The unfolded protein response (UPR) is a highly conserved pathway that allows cells to respond to stress in the endoplasmic reticulum caused by an accumulation of misfolded and unfolded protein. This ...is of great importance to secretory cells because, in order for proteins to traffic from the endoplasmic reticulum (ER), they need to be folded appropriately. While a wealth of literature has implicated UPR in immune responses, less attention has been given to the role of UPR in T cell development and function. This review discusses the importance of UPR in T cell development, homeostasis, activation, and effector functions. We also speculate about how UPR may be manipulated in T cells to ameliorate pathologies.
T cell activation induces ER stress and upregulates Inositol Requiring Enzyme 1 alpha (IRE1α), an activator of the unfolded protein response (UPR) pathway. Inhibition of IRE1α RNase activity in ...activated CD4
splenocytes from naïve mice, via treatment of the cells with the commercially available drug 4μ8c upon activation, results in the reduction of the secretion of proteins IL-5, IL-4, and IL-13. Prior to this work, it was unknown if 4μ8c could inhibit TH2 cytokines in established TH2 cells, cells that are crucial in promoting disease in severe asthma.
Treatment of a mouse T helper (TH)2 cell line and differentiated human TH2 cells with 4μ8c resulted in inhibition of IL-5, but not IL-4, as measured by ELISA. The reduced cytokine expression was not due to differences in mRNA stability or mRNA levels; it appears to be due to a defect in secretion, as the cells produce cytokines IL-5 as measured by flow cytometry and western blot.
These data suggest that the inhibition of IL-5 was due to post-translational processes. IL-5 promotes chronic, inflammatory asthma, and 4μ8c blocks its expression in T cells in vitro. Future studies will determine if 4μ8c treatment can ameliorate the effects of the cytokine IL-5 in a disease model.
T cell activation induces ER stress and upregulates Inositol Requiring Enzyme 1 alpha (IRE1alpha), an activator of the unfolded protein response (UPR) pathway. Inhibition of IRE1alpha RNase activity ...in activated CD4.sup.+ splenocytes from naïve mice, via treatment of the cells with the commercially available drug 4mu8c upon activation, results in the reduction of the secretion of proteins IL-5, IL-4, and IL-13. Prior to this work, it was unknown if 4mu8c could inhibit TH2 cytokines in established TH2 cells, cells that are crucial in promoting disease in severe asthma. Treatment of a mouse T helper (TH)2 cell line and differentiated human TH2 cells with 4mu8c resulted in inhibition of IL-5, but not IL-4, as measured by ELISA. The reduced cytokine expression was not due to differences in mRNA stability or mRNA levels; it appears to be due to a defect in secretion, as the cells produce cytokines IL-5 as measured by flow cytometry and western blot. These data suggest that the inhibition of IL-5 was due to post-translational processes. IL-5 promotes chronic, inflammatory asthma, and 4mu8c blocks its expression in T cells in vitro. Future studies will determine if 4mu8c treatment can ameliorate the effects of the cytokine IL-5 in a disease model.
To examine patterns of early brain growth in young children with fragile X syndrome (FXS) compared with a comparison group (controls) and a group with idiopathic autism.
The study included 53 boys 18 ...to 42 months of age with FXS, 68 boys with idiopathic autism (autism spectrum disorder), and a comparison group of 50 typically developing and developmentally delayed controls. Structural brain volumes were examined using magnetic resonance imaging across two time points, at 2 to 3 and again at 4 to 5 years of age, and total brain volumes and regional (lobar) tissue volumes were examined. In addition, a selected group of subcortical structures implicated in the behavioral features of FXS (e.g., basal ganglia, hippocampus, amygdala) was studied.
Children with FXS had larger global brain volumes compared with controls but were not different than children with idiopathic autism, and the rate of brain growth from 2 to 5 years of age paralleled that seen in controls. In contrast to children with idiopathic autism who had generalized cortical lobe enlargement, children with FXS showed specific enlargement in the temporal lobe white matter, cerebellar gray matter, and caudate nucleus, but a significantly smaller amygdala.
