Aberrant activation of the canonical Wnt signal transduction pathway is involved in many diseases including cancer and is especially implicated in the development and progression of colorectal cancer. The key effector protein of the canonical Wnt pathway is β-catenin, which functions with T-cell factor/lymphoid enhancer factor to activate expression of Wnt target genes. In this study, we used a new functional screen based on cell survival in the presence of cDNAs encoding proteins that activate the Wnt pathway thus identifying novel Wnt signaling components. Here we identify carboxypeptidase E (|CPE) and its splice variant, ΔN-CPE, as novel regulators of the Wnt pathway. We show that whereas ΔN-CPE activates the Wnt signal, the full-length CPE (F-CPE) protein is an inhibitor of Wnt/β-catenin signaling. F-CPE forms a complex with the Wnt3a ligand and the Frizzled receptor. Moreover, F-CPE disrupts disheveled-induced signalosomes that are important for transducing the Wnt signal and reduces β-catenin protein levels and activity. Taken together, our data indicate that F-CPE and ΔN-CPE regulate the canonical Wnt signaling pathway negatively and positively, respectively, and demonstrate that this screening approach can be a rapid means for isolation of novel Wnt signaling components.
Wnt signaling; carboxypeptidase E (CPE); β-catenin; functional screen
Our goal was to examine the association between parent-rated sleep problems during childhood and neuropsychological functioning during adolescence.
PARTICIPANTS AND METHODS
Longitudinal prospective data on an entire birth cohort from Dunedin, New Zealand, were obtained. One thousand thirty-seven children were enrolled in the study (52% male). Parents reported on sleep problems when the study members were 5, 7, and 9 years of age. Neuropsychological functioning was assessed by using 7 tests when the participants were 13 years of age.
After adjusting for gender and socioeconomic status, persistent sleep problems during childhood predicted scores on 2 neuropsychological tests: the copy score of the Rey-Osterrieth Complex Figure Test and 2 measures of performance on the Halstead Trail Making Test. These results were substantively replicated when sleep was assessed at the 5- and 9-year (but not 7-year) assessments separately.
Sleep problems during childhood may be associated with certain aspects of neuropsychological functioning during adolescence. This adds to the growing body of literature suggesting that childhood sleep problems may be a risk indicator of later difficulties.
sleep; neuropsychological; longitudinal; prospective
It is unclear how many people in the community have obsessions and compulsions and associated levels of interference. It is also unknown what variables predict help-seeking for these symptoms, whether they are developmentally stable, and whether they increase the risk of mental disorders.
The authors analyzed data from the prospective longitudinal Dunedin study of an unselected birth cohort. The presence of obsessions and compulsions and mental disorders was assessed using the Diagnostic Interview Schedule (DIS) at ages 11, 26, and 32. Data on interference and help-seeking were obtained at ages 26 and 32.
Obsessions and compulsions were frequent in individuals with mental disorders other than obsessive-compulsive disorder (OCD) and among people without mental disorders. Even in the latter group, these symptoms caused significant interference. The presence of anxiety/depression and of obsessions (particularly aggressive and shameful thoughts), but not compulsions, was associated with help-seeking. Harm/checking was the most prevalent symptom dimension. Symptom dimensions were temporally stable and associated with increased comorbidity. Obsessive-compulsive symptoms at age 11 predicted a high risk of an adult OCD diagnosis as well as elevated adult symptom dimensions.
Obsessions and compulsions are common in the adult population, have their roots in childhood, and are associated with interference, risk for disorders, and help-seeking. Subclinical obsessions and compulsions should be taken into account in research, intervention, and DSM-V.
Evidence from animal and human studies suggests that early-life stress such as physical maltreatment has long-lasting effects on the hypothalamic-pituitary-adrenal (HPA) axis and is associated with blunted HPA axis reactivity in adulthood. Few studies have investigated whether blunted HPA axis reactivity observed in children exposed to early-life stress signals social, emotional, and behavioral problems.
Participants were 190 12-year-old children (50.5% males) recruited from the Environmental Risk Longitudinal Twin Study, a nationally representative 1994 to 1995 cohort of families with twins. Cortisol responses to psychosocial stress were measured in maltreated/ bullied (n = 64) and comparison children (n = 126). We ascertained maltreatment and bullying victimization using mothers’ reports and assessed children’s social, emotional, and behavioral problems at ages 5 and 12 using mothers’ and teachers’ reports.
