Persistence of dysfunctional natural killer cells in adults with high-functioning autism spectrum disorders: stigma/consequence of unresolved early infectious events?

Abstract

Background Autism spectrum disorders (ASD) are characterized by abnormal neurodevelopment, genetic, and environmental risk factors, as well as immune dysfunctions. Several lines of evidence suggest alterations in innate immune responses in children with ASD. To address this question in adults with high-functioning ASD (hf-ASD), we sought to investigate the role of natural killer (NK) cells in the persistence of ASD. Methods NK cells from 35 adults with hf-ASD were compared to that of 35 healthy controls (HC), selected for the absence of any immune dysfunctions, at different time-points, and over a 2-year follow-up period for four patients. The phenotype and polyfunctional capacities of NK cells were explored according to infectious stigma and clinical parameters (IQ, social, and communication scores). Results As compared to HC, NK cells from patients with hf-ASD showed a high level of cell activation ( p < 0.0001), spontaneous degranulation ( p < 0.0001), and interferon-gamma production ( p = 0.0004), whereas they were exhausted after in vitro stimulations ( p = 0.0006). These data yielded a specific HLA-DR + KIR2DL1 + NKG2C + NK-cell signature. Significant overexpression of NKG2C in hf-ASD patients ( p = 0.0005), indicative of viral infections, was inversely correlated with the NKp46 receptor level ( r = − 0.67; p < 0.0001), regardless of the IgG status of tested pathogens. Multivariate linear regression analysis also revealed that expression of the late-activating HLA-DR marker was both associated with structural language ( r = 0.48; p = 0.007) and social awareness ( r = 0.60; p = 0.0007) scores in adult patients with hf-ASD, while KIR2DL1 expression correlated with IQ scores ( p = 0.0083). Conclusions This study demonstrates that adults with hf-ASD have specific NK-cell profile. Presence of NKG2C overexpression together with high-level activation of NK cells suggest an association with underlying pathogens, a hypothesis warranting further exploration in future studies. Electronic supplementary material The online version of this article (10.1186/s13229-019-0269-1) contains supplementary material, which is available to authorized users.

Preeclampsia Drives Molecular Networks to Shift Toward Greater Vulnerability to the Development of Autism Spectrum Disorder

“…In turn, these membrane molecules activate other molecular players previously implicated in ASD, such as ion transport pumps (29), and affect the release of nitric oxide (30). Importantly, all three of these membrane proteins promote the activity of interferon-gamma, which has been suggested to associate with increased oxidative stress in ASD (31), and also being produced at substantially elevated steady-state levels by natural killer (NK) cells of high-functioning adult individuals with ASD (32). Additional information regarding the activation of the IFNG pathway is provided in ASD_PE→RPS4Y1_Pathway.…”

Distinct immunopathological mechanisms of EBV-positive and EBV-negative posttransplant lymphoproliferative disorders

“…NK‐cell phenotypes including differentiation (CD56, CD16, CD57), expression of c‐lectin (NKG2A, NKG2C), natural cytotoxicity (NKp30, NKp46) and killer immunoglobulin receptors (Kir2DL2/3, Kir3DL1), immune‐checkpoints (PD‐1, Tim‐3) and apoptosis markers (caspase‐3, FAS), were assessed in thawed PBMCs. For NK‐cell functional assays, 26 PBMCs were incubated overnight at 37°C, 5% CO 2 with or without IL‐12 (10 ng/mL) and IL‐18 (100 ng/mL; RD systems), then stained with anti‐CD107a‐FITC (BD Biosciences) and incubated for 6 hours with media or K562 targets (E:T ratio of 1:1). After 1‐hour incubation, BD GolgiStop/GolgiPlug were added according to manufacturer instructions (BD Biosciences).…”

The pathogenesis of autism spectrum disorder

“…The profile HLA-DR + KIR2DL1 + NKG2C + NK-cell was observed in ASD patients. This overexpression of NKG2C is indicative of viral infections, and it was inversely correlated with the NKp46 receptor level 28 . On the other hand, NK cells are activated by the interaction between killer-cell immune globulin-like receptor (KIR) and the HLA ligands.…”

“…In high-functioning ASD adult patients, a high level of NK cell activation has been observed with spontaneous degranulation and interferon-gamma production when compared with healthy controls, whereas these cells become exhausted after in vitro stimulations 28 . The profile HLA-DR + KIR2DL1 + NKG2C + NK-cell was observed in ASD patients.…”