Responsive parental support buffers the link between chronic stress and cardiometabolic risk among adolescents.

Youth exposed to chronic stress exhibit increased cardiometabolic risk which parental social support may attenuate. Notably, theories emphasize that support should be delivered responsively for it to exert buffering effects, but this has not been thoroughly tested empirically. This study examined whether timing of support is an important but unrecognized element of responsiveness during adolescence in buffering the link between chronic stress and cardiometabolic risk. Participants were 242 adolescents aged 15 years (63 % female, 38 % Black). Adolescents completed assessments of chronic stress (Life Stress Interview), and trained personnel collected anthropometric measures and blood samples to assess cardiometabolic risk (reflected in low-grade inflammation and metabolic syndrome). Adolescents also completed an eight-day diary assessment to report daily stressor exposure and parental support. Using the diary data, responsiveness of parental support was operationalized as the within-individual difference in parental support received on stressor (vs. non-stressor) days, such that increased parental support on stressor days reflected more timely support. Results suggest that responsive parental support buffered the link between chronic stress and cardiovascular risk. Specifically, chronic stress was associated with greater risk only when parental support was not temporally aligned with stress exposure, but this association was not observed among adolescents who received timely parental support. These findings shed light on why parental support may not always exert buffering effects during adolescence, highlighting the importance of taking a developmental approach to understanding protective effects.

Higher substance use is associated with low executive control neural activity and higher inflammation.

Individuals with substance use problems show lower executive control and alterations in prefrontal brain systems supporting emotion regulation and impulse control. A separate literature suggests that heightened inflammation also increases risk for substance use, in part, through targeting brain systems involved in executive control. Research on neural and inflammatory signaling in substance use, however, has occurred in parallel. Drawing on recent neuroimmune network models, we used fMRI to examine the relationships between executive control-related brain activity (as elicited by an n-back working memory task), peripheral inflammation, as quantified by inflammatory cytokines and C-reactive protein (CRP), and substance use for the past month in 93 participants [mean age = 24.4 (SD = 0.6)]. We operationalized low executive control as a neural inefficiency during the n-back task to achieve normative performance, as reflected in higher working memory-related brain activity and lower activity in the default mode network (DMN). Consistent with prediction, individuals with low executive control and high inflammation reported more substance use over the past month, controlling for behavioral performance on the n-back, sex, time between assessments, body-mass-index (BMI), and personal socioeconomic status (SES) (interaction between inflammation and working memory-related brain activity, b = 0.210, p = 0.005; interaction between inflammation and DMN, b = -0.219, p < 0.001). Findings suggest that low executive control and high inflammation may be associated with higher substance use. This has implications for understanding psychological, neural, and immunological risk for substance use problems and the development of interventions to target each of these components.

Exposure to parental depression in adolescence and proinflammatory phenotypes 20 years later.

Although the biological embedding model of adversity proposes that stressful experiences in childhood create a durable proinflammatory phenotype in immune cells, research to date has relied on study designs that limit our ability to make conclusions about whether the phenotype is long-lasting. The present study leverages an ongoing 20-year investigation of African American youth to test research questions about the extent to which stressors measured in childhood forecast a proinflammatory phenotype in adulthood, as indicated by exaggerated cytokine responses to bacterial stimuli, monocyte insensitivity to inhibitory signals from hydrocortisone, and low-grade inflammation. Parents reported on their depressive symptoms and unsupportive parenting tendencies across youths' adolescence. At age 31, youth participants (now adults) completed a fasting blood draw. Samples were incubated with lipopolysaccharide and doses of hydrocortisone to evaluate proinflammatory processes. Additionally, blood samples were tested for indicators of low-grade inflammation, including IL-6, IL-8, IL-10, and TNF-α, and soluble urokinase plasminogen activator receptor. Analyses revealed that parental depression across youths' adolescence prospectively predicted indicators of proinflammatory phenotypes at age 31. Follow-up analyses suggested that unsupportive parenting mediated these associations. These findings suggest that exposure to parental depression in adolescence leaves an imprint on inflammatory activity that can be observed 20 years later.

Major stress in early childhood strengthens the association between peripheral inflammatory activity and corticostriatal responsivity to reward.