Piecewise multilevel growth curve analyses indicated that maltreated/bullied and comparison children showed distinct cortisol responses to stress. Specifically, maltreated/bullied children had lower cortisol responses than comparison children who exhibited a significant increase. Lower cortisol responses were, in turn, associated with more social and behavioral problems among maltreated/bullied children.
These findings provide support for the influence of childhood harm on blunted HPAaxis reactivity and its potential impacton children’s functioning. Our findings emphasize the need to integrate stress biomarkers in guiding prevention efforts for young victims.
Behavioral problems; bullying; cortisol; HPA axis; maltreatment; social problems
The model of experimental autoimmune uveitis (EAU) in mice and in rats is described. EAU targets immunologically privileged retinal antigens and serves as a model of autoimmune uveitis in humans as well as a model for autoimmunity in a more general sense. EAU is a well-characterized, robust, and reproducible model that is easily followed and quantitated. It is inducible with synthetic peptides derived from retinal autoantigens in commonly available strains of rats and mice. The ability to induce EAU in various gene-manipulated, including HLA-transgenic, mouse strains makes the EAU model suitable for the study of basic mechanisms as well as in clinically relevant interventions.
Uveitis; Uveoretinitis; EAU; Autoimmunity; T cells; Tolerance; Th1; Th2; IRBP; S-Ag
The effects of cannabis on lung function remain unclear and may be different from those of tobacco. We compared the associations between use of these substances and lung function in a population-based cohort (n=1,037).
Cannabis and tobacco use were reported at ages 18, 21, 26 and 32 yrs. Spirometry, plethysmography and carbon monoxide transfer factor were measured at 32 yrs. Associations between lung function and exposure to each substance were adjusted for exposure to the other substance.
Cumulative cannabis use was associated with higher forced vital capacity, total lung capacity, functional residual capacity and residual volume. Cannabis was also associated with higher airway resistance but not with forced expiratory volume in 1 s, forced expiratory ratio or transfer factor. These findings were similar among those who did not smoke tobacco. In contrast, tobacco use was associated with lower forced expiratory volume in 1 s, lower forced expiratory ratio, lower transfer factor and higher static lung volumes, but not with airway resistance.
Cannabis appears to have different effects on lung function from those of tobacco. Cannabis use was associated with higher lung volumes, suggesting hyperinflation and increased large-airways resistance, but there was little evidence for airflow obstruction or impairment of gas transfer.
Cannabis; cohort study; marijuana; respiratory function; smoking; tobacco
F11R is a cell adhesion molecule found on the surface of human platelets. It plays a role in platelet aggregation, cell migration and cell proliferation. F11R is subjected to RNA editing, a post-transcriptional modification which affects RNA structure, stability, localization, translation and splicing. RNA editing in the 3'UTR of F11R and RNA levels are increased upon hypoxia. We therefore set to examine if RNA editing plays a role in the increase of F11R RNA seen upon hypoxic conditions. We show that ADAR1, but not ADAR2, takes part in the editing of F11R however editing alone is not sufficient for obtaining an elevation in RNA levels. In addition we show that hyper-edited mature mRNAs are retained in the nucleus and are associated with p54nrb. We therefore conclude that hypoxia-induced edited RNAs of F11R are preferentially stabilized and accumulate in the nucleus preventing their export to the cytoplasm for translation. This mechanism may be used by additional proteins in the cell as part of the cell's effort to reduce metabolism upon hypoxic stress.