This structural longitudinal magnetic resonance imaging study of preschoolers with FXS observed generalized brain overgrowth in children with FXS compared with controls, evident at age 2 and maintained across ages 4 to 5. In addition, different patterns of brain growth that distinguished boys with FXS from boys with idiopathic autism were found.
A number of studies have found brain enlargement in autism, but there is disagreement as to whether this enlargement is limited to early development or continues into adulthood. In this study, ...cortical gray and white tissue volumes were examined in a sample of adolescents and adults with autism who had demonstrated total brain enlargement in a previous magnetic resonance imaging (MRI) study.
An automated tissue segmentation program was applied to structural MRI scans to obtain volumes of gray, white, and cerebrospinal fluid (CSF) tissue on a sample of adolescent and adult males ages 13-29 with autism (
n = 23) and controls (
n = 15). Regional differences for brain lobes and brain hemispheres were also examined.
Significant enlargement in gray matter volume was found for the individuals with autism, with a disproportionate increase in left-sided gray matter volume. Lobe volume enlargements were detected for frontal and temporal, but not parietal or occipital lobes, in the subjects with autism. Age and nonverbal IQ effects on tissue volume were also observed.
These findings give evidence for left-lateralized gray tissue enlargement in adolescents and adults with autism, and demonstrate a regional pattern of cortical lobe volumes underlying this effect.
A few examples of research enabled by whole-organism specimens and their associated tissues and data illustrate the value of museum collections 2–13. * Discovery and description of new species * The ...origins and spread of infectious diseases * Studies of environmental degradation such as the accumulation of microplastics and mercury in fish or DDT in eggshells * Most research on endoparasites and small invertebrates (which constitute the majority of all animals) * Research on morphology and physiology of whole organisms * Studies of gene expression and epigenetic modifications in wild animals, including gene regulatory changes associated with adaptation to different environments * Research that links genomic variation to phenotypic differences * Studies of the biotic consequences of global change in the Anthropocene * A global scientific resource for future studies and future technologies Documenting biodiversity Most of the Earth’s biodiversity remains to be characterized, with an estimated 86% of species yet to be described 14. ...verification of these species requires intensive anatomical analyses that are impossible without whole-organism voucher specimens. ...most animal species are small arthropods such as insects and mites, the majority of which cannot be found using nonlethal means and cannot be identified without microscopic examination 5. ...understanding evolutionary processes often involves the study of large series of voucher specimens that document geographic, temporal, age, or sexual variation in specific traits. Conservation of species The International Union for Conservation of Nature (IUCN) assesses species once they are described. ...there is typically no mechanism to initiate conservation efforts prior to species descriptions.
To examine brain volumes in substructures associated with the behavioral features of children with FXS compared to children with idiopathic autism and controls. A cross-sectional study of brain ...substructures was conducted at the first time-point as part of an ongoing longitudinal MRI study of brain development in FXS. The study included 52 boys between 18-42 months of age with FXS and 118 comparison children (boys with autism-non FXS, developmental-delay, and typical development). Children with FXS and autistic disorder had substantially enlarged caudate volume and smaller amygdala volume; whereas those children with autistic disorder without FXS (i.e., idiopathic autism) had only modest enlargement in their caudate nucleus volumes but more robust enlargement of their amygdala volumes. Although we observed this double dissociation among selected brain volumes, no significant differences in severity of autistic behavior between these groups were observed. This study offers a unique examination of early brain development in two disorders, FXS and idiopathic autism, with overlapping behavioral features, but two distinct patterns of brain morphology. We observed that despite almost a third of our FXS sample meeting criteria for autism, the profile of brain volume differences for children with FXS and autism differed from those with idiopathic autism. These findings underscore the importance of addressing heterogeneity in studies of autistic behavior.
Brain enlargement has been observed in 2-year-old children with autism, but the underlying mechanisms are unknown.
To investigate early growth trajectories in brain volume and cortical thickness.
...Longitudinal magnetic resonance imaging study.
Academic medical centers.
Fifty-nine children with autism spectrum disorder (ASD) and 38 control children.