BACKGROUND: Severe, chronic stress during childhood accentuates vulnerability to mental and physical health problems across the lifespan. To explain this phenomenon, the neuroimmune network hypothesis proposes that childhood stressors amplify signaling between peripheral inflammatory cells and developing brain circuits that support processing of rewards and threats. Here, we conducted a preliminary test of the basic premises of this hypothesis. METHODS: 180 adolescents (mean age = 19.1 years; 68.9 % female) with diverse racial and ethnic identities (56.1 % White; 28.3 % Hispanic; 26.1 % Asian) participated. The Childhood Trauma Interview was administered to quantify early adversity. Five inflammatory biomarkers were assayed in antecubital blood - C-reactive protein, tumor necrosis factor-a, and interleukins-6, -8, and -10 - and were averaged to form a composite score. Participants also completed a functional MRI task to measure corticostriatal responsivity to the anticipation and acquisition of monetary rewards. RESULTS: Stress exposure and corticostriatal responsivity interacted statistically to predict the inflammation composite. Among participants who experienced major stressors in the first decade of life, higher inflammatory activity covaried with lower corticostriatal responsivity during acquisition of monetary rewards. This relationship was specific to participants who experienced major stress in early childhood, implying a sensitive period for exposure, and were evident in both the orbitofrontal cortex and the ventral striatum, suggesting the broad involvement of corticostriatal regions. The findings were independent of participants' age, sex, racial and ethnic identity, family income, and depressive symptoms. CONCLUSIONS: Collectively, the results are consistent with hypotheses suggesting that major stress in childhood alters brain-immune signaling.

Annual Research Review: Neuroimmune network model of depression: a developmental perspective.

Depression is a serious public health problem, and adolescence is an 'age of risk' for the onset of Major Depressive Disorder. Recently, we and others have proposed neuroimmune network models that highlight bidirectional communication between the brain and the immune system in both mental and physical health, including depression. These models draw on research indicating that the cellular actors (particularly monocytes) and signaling molecules (particularly cytokines) that orchestrate inflammation in the periphery can directly modulate the structure and function of the brain. In the brain, inflammatory activity heightens sensitivity to threats in the cortico-amygdala circuit, lowers sensitivity to rewards in the cortico-striatal circuit, and alters executive control and emotion regulation in the prefrontal cortex. When dysregulated, and particularly under conditions of chronic stress, inflammation can generate feelings of dysphoria, distress, and anhedonia. This is proposed to initiate unhealthy, self-medicating behaviors (e.g. substance use, poor diet) to manage the dysphoria, which further heighten inflammation. Over time, dysregulation in these brain circuits and the inflammatory response may compound each other to form a positive feedback loop, whereby dysregulation in one organ system exacerbates the other. We and others suggest that this neuroimmune dysregulation is a dynamic joint vulnerability for depression, particularly during adolescence. We have three goals for the present paper. First, we extend neuroimmune network models of mental and physical health to generate a developmental framework of risk for the onset of depression during adolescence. Second, we examine how a neuroimmune network perspective can help explain the high rates of comorbidity between depression and other psychiatric disorders across development, and multimorbidity between depression and stress-related medical illnesses. Finally, we consider how identifying neuroimmune pathways to depression can facilitate a 'next generation' of behavioral and biological interventions that target neuroimmune signaling to treat, and ideally prevent, depression in youth and adolescents.

Socioeconomic disadvantage and high-effort coping in childhood: evidence of skin-deep resilience.

BACKGROUND: Low socioeconomic status (SES) is a risk factor for poor outcomes across development. Recent evidence suggests that, although psychosocial resilience among youth living in low-SES households is common, such expressions of resilience may not extend to physical health. Questions remain about when these diverging mental and physical health trajectories emerge. The current study hypothesized that skin-deep resilience - a pattern wherein socioeconomic disadvantage is linked to better mental health but worse physical health for individuals with John Henryism high-effort coping - is already present in childhood. METHODS: Analyses focus on 165 Black and Latinx children (Mage = 11.5) who were free of chronic disease and able to complete study procedures. Guardians provided information about their SES. Children reported on their John Henryism high-effort coping behaviors. They also provided reports of their depressed and anxious mood, which were combined into a composite of internalizing symptoms. Children's cardiometabolic risk was captured as a composite reflecting high levels of systolic or diastolic blood pressure, waist circumference, HbA1c, triglycerides, and low high-density lipoprotein cholesterol. RESULTS: Among youth who reported using John Henryism high-effort coping, SES risk was unrelated to internalizing symptoms and was positively associated with cardiometabolic risk. In contrast, for youth who did not engage in high-effort coping, SES risk was positively associated with internalizing symptoms and was unrelated to cardiometabolic risk. CONCLUSIONS: For youth with high-effort coping tendencies, socioeconomic disadvantage is linked to cardiometabolic risk. Public health efforts to support at-risk youth must consider both mental and physical health consequences associated with striving in challenging contexts.