In the U.S., supermarkets serve as an important source of year-round produce (Chung & Myers, 1999), and yet access to supermarkets may be scarce in “food deserts,” or poor, urban areas that lack sources of healthy, affordable food (Cummins & Macintyre, 2002). This study examined objective distance to the nearest supermarket and participant-report of supermarket access in relation to fruit and vegetable intake. Street-network distance to the closest supermarket was calculated using GIS mapping. Perceived access was assessed by a survey question asking whether participants had a supermarket within walking distance of home. Cross-sectional survey data were collected from 828 low-income housing residents in three urban areas in greater-Boston. Generalized estimating equations were used to estimate the association between perceived and objective supermarket access and diet. Fruit and vegetable consumption was low (2.63 servings/day). Results suggest that most low-income housing residents in greater-Boston do not live in “food deserts,” as the average distance to a supermarket was 0.76 km (range 0.13–1.22 km). Distance to a supermarket was not associated with fruit and vegetable intake (p = 0.22). Perceived supermarket access was strongly associated with increased fruit and vegetable intake (0.5 servings/day) after controlling for socio-demographic covariates (p < 0.0001). Patterns of mismatch between perceived and objective measures revealed that mismatch between the two measures were high (31.45%). Those who did not report a supermarket within walking distance from home despite the objective presence of a supermarket within 1 km consumed significantly fewer fruits and vegetables (0.56 servings/day) than those with a supermarket who reported one, even after controlling for socio-demographic variables (p = 0.0008). Perceived measures of the food environment may be more strongly related to dietary behaviors than objective ones, and may incorporate components of food access not captured in objective measures.
USA; Food access; Neighborhood; Low-income housing; Health behaviors; Perceived measures; Objective measures
It has been reported that childhood psychotic symptoms are common in the general population and may signal neurodevelopmental processes that lead to schizophrenia. However, it is not clear whether these symptoms are associated with the same extensive risk factors established for adult schizophrenia.
To examine the construct validity of children’s self-reported psychotic symptoms by testing whether these symptoms share the risk factors and clinical features of adult schizophrenia.
Prospective, longitudinal cohort study of a nationally representative birth cohort in Great Britain.
A total of 2232 twelve-year-old children followed up since age 5 years (retention, 96%).
Main Outcome Measure
Children’s self-reported hallucinations and delusions.
Children’s psychotic symptoms are familial and heritable and are associated with social risk factors (eg, urbanicity); cognitive impairments at age 5; home-rearing risk factors (eg, maternal expressed emotion); behavioral, emotional, and educational problems at age 5; and comorbid conditions, including self-harm.
The results provide a comprehensive picture of the construct validity of children’s self-reported psychotic symptoms. For researchers, the findings indicate that children who have psychotic symptoms can be recruited for neuroscience research to determine the pathogenesis of schizophrenia. For clinicians, the findings indicate that psychotic symptoms in childhood are often a marker of an impaired developmental process and should be actively assessed.
Despite growing attention to the problem of obesogenic environments, there has not been a comprehensive review evaluating the food environment-diet relationship. This study aims to evaluate this relationship in the current literature, focusing specifically on the method of exposure assessment (GIS, survey, or store audit). This study also explores 5 dimensions of “food access” (availability, accessibility, affordability, accommodation, acceptability) using a conceptual definition proposed by Penchansky and Thomas (1981). Articles were retrieved through a systematic keyword search in Web of Science and supplemented by the reference lists of included studies. Thirty-eight studies were reviewed and categorized by the exposure assessment method and the conceptual dimensions of access it captured. GIS-based measures were the most common measures, but were less consistently associated with diet than other measures. Few studies examined dimensions of affordability, accommodation, and acceptability. Because GIS-based measures on their own may not capture important non-geographic dimensions of access, a set of recommendations for future researchers is outlined.
Food environment; diet; measurement; GIS; survey; store audit
Animal models of autoimmunity to the retina mimic specific features of human uveitis, but no model by itself reproduces the full spectrum of human disease. We compared three mouse models of uveitis that target the interphotoreceptor retinoid binding protein (IRBP): (i) the “classical” model of experimental autoimmune uveitis (EAU) induced by immunization with IRBP; (ii) spontaneous uveitis in IRBP T cell receptor transgenic mice (R161H) and (iii) spontaneous uveitis in Autoimmune Regulator (AIRE)−/− mice. Disease course and severity, pathology and changes in visual function were studied using fundus imaging and histological examinations, optical coherence tomography and electroretinography. All models were on the B10.RIII background. Unlike previously reported, IRBP-induced EAU in B10.RIII mice exhibited two distinct patterns of disease depending on clinical scores developed after onset: severe monophasic with extensive destruction of the retina and rapid loss of visual signal, or lower grade with a prolonged chronic phase culminating after several months in retinal degeneration and loss of vision. R161H and AIRE−/− mice spontaneously developed chronic progressive inflammation; visual function declined gradually as retinal degeneration developed. Spontaneous uveitis in R161H mice was characterized by persistent cellular infiltrates and lymphoid aggregation, whereas AIRE−/− mice characteristically developed multi-focal infiltrates and severe choroidal inflammation. These data demonstrate variability and unique distinguishing features in the different models of uveitis, suggesting that each one can represent distinct aspects of uveitis in humans.