Children were examined at approximately 2 years of age. Magnetic resonance imaging was repeated approximately 24 months later (when aged 4-5 years; 38 children with ASD; 21 controls).
Cerebral gray and white matter volumes and cortical thickness.
We observed generalized cerebral cortical enlargement in individuals with ASD at both 2 and 4 to 5 years of age. Rate of cerebral cortical growth across multiple brain regions and tissue compartments in children with ASD was parallel to that seen in the controls, indicating that there was no increase in rate of cerebral cortical growth during this interval. No cerebellar differences were observed in children with ASD. After controlling for total brain volume, a disproportionate enlargement in temporal lobe white matter was observed in the ASD group. We found no significant differences in cortical thickness but observed an increase in an estimate of surface area in the ASD group compared with controls for all cortical regions measured (temporal, frontal, and parieto-occipital lobes).
Our longitudinal magnetic resonance imaging study found generalized cerebral cortical enlargement in children with ASD, with a disproportionate enlargement in temporal lobe white matter. There was no significant difference from controls in the rate of brain growth for this age interval, indicating that brain enlargement in ASD results from an increased rate of brain growth before age 2 years. The presence of increased cortical volume, but not cortical thickness, suggests that early brain enlargement may be associated with increased cortical surface area. Cortical surface area overgrowth in ASD may underlie brain enlargement and implicates a distinct set of pathogenic mechanisms.
Cerebral cortical volume enlargement has been reported in 2- to 4-year-olds with autism. Little is known about the volume of subregions during this period of development. The amygdala is hypothesized ...to be abnormal in volume and related to core clinical features in autism.
To examine amygdala volume at 2 years with follow-up at 4 years of age in children with autism and to explore the relationship between amygdala volume and selected behavioral features of autism.
Longitudinal magnetic resonance imaging study.
University medical setting.
Fifty autistic and 33 control (11 developmentally delayed, 22 typically developing) children between 18 and 35 months (2 years) of age followed up at 42 to 59 months (4 years) of age.
Amygdala volumes in relation to joint attention ability measured with a new observational coding system, the Social Orienting Continuum and Response Scale; group comparisons including total tissue volume, sex, IQ, and age as covariates.
Amygdala enlargement was observed in subjects with autism at both 2 and 4 years of age. Significant change over time in volume was observed, although the rate of change did not differ between groups. Amygdala volume was associated with joint attention ability at age 4 years in subjects with autism.
The amygdala is enlarged in autism relative to controls by age 2 years but shows no relative increase in magnitude between 2 and 4 years of age. A significant association between amygdala volume and joint attention suggests that alterations to this structure may be linked to a core deficit of autism.
While the neuroanatomical basis of autism is not yet known, evidence suggests that brain enlargement may be characteristic of this disorder. Inferences about the timing of brain enlargement have ...recently come from studies of head circumference (HC).
To examine brain volume and HC in individuals with autism as compared with control individuals.
A cross-sectional study of brain volume was conducted at the first time point in an ongoing longitudinal magnetic resonance imaging study of brain development in autism. Retrospective longitudinal HC measurements were gathered from medical records on a larger sample of individuals with autism and local control individuals.
Clinical research center.
The magnetic resonance imaging study included 51 children with autism and 25 control children between 18 and 35 months of age (the latter included both developmentally delayed and typically developing children). Retrospective, longitudinal HC data were examined from birth to age 3 years in 113 children with autism and 189 local control children.
Cerebral cortical (including cortical lobes) and cerebellar gray and white matter magnetic resonance imaging brain volumes as well as retrospective HC data from medical records were studied.
Significant enlargement was detected in cerebral cortical volumes but not cerebellar volumes in individuals with autism. Enlargement was present in both white and gray matter, and it was generalized throughout the cerebral cortex. Head circumference appears normal at birth, with a significantly increased rate of HC growth appearing to begin around 12 months of age.
Generalized enlargement of gray and white matter cerebral volumes, but not cerebellar volumes, are present at 2 years of age in autism. Indirect evidence suggests that this increased rate of brain growth in autism may have its onset postnatally in the latter part of the first year of life.
PDF