Ambient PM2.5 and specific sources increase inflammatory cytokine responses to stimulators and reduce sensitivity to inhibitors.

Ambient exposure to fine particulate matter (PM2.5) is associated with increased morbidity and mortality from multiple diseases. Recent observations suggest the hypothesis that trained immunity contributes to these risks, by demonstrating that ambient PM2.5 sensitizes innate immune cells to mount larger inflammatory response to subsequent bacterial stimuli. However, little is known about how general and durable this sensitization phenomenon is, and whether specific sources of PM2.5 are responsible. Here we consider these issues in a longitudinal study of children. The sample consisted of 277 children (mean age 13.92 years; 63.8% female; 38.4% Black; 32.2% Latinx) who completed baseline visits and were re-assessed two years later. Fasting whole blood was ex vivo incubated with 4 stimulating agents reflecting microbial and sterile triggers of inflammation, and with 2 inhibitory agents, followed by assays for IL-1ß, IL-6, IL-8, and TNF-α. Blood also was assayed for 6 circulating biomarkers of low-grade inflammation: C-reactive protein, interleukin-6, -8, and -10, tumor necrosis factor-α, and soluble urokinase-type plasminogen activator receptor. Using machine learning, levels of 15 p.m.2.5 constituents were estimated for a 50 m grid around children's homes. Models were adjusted for age, sex, race, pubertal status, and household income. In cross-sectional analyses, higher neighborhood PM2.5 was associated with larger cytokine responses to the four stimulating agents. These associations were strongest for constituents released by motor vehicles and soil/crustal dust. In longitudinal analyses, residential PM2.5 was associated with declining sensitivity to inhibitory agents; this pattern was strongest for constituents from fuel/biomass combustion and motor vehicles. By contrast, PM2.5 constituents were not associated with the circulating biomarkers of low-grade inflammation. Overall, these findings suggest the possibility of a trained immunity scenario, where PM2.5 heightens inflammatory cytokine responses to multiple stimulators, and dampens sensitivity to inhibitors which counter-regulate these responses.

Reflections on resilience.

Resilience research has long sought to understand how factors at the child, family, school, community, and societal levels shape adaptation in the face of adversities such as poverty and war. In this article we reflect on three themes that may prove to be useful for future resilience research. First is the idea that mental and physical health can sometimes diverge, even in response to the same social process. A better understanding of explanations for this divergence will have both theoretical and public health implications when it comes to efforts to promote resilience. Second is that more recent models of stress suggest that stress can accelerate aging. Thus, we suggest that research on resilience may need to also consider how resilience strategies may need to be developed in an accelerated fashion to be effective. Third, we suggest that if psychological resilience interventions can be conducted in conjunction with efforts to enact system-level changes targeted at adversities, this may synergize the impact that any single intervention can have, creating a more coordinated and effective set of approaches for promoting resilience in young people who confront adversity in life.

The balance of giving versus receiving social support and all-cause mortality in a US national sample.

While numerous studies exist on the benefits of social support (both receiving and giving), little research exists on how the balance between the support that individuals regularly give versus that which they receive from others relates to physical health. In a US national sample of 6,325 adults from the National Survey of Midlife Development in the United States, participants were assessed at baseline on hours of social support given and received on a monthly basis, with all-cause mortality data collected from the National Death Index over a 23-y follow-up period. Participants who were relatively balanced in the support they gave compared to what they received had a lower risk of all-cause mortality than those who either disproportionately received support from others (e.g., received more hours of support than they gave each month) or disproportionately gave support to others (e.g., gave many more hours of support a month than they received). These findings applied to instrumental social support (e.g., help with transportation, childcare). Additionally, participants who gave a moderate amount of instrumental social support had a lower risk of all-cause mortality than those who either gave very little support or those who gave a lot of support to others. Associations were evident over and above demographic, medical, mental health, and health behavior covariates. Although results are correlational, one interpretation is that promoting a balance, in terms of the support that individuals regularly give relative to what they receive in their social relationships, may not only help to strengthen the social fabric of society but may also have potential physical health benefits.

The human gut microbiome and health inequities.