There is increased interest in assessing the family history of psychiatric disorders for both genetic research and public health screening. It is unclear how best to combine family history reports into an overall score. We compare the predictive validity of different family history scores.
Probands from the Dunedin Study (n=981, 51% male) had their family history assessed for nine different conditions. We computed four family history scores for each disorder: (1) a simple dichotomous categorization of whether or not probands had any disordered first-degree relatives ; (2) the observed number of disordered first-degree relatives ; (3) the proportion of first-degree relatives who are disordered; and (4) Reed’s score, which expressed the observed number of disordered first-degree relatives in terms of the number expected given the age and sex of each relative. We compared the strength of association between each family history score and probands’ disorder outcome.
Each score produced significant family history associations for all disorders. The scores that took account of the number of disordered relatives within families (i.e. the observed, proportion, and Reed’s scores) produced significantly stronger associations than the dichotomous score for conduct disorder, alcohol dependence and smoking. Taking account of family size (i.e. using the proportion or Reed’s score) produced stronger family history associations depending on the prevalence of the disorder among family members.
Dichotomous family history scores can be improved upon by considering the number of disordered relatives in a family and the population prevalence of the disorder.
Family history; predictive validity; prevalence; psychiatry
Research into social inequalities in health has tended to focus on low socioeconomic status in adulthood. We aimed to test the hypothesis that children’s experience of socioeconomic disadvantage is associated with a wide range of health risk factors and outcomes in adult life.
We studied an unselected cohort of 1000 children (born in New Zealand during 1972–73) who had been assessed at birth and ages 3, 5, 7, 9, 11, 13, and 15 years. At age 26 years, we assessed these individuals for health outcomes including body-mass index, waist:hip ratio, blood pressure, cardiorespiratory fitness, dental caries, plaque scores, gingival bleeding, periodontal disease, major depression, and tobacco and alcohol dependence, and tested for associations between these variables and childhood and adult socioeconomic status.
Compared with those from high socioeconomic status backgrounds, children who grew up in low socioeconomic status families had poorer cardiovascular health. Significant differences were also found on all dental health measures, with a threefold increase in adult periodontal disease (31·1% vs 11·9%) and caries level (32·2% vs 9·9%) in low versus high childhood socioeconomic status groups. Substance abuse resulting in clinical dependence was related in a similar way to childhood socioeconomic status (eg, 21·5% vs 12·1% for adult alcohol dependence). The longitudinal associations could not be attributed to life-course continuity of low socioeconomic status, and upward mobility did not mitigate or reverse the adverse effects of low childhood socioeconomic status on adult health.
Protecting children against the effects of socioeconomic adversity could reduce the burden of disease experienced by adults. These findings provide strong impetus for policy makers, practitioners, and researchers to direct energy and resources towards childhood as a way of improving population health.
The objective of the study was to examine the link between anxiety and allergies to establish whether it reflects a psychobiological reality or a possible methodological bias. A cohort of 1,037 children enrolled in the study. Anxiety disorders were assessed between 11 and 21 years. Anxious personality was assessed at 18 years. Allergies were examined at 21 years by (a) self reports, (b) skin pricks, and (c) serum total immunoglobulin E (IgE). Self-reported allergies were predicted by recurrent anxiety disorders (OR [95% CI]=1.56 [1.06–2.30], p=.023) and self-reports of anxious personality (OR [95% CI]=1.67 [1.17–2.37], p=.004): Objectively verified allergies were not. These results suggest that the link between anxiety and allergies may reflect a methodological artifact rather than a psychobiological reality.
