) were incubated with TLR agonists as indicated overnight and cytokine levels in the culture supernatant were measured by ELISA. In Figs 1-2, the results of cytokine production with stimuli shown were those corrected by subtracting the levels of cytokines produced without a stimulus. *; lower than all the study groups (p < 0.05).

Mentions: ASD/SPAD PBMCs produced different patterns of cytokine production. Namely, ASD/SPAD PBMCs produced lower amounts of IL-6 (without a stimulus and with TLR2/6 agonists), IL-1ß (without a stimulus), and IL-23 (with TLR 7/8 agonist) as compared to all the control groups (Figure 1 A, B, C). In, addition, ASD/SPAD PBMCs produced less IL-12p40 than normal and non-ASD/SPAD control cells in response to a TLR4 agonist (Figure 1-A). These cells also produced lower amounts of IL-6 (with the TLR 7/8 agonist) and TNF-α/IL-10 (in the absence of stimulus) than normal controls (Figure 1-B). PBMCs from ASD/non-SPAD children revealed similar patterns of cytokine production as compared to normal controls (Figure 1). In contrast, non-ASD/SPAD PBMCs revealed altered patterns of cytokine production which did not resemble those observed in ASD/SPAD children. That is, non-ASD/SPAD PBMC revealed lower IL-10 production than ASD/SPAD and normal control cells (Figure 1-A) and lower IL-6/IL-23 production than normal controls (Figure 1-C, D) in response to a TLR4 agonist. The only common feature observed between the ASD/SPAD and non-ASD/SPAD groups was production of lower levels of IL-10 in the absence of a stimulus, than normal controls (Figure 1-C). These results indicate that the altered responses to TLR agonists observed in the ASD/SPAD group are unlikely to be associated with SPAD.


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.

Jyonouchi H, Geng L, Streck DL, Toruner GA - J Neuroinflammation (2012)

Cytokine production by PBMCs from ASD/SPAD, normal control, ASD/non-SPAD and non-ASD/SPAD children when stimulated by TLR agonists. IL-12p40/IL-10 production with TLR4 agonist (LPS) (Panel A), IL-6 production with TLR2/6 and 7/8 agonists or without a stimulus (Panel B), spontaneous production of TNF-α, IL-1ß, and IL-10 as well as IL-23 production with TLR4 and 7/8 agonists (Panel C), and IL-6 production with TLR4 agonist (Panel D) was shown. PBMCs (106 cells/ml) were incubated with TLR agonists as indicated overnight and cytokine levels in the culture supernatant were measured by ELISA. In Figs 1-2, the results of cytokine production with stimuli shown were those corrected by subtracting the levels of cytokines produced without a stimulus. *; lower than all the study groups (p < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3275444&req=5

Figure 1: Cytokine production by PBMCs from ASD/SPAD, normal control, ASD/non-SPAD and non-ASD/SPAD children when stimulated by TLR agonists. IL-12p40/IL-10 production with TLR4 agonist (LPS) (Panel A), IL-6 production with TLR2/6 and 7/8 agonists or without a stimulus (Panel B), spontaneous production of TNF-α, IL-1ß, and IL-10 as well as IL-23 production with TLR4 and 7/8 agonists (Panel C), and IL-6 production with TLR4 agonist (Panel D) was shown. PBMCs (106 cells/ml) were incubated with TLR agonists as indicated overnight and cytokine levels in the culture supernatant were measured by ELISA. In Figs 1-2, the results of cytokine production with stimuli shown were those corrected by subtracting the levels of cytokines produced without a stimulus. *; lower than all the study groups (p < 0.05).
Mentions: ASD/SPAD PBMCs produced different patterns of cytokine production. Namely, ASD/SPAD PBMCs produced lower amounts of IL-6 (without a stimulus and with TLR2/6 agonists), IL-1ß (without a stimulus), and IL-23 (with TLR 7/8 agonist) as compared to all the control groups (Figure 1 A, B, C). In, addition, ASD/SPAD PBMCs produced less IL-12p40 than normal and non-ASD/SPAD control cells in response to a TLR4 agonist (Figure 1-A). These cells also produced lower amounts of IL-6 (with the TLR 7/8 agonist) and TNF-α/IL-10 (in the absence of stimulus) than normal controls (Figure 1-B). PBMCs from ASD/non-SPAD children revealed similar patterns of cytokine production as compared to normal controls (Figure 1). In contrast, non-ASD/SPAD PBMCs revealed altered patterns of cytokine production which did not resemble those observed in ASD/SPAD children. That is, non-ASD/SPAD PBMC revealed lower IL-10 production than ASD/SPAD and normal control cells (Figure 1-A) and lower IL-6/IL-23 production than normal controls (Figure 1-C, D) in response to a TLR4 agonist. The only common feature observed between the ASD/SPAD and non-ASD/SPAD groups was production of lower levels of IL-10 in the absence of a stimulus, than normal controls (Figure 1-C). These results indicate that the altered responses to TLR agonists observed in the ASD/SPAD group are unlikely to be associated with SPAD.

Bottom Line: 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).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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Allergy/Immunology and Infectious Diseases, Department of pediatrics, UMDN-NJMS, 185 South Orange Ave, Newark, NJ 07101-1709, USA. jyanouha@umdnj.edu

ABSTRACT

Introduction: 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.

Case description: 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).

Discussion and evaluation: 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.

Show MeSH
Related in: MedlinePlus