Individuals who are minoritized as a result of race, sexual identity, gender, or socioeconomic status experience a higher prevalence of many diseases. Understanding the biological processes that cause and maintain these socially driven health inequities is essential for addressing them. The gut microbiome is strongly shaped by host environments and affects host metabolic, immune, and neuroendocrine functions, making it an important pathway by which differences in experiences caused by social, political, and economic forces could contribute to health inequities. Nevertheless, few studies have directly integrated the gut microbiome into investigations of health inequities. Here, we argue that accounting for host-gut microbe interactions will improve understanding and management of health inequities, and that health policy must begin to consider the microbiome as an important pathway linking environments to population health.

Skin-deep Resilience and Early Adolescence: Neighborhood Disadvantage, Executive Functioning, and Pubertal Development in Minority Youth.

Skin-deep resilience, in which youth overcome adversity and achieve success in psychological and academic domains but at a cost to their physiological well-being, has been documented in late adolescence and adulthood. However, its potential to emerge at earlier developmental stages is unknown. To address this gap, secondary data analyses were executed using waves 1 and 2 of the Adolescent Brain Cognitive Development study (n = 7712; ages 9-10 years at baseline [mean: 9.92; SD = 0.63]; 47.1% female; 66.1% White, 13.4% Black, and 20.6% Hispanic). The results indicated high levels of executive functioning were associated with improved psychological and behavioral outcomes at one-year follow-up. However, for racial and ethnic minority (i.e., Black or Hispanic) youth from disadvantaged neighborhoods, high levels of executive functioning were also associated with accelerated pubertal development. No significant interaction was observed among White youth. The findings suggest the skin-deep resilience pattern may be evident in early adolescence.

Multi-omics approach to socioeconomic disparity in metabolic syndrome reveals roles of diet and microbiome.

The epidemy of metabolic syndrome (MetS) is typically preceded by adoption of a "risky" lifestyle (e.g., dietary habit) among populations. Evidence shows that those with low socioeconomic status (SES) are at an increased risk for MetS. To investigate this, we recruited 123 obese subjects (body mass index [BMI] ≥ 30) from Chicago. Multi-omic data were collected to interrogate fecal microbiota, systemic markers of inflammation and immune activation, plasma metabolites, and plasma glycans. Intestinal permeability was measured using the sugar permeability testing. Our results suggest a heterogenous metabolic dysregulation among obese populations who are at risk of MetS. Systemic inflammation, linked to poor diet, intestinal microbiome dysbiosis, and gut barrier dysfunction may explain the development of MetS in these individuals. Our analysis revealed 37 key features associated with increased numbers of MetS features. These features were used to construct a composite metabolic-inflammatory (MI) score that was able to predict progression of MetS among at-risk individuals. The MI score was correlated with several markers of poor diet quality as well as lower levels of gut microbial diversity and abnormalities in several species of bacteria. This study reveals novel targets to reduce the burden of MetS and suggests access to healthy food options as a practical intervention.

What Are the Health Consequences of Upward Mobility?

Health disparities by socioeconomic status (SES) have been extensively documented, but less is known about the physical health implications of achieving upward mobility. This article critically reviews the evolving literature in this area, concluding that upward mobility is associated with a trade-off, whereby economic success and positive mental health in adulthood can come at the expense of physical health, a pattern termed skin-deep resilience. We consider explanations for this phenomenon, including prolonged high striving, competing demands between the environments upwardly mobile individuals seek to enter and their environments of origin, cultural mismatches between adaptive strategies from their childhood environments and those that are valued in higher-SES environments, and the sense of alienation, lack of belonging, and discrimination that upwardly mobile individuals face as they move into spaces set up by and for high-SES groups. These stressors are hypothesized to lead to unhealthy behaviors and a dysregulation of biological systems, with implications for cardiometabolic health.

Resilience in children with chronic illness: Tests of the shift-and-persist and skin-deep resilience theories.

This study investigated, and discusses the integration of, the shift-and-persist (SAP) and skin-deep resilience (SDR) theories. The SAP theory states that the combination of shifting (adjusting oneself to stressful situations through strategies like emotion regulation) and persisting (enduring adversity with strength by finding meaning and maintaining optimism) will be beneficial to physical health in children experiencing adversity. The SDR theory states that high striving/self-control will be beneficial to mental health but detrimental to physical health among those confronting adversity. This study investigated 308 children ages 8-17 experiencing the adversity of a chronic illness (asthma). SAP and SDR (striving/self-control) were assessed via questionnaires, and physical health (asthma symptoms, inflammatory profiles), mental health (anxiety/depression, emotional functioning), and behavioral (medication adherence, activity limitations, collaborative relationships with providers) outcomes were measured cross-sectionally. SAP was associated with better physical health, whereas SDR was associated with worse physical health. Both were associated with better mental health. Only SDR was associated with better behavioral outcomes. Implications of findings and discussion of how to integrate these theories are provided. We suggest that future interventions might seek to cultivate both SAP and SDR to promote overall better health and well-being across multiple domains in children experiencing adversity.

