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Variations in Mitochondrial Respiration Differ in IL-1ß/IL-10 Ratio Based Subgroups in Autism Spectrum Disorders.

ABSTRACT: Autism spectrum disorder (ASD)7 is associated with multiple physiological abnormalities, including immune dysregulation, and mitochondrial dysfunction. However, an association between these two commonly reported abnormalities in ASD has not been studied in depth. This study assessed the association between previously identified alterations in cytokine profiles by ASD peripheral blood monocytes (PBMo) and mitochondrial dysfunction. In 112 ASD and 38 non-ASD subjects, cytokine production was assessed by culturing purified PBMo overnight with stimuli of innate immunity. Parameters of mitochondrial respiration including proton-leak respiration (PLR), ATP-linked respiration (ALR), maximal respiratory capacity (MRC), and reserve capacity (RC) were measured in peripheral blood mononuclear cells (PBMCs). The ASD samples were analyzed by subgrouping them into high, normal, and low IL-1ß/IL-10 ratio groups, which was previously shown to be associated with changes in behaviors and PBMo miRNA expression. MRC, RC, and RC/PLR, a marker of electron transport chain (ETC) efficiency, were higher in ASD PBMCs than controls. The expected positive associations between PLR and ALR were found in control non-ASD PBMCs, but not in ASD PBMCs. Higher MRC, RC, RC/PLR in ASD PBMCs were secondary to higher levels of these parameters in the high and normal IL-1ß/IL-10 ratio ASD subgroups than controls. Associations between mitochondrial parameters and monocyte cytokine profiles differed markedly across the IL-1ß/IL-10 ratio based ASD subgroups, rendering such associations less evident when ASD samples as a whole were compared to non-ASD controls. Our results indicate for the first time, an association between PBMC mitochondrial function and PBMo cytokine profiles in ASD subjects. This relationship differs across the IL-1ß/IL-10 ratio based ASD subgroups. Changes in mitochondrial function are likely due to adaptive changes or mitochondrial dysfunction, resulting from chronic oxidative stress. These results may indicate alteration in molecular pathways affecting both the immune system and mitochondrial function in some ASD subjects.

SUBMITTER: Jyonouchi H

PROVIDER: S-EPMC6391925 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundDespite the global increase in the prevalence of autism spectrum disorders (ASD), relevant research studies are lacking in Brunei Darussalam. Various studies have shown a significant association between a lowered 2D:4D ratio (ratio of second digit/index finger to the fourth digit/ring finger) and ASD, making it one of the potential phenotypic biomarkers for early detection of autism, which is important for early intervention and management.ObjectiveThe objective of this study is to explore the association between 2D:4D ratio and ASD in Brunei Darussalam, as a potential tool to complement early ASD diagnosis.MethodsWe conducted a case-control study comprising 28 ASD and 62 typically developing (TD) children in the case and control group, respectively (age range: 3-11 years old; median age: 6 years old). Median 2D:4D ratios were measured, compared and analysed between the two groups. Logistic regression models were used to explore potential associations between the median 2D:4D ratio and ASD in respective gender, for both left and right hands, independently.ResultsOur study shows that the median 2D:4D ratio of left hand in ASD males is significantly lower than those in TD males, after adjusting for ethnicity and age [Odds Ratio (OR) = 0.57 (95% Confidence Interval (CI): 0.31-0.96); p = 0.044]. For females, there is no association of ASD with the median left hand 2D:4D ratio [OR = 3.09 (95% CI: 0.98-19.86); p = 0.144] or the median right hand 2D:4D ratio [OR = 1.23 (95% CI: 0.42-3.88); p = 0.702]. Our study also shows a significant positive correlation and/or a reduced asymmetry between the average 2D:4D ratio of left hands and right hands in ASD males (Pearson's correlation (r) = 0.48; 95% CI: 0.076-0.75, p = 0.023).ConclusionsThere is significant association between a lowered median 2D:4D ratio of the left hand (in males only) and ASD diagnosis. Once validated in a larger sample size, a lowered median 2D:4D ratio on the left hand may be a potential tool to complement ASD diagnosis for males in our study population. There is no association between the median 2D:4D ratio (left or right hands) and ASD in females, which could be due to the small female sample size and/or the possibility of different aetiology for ASD in females. Reduced asymmetry between the average 2D:4D ratio of left and right hands observed in ASD males only (not in ASD females) also suggests the importance of considering gender-specific biomarkers for ASD diagnosis.

Project description:Malaria, blood-borne filarial worms and intestinal parasites are all endemic in Gabon. This geographical co-distribution leads to polyparasitism and, consequently, the possibility of immune-mediated interactions among different parasite species. Intestinal protozoa and helminths could modulate antimalarial immunity, for example, thereby potentially increasing or reducing susceptibility to malaria. The aim of the study was to compare the cytokine levels and cytokine ratios according to parasitic profiles of the population to determine the potential role of co-endemic parasites in the malaria susceptibility of populations. Blood and stool samples were collected during cross-sectional surveys in five provinces of Gabon. Parasitological diagnosis was performed to detect plasmodial parasites, Loa loa, Mansonella perstans, intestinal helminths (STHs) and protozoan parasites. Nested PCR was used to detect submicroscopic plasmodial infection in individuals with negative blood smears. A cytometric bead array was used to quantify interleukin (IL)-6, IL-10 and tumour necrosis factor (TNF)-α in the plasma of subjects with different parasitological profiles. Median IL-6 and IL-10 levels and the median IL-10/TNF-α ratio were all significantly higher among individuals with Plasmodium (P.) falciparum infection than among other participants (p<0.0001). The median TNF-α level and IL-10/IL-6 ratio were higher in subjects with STHs (p = 0.09) and P. falciparum-intestinal protozoa co-infection (p = 0.04), respectively. IL-6 (r = -0.37; P<0.01) and IL-10 (r = -0.37; P<0.01) levels and the IL-10/TNF-α ratio (r = -0.36; P<0.01) correlated negatively with age. Among children under five years old, the IL-10/TNF-α and IL-10/IL-6 ratios were higher in those with intestinal protozoan infections than in uninfected children. The IL-10/TNF-α ratio was also higher in children aged 5-15 years and in adults harbouring blood-borne filariae than in their control counterparts, whereas the IL-10/IL-6 ratio was lower in those aged 5-15 years with filariae and intestinal parasites but higher in adults with intestinal parasitic infections. Asymptomatic malaria is associated with a strong polarization towards a regulatory immune response, presenting high circulating levels of IL-10. P. falciparum/intestinal protozoa co-infections were associated with an enhanced IL-10 response. Immunity against malaria could differ according to age and carriage of other parasites. Helminths and intestinal protozoa can play a role in the high susceptibility to malaria currently observed in some areas of Gabon, but further investigations are necessary.

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Variations in Mitochondrial Respiration Differ in IL-1ß/IL-10 Ratio Based Subgroups in Autism Spectrum Disorders.

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