Abstract
IntroductionThere 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 descriptionWe 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 EvaluationWe 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.ConclusionsThe 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.
Highlights
There exists a small subset of children with autism spectrum disorders (ASD) characterized by fluctuating behavioral symptoms and cognitive skills following immune insults
The Immunological findings in the ASD/specific polysaccharide antibody deficiency (SPAD) children who exhibit fluctuating behavioral symptoms and cognitive skills cannot be solely attributed to SPAD
Among this subset of ASD children, designated as the ASD-test group in the previous study, we found a high frequency of immunodeficiency, requiring treatment of intravenous immunoglobulin (IVIG) [8]
Summary
Clinical features of infection found in ASD/SPAD children are similar to those found in non-ASD/SPAD children and all of the ASD/SPAD children suffered from frequent sinopulmonary infection (Table 2) [17]. No subjects in the normal control and ASD/non-SPAD groups suffered from seizure disorders As noted previously, these ASD/SPAD subjects are those with markedly worsening behavioral symptoms/cognitive skills following each immune insult [8]. 5 of 8 ASD/SPAD children had chronic GI inflammation often complicated by dysbiosis and/or candida enteritis with evidence of positive reactivity to candida antigen when assessed by production of IFN-g and IL-17A production at the time of flare up These children frequently required treatments with oral anti-fungal medications. The results of transcription profiling of PB monocytes revealed enriched expression of genes in TGFBR (TGF-b receptor), NOTCH, and EGFR (epidermal growth factor receptor) signaling pathways in ASD/ SPAD children, as compared to ASD/non-SPAD controls. These results again indicate that the immune abnormalities observed in ASD/SPAD children with fluctuating behavioral symptoms/cognitive skills are not solely attributed to SPAD
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