Low Socioeconomic Status Is Associated with a Greater Neural Response to Both Rewards and Losses.

Low socioeconomic status (SES) has been associated with distinct patterns of reward processing, which appear to have adverse implications for health outcomes, well-being, and human capital. However, most studies in this literature have used complex tasks that engage more than reward processing and/or retrospectively studied childhood SES in samples of adults. To clarify how SES relates to the development of reward processing tendencies, we measured income-to-poverty ratio (IPR) in 172 youth who subsequently underwent functional MRI while completing a passive avoidance task to assess neural responses to reward and loss information. Participants were 12-15 years old (mean = 13.94, SD = .52; 65.7% female) from a sample broadly representative of the Chicago area in terms of SES (IPR range = 0.1-34.53; mean = 3.90; SD = 4.15) and racial makeup (40.1% White 30.8% Black; 29.1% Hispanic). To the extent they had lower IPR, children displayed a trend toward worse behavioral performance on the passive avoidance task. Lower IPR also was associated with a greater response in attention brain regions to reward and loss cues and to reward and loss feedback. Lower IPR also was associated with reduced differentiation between reward and loss feedback in the ventromedial prefrontal and parietal cortex. The current data suggest that both increased salience of reward/loss information and reduced discrimination between reward and loss feedback could be factors linking SES with the development of human capital and health outcomes.

Violence-related distress and lung function in two longitudinal studies of youth.

BACKGROUND: Exposure to violence has been associated with lower lung function in cross-sectional studies. METHODS: We examined whether increasing violence-related distress over time is associated with worse lung function and worse asthma control or quality of life in a secondary analysis of a 48-week randomised clinical trial in 98 youth with asthma (aged 9-16 years) treated with low-dose inhaled corticosteroids (Vitamin D Kids Asthma Study (VDKA)). We then replicated our findings for lung function in a prospective study of 232 Puerto Rican youth followed for an average of 5.4 years. Violence-related distress was assessed using the Checklist of Children's Distress Symptoms (CCDS) scale. Our outcomes of interest were percent predicted lung function measures and (in VDKA only) asthma control (assessed using the Asthma Control Test) and asthma-related quality of life (assessed using the Pediatric Asthma Quality of Life Questionnaire (PAQLQ)). RESULTS: In a multivariable analysis in VDKA, each 1-point increment in CCDS score was associated with decrements of 3.27% in forced expiratory volume in 1 s (FEV1) % pred (95% CI -6.44- -0.22%; p=0.04), 2.65% in forced vital capacity (FVC) % pred (95% CI -4.86- -0.45%; p=0.02) and 0.30 points in the overall PAQLQ score (95% CI -0.50- -0.10 points; p<0.01). Similar findings for FEV1 and FVC were obtained in the prospective study of Puerto Rican youth. CONCLUSIONS: Our findings suggest that violence-related distress may worsen lung function and quality of life in youth with asthma (even those treated with low-dose inhaled corticosteroids), and further support policies to reduce exposure to violence among children in the USA and Puerto Rico.

Prospective associations between neighborhood violence and monocyte pro-inflammatory transcriptional activity in children.

Individuals exposed to persistent neighborhood violence are at increased risk for developing mental and physical health problems across the lifespan. The biological mechanisms underlying this phenomenon are not well understood. Thus, we examined the relationship between children's exposure to neighborhood violence and inflammatory activity, a process involved in the pathogenesis of multiple health problems. 236 children from the Chicago area participated in a two-year longitudinal study (mean age at baseline, 13.9 years; 67% female; 39% White, 34% Black, 33% Hispanic). Neighborhood violence was measured as the homicide frequency in a child's Census block group in the five years before study entry. Fasting blood was drawn at study entry and two years later (in eighth and tenth grade). The blood was used to quantify protein biomarkers of systemic inflammatory activity and perform genome-wide expression profiling of isolated monocytes. Neighborhood violence was associated with higher systemic inflammatory activity at both assessments. It also was associated with a monocyte transcriptional profile indicative of increased signaling along the nuclear factor-kappa B (NF-κB) and activator protein 1 (AP-1) control pathways, which are key orchestrators of pro-inflammatory effector functions. Neighborhood violence also was associated with transcriptional indications of higher beta-adrenergic and lower glucocorticoid signaling, which could function as neuroendocrine conduits linking threatening experiences with inflammatory activity. Neighborhood violence was not associated with two-year changes in protein biomarkers, although it did presage a transcriptional profile indicative of increasing AP-1 and declining glucocorticoid signaling over follow-up. Collectively, these observations highlight cellular and molecular pathways that could underlie health risks associated with neighborhood violence.