Genetic and environmental factors shape life-long vulnerability to depression, but most gene–environment interaction (G×E) research has focused on cross-sectional assessments rather than life-course phenotypes. This study tests the hypothesis that the G×E involving the length polymorphism in the serotonin-transporter-gene-linked-promoter-region (5-HTTLPR) and childhood maltreatment is specific to depression that runs a persistent course in adulthood.
The hypothesis is tested in two cohorts. Men and women in the Dunedin Study (N=847), New Zealand, followed to age 32 years with 96% retention and women in the E-Risk Study (N=930), England, followed to age 40 years with 96% retention. Diagnoses of past-year major depressive episode were established at four separate assessments. Depression diagnosed on two or more occasions was considered persistent.
In both cohorts, statistical tests of gene–environment interactions showed positive results for persistent depression but not single-episode depression. Individuals with two short 5-HTTLPR alleles and childhood maltreatment had elevated risk of persistent but not single-episode depression.
Some cases of recurrent depression may have been misclassified as single-episode due to non-contiguous assessment windows, but this would have a conservative effect on the findings. Chronic and recurrent depression could not be reliably distinguished due to non-contiguous periods of assessment. Therefore, the term persistent depression is used to describe either chronic or recurrent course.
The specific effect on persistent depression increases the significance of this G×E for public health. Research that does not distinguish persistent course may underestimate G×E effects and account for some replication failures in G×E research.
Depression; Persistent course; Gene–environment interactions; Serotonin transporter; Childhood maltreatment
If family history is associated with clinical features that are thought to index seriousness of disorder, this could inform clinicians predicting patients’ prognosis and researchers selecting cases for genetic studies. Although tests of associations between family history and clinical features are numerous for depression, such tests are relatively lacking for other disorders.
To test the hypothesis that family history is associated with 4 clinical indexes of disorder (recurrence, impairment, service use, and age at onset) in relation to 4 psychiatric disorders (major depressive episode, anxiety disorder, alcohol dependence, and drug dependence).
Prospective longitudinal cohort study.
A total of 981 members of the 1972 to 1973 Dunedin Study birth cohort (96% retention).
Main Outcome Measures
For each disorder, family history scores were calculated as the proportion of affected family members from data on 3 generations of the participants’ families. Data collected prospectively at the study’s repeated assessments (ages 11–32 years) were used to assess recurrence, impairment, and age at onset; data collected by means of a life history calendar at age 32 years were used to assess service use.
Family history was associated with the presence of all 4 disorder types. In addition, family history was associated with a more recurrent course for all 4 disorders (but not significantly for women with depression), worse impairment, and greater service use. Family history was not associated with younger age at onset for any disorder.
Associations between family history of a disorder and clinical features of that disorder in probands showed consistent direction of effects across depression, anxiety disorder, alcohol dependence, and drug dependence. For these disorder types, family history is useful for determining patients’ clinical prognosis and for selecting cases for genetic studies.
We investigated age-26 personality characteristics and age-32 oral health in a prospective study of a complete birth cohort born in Dunedin, New Zealand. Personality was measured using the Multidimensional Personality Questionnaire (MPQ). Oral health was measured using the short-form Oral Health Impact Profile (OHIP-14), a global measure, and dental examinations. Personality profiles were constructed for 916 individuals (50.8% men) using standardized MPQ scores, and multivariate analyses examined their association with oral health. Those reporting 1+ OHIP-14 impacts had higher Negative Emotionality scores (and lower Constraint and Positive Emotionality MPQ superfactor scores) than those who did not. After controlling for gender, clinical status, and the other two MPQ superfactors, those scoring higher on Negative Emotionality had a greater risk of reporting 1+ OHIP-14 impacts, as well as 3+ OHIP-14 impacts and worse-than-average oral health. They also had a greater risk of having lost at least one tooth from caries and of having 3+ decayed surfaces. Personality characteristics appear to shape self-reports of oral health. Personality is also a risk factor for clinical disease status, at least with respect to dental caries and its sequelae. Because the attitudes and values tapped into by personality tests can be altered by brief cognitive interventions, those might be useful in preventive dentistry.
cohort studies; oral health; personality; psychology; social
A previous study reported a gene × environment interaction in which a haplotype in the corticotropin-releasing hormone receptor 1 gene (CRHR1) was associated with protection against adult depressive symptoms in individuals who were maltreated as children (as assessed by the Childhood Trauma Questionnaire [CTQ]).