Inflammatory markers, brain-derived neurotrophic factor, and the symptomatic course of adolescent bipolar disorder: A prospective repeated-measures study.

BACKGROUND: Numerous studies have found elevated pro-inflammatory markers and reduced brain-derived neurotrophic factor (BDNF) during symptomatic episodes of bipolar disorder (BD) in adults. There is a paucity of research examining these markers in youth with BD, or longitudinally in any BD age group. METHODS: 79 adolescents, ages 13-19 years, were enrolled, including 43 symptomatic adolescents with BD and 36 age-matched healthy controls (HC). Blood samples were collected from all participants at intake, and repeatedly from BD participants at pre-specified intervals over the course of two years. Serum was assayed for levels of pro-inflammatory markers (c-reactive protein [CRP], interleukin [IL]-6, tumor necrosis factor alpha [TNF-α]), BDNF and the anti-inflammatory marker, IL-10. Week-by-week severity of mood symptoms was assessed using semi-structured interviews. RESULTS: Adolescents with BD provided an average of 4.6 blood samples, on average every 5.0 months. During the most severe symptomatic interval (i.e., highest sum of mood symptom scores) among BD adolescents, levels of CRP (p = 0.01) and pro- to anti-inflammatory ratios (CRP/IL-10; p < 0.001 and IL-6/IL-10; p = 0.046) were significantly greater, and IL-10 levels (p = 0.004) were significantly lower, vs. HC. There were no differences between BD and HC in IL-6, TNF-α or BDNF. Within BD participants, higher BDNF (p = 0.01) and IL-10 levels (p = 0.001) significantly predicted greater burden of mood symptoms over the subsequent epoch. Moreover, higher CRP levels (p = 0.009) at intake predicted greater time to recovery from the index symptomatic episode. CONCLUSIONS: In the first repeated-measures study on this topic in adolescents with BD, we found evidence that CRP, an inexpensive and ubiquitous blood test, may be useful in predicting the prospective course of BD symptoms. Future larger studies are warranted.

Childhood poverty, immune cell aging, and African Americans' insulin resistance: A prospective study.

The present study investigated developmental pathways that can contribute to chronic disease among rural African Americans. With a sample of 342 African American youth (59% female) from the southeastern United States followed for nearly two decades (2001-2019), we examined the prospective association between family poverty during adolescence (ages 11-18) and insulin resistance (IR) in young adulthood (ages 25-29) as well as underlying biological and psychosocial mechanisms. Results indicated family poverty during adolescence forecast higher levels of IR in young adulthood, with accelerated immune cell aging at age 20 partially mediating this association. Serial mediational models confirmed the hypothesized pathway linking family poverty, perceived life chances, cellular aging, and IR. Findings provide empirical support for theorized developmental precursors of chronic disease.

Harshness and unpredictability: Childhood environmental links with immune and asthma outcomes.

The environment has pervasive impacts on human development, and two key environmental conditions - harshness and unpredictability - are proposed to be instrumental in tuning development. This study examined (1) how harsh and unpredictable environments related to immune and clinical outcomes in the context of childhood asthma, and (2) whether there were independent associations of harshness and unpredictability with these outcomes. Participants were 290 youth physician-diagnosed with asthma. Harshness was assessed with youth-reported exposure to violence and neighborhood-level murder rate. Unpredictability was assessed with parent reports of family structural changes. Youth also completed measures of asthma control as well as asthma quality of life and provided blood samples to assess immune profiles, including in vitro cytokine responses to challenge and sensitivity to inhibitory signals from glucocorticoids. Results indicated that harshness was associated with more pronounced pro-inflammatory cytokine production following challenge and less sensitivity to the inhibitory properties of glucocorticoids. Furthermore, youth exposed to harsher environments reported less asthma control and poorer quality of life. All associations with harshness persisted when controlling for unpredictability. No associations between unpredictability and outcomes were found. These findings suggest that relative to unpredictability, harshness may be a more consistent correlate of asthma-relevant immune and clinical outcomes.