To replicate the interaction between childhood maltreatment and a TAT haplotype formed by rs7209436, rs110402, and rs242924 in CRHR1, predicting adult depression.
Two prospective longitudinal cohort studies.
England and New Zealand.
Participants in the first sample were women in the E-Risk Study (N= 1116), followed up to age 40 years with 96% retention. Participants in the second sample were men and women in the Dunedin Study (N= 1037), followed up to age 32 years with 96% retention.
Main Outcome Measure
Research diagnoses of pastyear and recurrent major depressive disorder.
In the E-Risk Study, the TAT haplotype was associated with a significant protective effect. In this effect, women who reported childhood maltreatment on the CTQ were protected against depression. In the Dunedin Study, which used a different type of measure of maltreatment, this finding was not replicated.
A haplotype in CRHR1 has been suggested to exert a protective effect against adult depression among research participants who reported maltreatment on the CTQ, a measure that elicits emotional memories. This suggests the hypothesis that CRHR1’s protective effect may relate to its function in the consolidation of memories of emotionally arousing experiences.
There is a need to collect psychiatric family history information quickly and economically (e.g., for genome-wide studies and primary care practice). We sought to evaluate the validity of family history reports using a brief screening instrument, the Family History Screen (FHS). We assessed the validity of parents’ reports of seven psychiatric disorders in their adult children probands from the Dunedin Study (n=959, 52% male), using the proband’s diagnosis as the criterion outcome. We also investigated whether there were informant characteristics that enhanced accuracy of reporting or were associated with reporting biases. Using reports from multiple informants, we obtained sensitivities ranging from 31.7% (alcohol dependence) to 60.0% (conduct disorder) and specificities ranging from 76.0% (major depressive episode) to 97.1% (suicide attempt). There was little evidence that any informant characteristics enhanced accuracy of reporting. However, three reporting biases were found: the probability of reporting disorder in the proband was greater for informants with versus without a disorder, for female versus male informants, and for younger versus older informants. We conclude that the FHS is as valid as other family history instruments (e.g., the FH-RDC, FISC), and its brief administration time makes it a cost-effective method for collecting family history data. To avoid biasing results, researchers who aim to compare groups in terms of their family history should ensure that the informants reporting on these groups do not differ in terms of age, sex or personal history of disorder.
family history; sensitivity; specificity; accuracy; bias
Childhood adverse experiences are known to engender persistent changes in stress-related systems and brain structures involved in mood, cognition, and behavior in animal models. Uncertainty remains about the causal effect of early stressful experiences on physiological response to stress in human beings, as the impact of these experiences has rarely been investigated while controlling for both genetic and shared environmental influences.
We tested whether bullying victimization, a repeated adverse experience in childhood, influences cortisol responses to a psychosocial stress test (PST) using a discordant monozygotic (MZ) twin design. Thirty pairs (43.3% males) of 12-year-old MZ twins discordant for bullying victimization were identified in the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative 1994–1995 cohort of families with twins.
Bullied and nonbullied MZ twins showed distinct patterns of cortisol secretion after the PST. Specifically, bullied twins exhibited a blunted cortisol response compared with their nonbullied MZ co-twins, who showed the expected increase. This difference in cortisol response to stress could not be attributed to children's genetic makeup, their familial environments, pre-existing and concomitant individual factors, or the perception of stress and emotional response to the PST.
Results from this natural experiment provide support for a causal effect of adverse childhood experiences on the neuroendocrine response to stress.
early-life stress; cortisol; HPA axis; discordant MZ twin design; bullying
In vitro studies have shown that p53 mediates a protective response against DNA damage by causing either cell-cycle arrest and DNA repair, or apoptosis. These responses have not yet been demonstrated in humans. A common source of DNA damage in humans is cigarette smoke, which should activate p53 repair mechanisms. The level of p53 is regulated by HDM2, which targets p53 for degradation. The G-allele of a polymorphism in intron 1 of HDM2 (rs2279744:G/T) results in higher HDM2 levels, and should be associated with a reduced p53 response and hence more DNA damage and corresponding tissue destruction. Similarly, the alleles of a polymorphism (rs1042522) in TP53 that encode arginine (G-allele) or proline (C-allele) at codon 72 cause increased pro-apoptotic (G-allele) or cell-cycle arrest activities (C-allele), respectively, and may moderate p53's ability to prevent DNA damage. To test these hypotheses we examined lung function in relation to cumulative history of smoking in a population-based cohort. The G-alleles in HDM2 and TP53 were found to be associated with accelerated smoking-related decline in lung function. These data support the hypothesis that p53 protects from DNA damage in humans and provides a potential explanation for variation in lung function impairment amongst smokers.
Subpopulations of pathogenic or nonpathogenic Th17 cells were reported to develop when pre-sensitized CD4 cells were activated with their target Ag during polarization by either IL-23 or IL-6 and TGF-β, respectively. Here, we generated two Th17 subpopulations by using a system in which naïve CD4 cells from TCR transgenic mice specific to hen egg lysozyme (HEL) are polarized with IL-6/TGF-β and, concurrently, are activated either with HEL presented by APC, or with anti-CD3/CD28 Abs. Only the former cells were pathogenic, inducing inflammation in eyes expressing HEL. Naïve CD4 cells activated by the anti-CD3/CD28 Abs acquired pathogenicity, however, when co-cultured with HEL/APC. Importantly, however, the naïve CD4 cells did not acquire pathogenicity when co-cultured with APC stimulated with LPS, or when separated from the HEL presenting cells by a semi-permeable membrane. Unlike with pre-sensitized Th17, soluble IL-23 does not participate in pathogenicity acquisition by naïve CD4 cells: no pathogenicity was induced by adding IL-23 to cultures activated with anti-CD3/CD28 Abs. Furthermore, Abs against IL-23 or IL-23R did not inhibit acquisition of pathogenicity in cultures of naïve CD4 cells activated by HEL/APC. Our data thus show that, unlike pre-sensitized CD4 cells, naïve CD4 polarized toward Th17 phenotype acquire pathogenicity only by direct interaction with APC presenting the Ag, with no apparent involvement of soluble IL-23. We suggest that the Th17 lymphocytes derived from naive CD4 cells participate in pathogenic and other immune processes, along with the IL-23 dependent Th17 cells.
T cells; Autoimmunity; Inflammation; Transgenic/Knockout mice
Innate immunity to viral infection is initiated within the infected cells through the recognition of unique viral signatures by pattern recognition receptors (PRRs) that mediate the induction of potent antiviral factor, type I interferons (IFNs). Infection with RNA viruses is recognized by the members of the retinoic acid inducible gene I (RIG-I)-like receptor (RLR) family in the cytosol. Our recent study demonstrates that IFN production in response to RNA viral ligands is increased in the absence of autophagy. The process of autophagy functions as an internal clean-up crew within the cell, shuttling damaged cellular organelles and long-lived proteins to the lysosomes for degradation. Our data show that the absence of autophagy leads to the amplification of RLR signaling in two ways. First, in the absence of autophagy, mitochondria accumulate within the cell leading to the build up of mitochondrial associated protein, IPS-1, a key signaling protein for RLRs. Second, damaged mitochondria that are not degraded in the absence of autophagy provide a source of reactive oxygen species (ROS), which amplify RLR signaling in Atg5 knockout cells. Our study provides the first link between ROS and cytosolic signaling mediated by the RLRs, and suggests the importance of autophagy in the regulation of signaling emanating from mitochondria.
Exposure to alcohol and illicit drugs during early adolescence has been associated with poor outcomes in adulthood. However, many adolescents with exposure to these substances also have a history of conduct problems, which raises the question of whether early exposure to alcohol and drugs leads to poor outcomes only for those adolescents who are already at risk. In a 30-year prospective study, we tested whether there was evidence that early substance exposure can be a causal factor for adolescents’ future lives. After propensity-score matching, early-exposed adolescents remained at an increased risk for a number of poor outcomes. Approximately 50% of adolescents exposed to alcohol and illicit drugs prior to age 15 had no conduct-problem history, yet were still at an increased risk for adult substance dependence, herpes infection, early pregnancy, and crime. Efforts to reduce or delay early substance exposure may prevent a wide range of adult health problems and should not be restricted to adolescents who are already at risk.