Suzi Hong

Inflammation as a psychophysiological biomarker in chronic psychosocial stress.

The measurement of inflammation by biomarkers not only documents clinically relevant infections but also offers an important tool to pin point potentially harmful effects of chronic psychosocial stressors. This article focuses firstly on basic biology of inflammation and lists main biomarkers currently used in psycho-physiologic research. In the second part, the effects of the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system as pathways modulating stress-related inflammation are discussed. Furthermore, current evidence of how chronic psychosocial stressors are related to alterations in inflammatory activity is presented. In summary, job stress, low socioeconomic status, childhood adversities as well as life events, caregiver stress, and loneliness were all shown to exert effects on immunologic activity.

Role of the immune system in HIV-associated neuroinflammation and neurocognitive implications ☆

Individuals living with HIV who are optimally treated with combination antiretroviral therapy (cART) can now lead an extended life. In spite of this remarkable survival benefit from viral suppression achieved by cART in peripheral blood, the rate of mild to moderate cognitive impairment remains high. A cognitive decline that includes impairments in attention, learning and executive function is accompanied by increased rates of mood disorders that together adversely impact the daily life of those with chronic HIV infection. The evidence is clear that cells in the brain are infected with HIV that has crossed the blood-brain barrier both as cell-free virus and within infected monocytes and T cells. Viral proteins that circulate in blood can induce brain endothelial cells to release cytokines, invoking another source of neuroinflammation. The difficulty of efficient delivery of cART to the central nervous system (CNS) contributes to elevated viral load in the CNS, resulting in a persistent HIV-associated neurocognitive disorders (HAND). The pathogenesis of HAND is multifaceted, and mounting evidence indicates that immune cells play a major role. HIV-infected monocytes and T cells not only infect brain resident cells upon migration into the CNS but also produce proinflammatory cytokines such as TNF and IL-1ß, which in turn, further activate microglia and astrocytes. These activated brain resident cells, along with perivascular macrophages, are the main contributors to neuroinflammation in HIV infection and release neurotoxic factors such as excitatory amino acids and inflammatory mediators, resulting in neuronal dysfunction and death. Cytokines, which are elevated in the blood of patients with HIV infection, may also contribute to brain inflammation by entering the brain from the blood. Host factors such as aging and co-morbid conditions such as cytomegalovirus co-infection and vascular pathology are important factors that affect the HIV-host immune interactions in HAND pathogenesis. By these diverse mechanisms, HIV-1 induces a neuroinflammatory response that is likely to be a major contributor to the cognitive and behavior changes seen in HIV infection.

Relation of nocturnal blood pressure dipping to cellular adhesion, inflammation and hemostasis.

Background Subjects who fail to dip their nocturnal blood pressure (BP) are at substantially increased risk for cardiovascular diseases. The pathogenetic mechanisms of this relationship have not been elucidated. We investigated whether non-dipping would relate to procoagulant and proinflammatory activity. Design Study participants were 76 unmedicated normotensive and hypertensive subjects (44 male, 32 female; 41 white, 35 black; mean age, 36 ± 8 years) who underwent 24-h outpatient ambulatory BP monitoring. Based on whether their average nocturnal systolic BP relative to their average daytime systolic BP declined by less than 10%, 34 subjects were categorized as non-dippers. D-dimer, plasminogen activator inhibitor-1, von Willebrand factor, soluble intercellular adhesion molecule-1, and interleukin-6 were measured in plasma. Results Multivariate analyses showed that D-dimer (median/interquartile range, 242/162–419 ng/ml versus 175/132–254 ng/ml; P = 0.041), plasminogen activator inhibitor-1 (36/19–61 ng/ml versus 17/6–44 ng/ml; P = 0.010), von Willebrand factor (122/91–179% versus 92/66–110%; P = 0.001), and soluble intercellular adhesion molecule-1(227/187–291 ng/ml versus 206/185–247 ng/ml; P = 0.044) were all higher in non-dippers than in dippers. Adjustment for gender, ethnicity, age, body mass index, smoking status, hypertension status, and social class revealed independent effects of non-dipping. Non-dippers continued to have higher D-dimer (P = 0.030) and von Willebrand factor (P = 0.034) than dippers. A similar trend not reaching statistical significance emerged for soluble intercellular adhesion molecule-1 (P = 0.055). In contrast, dipping status had no effect on interleukin-6. Conclusion Nocturnal BP non-dipping is associated with elevated levels of molecules related to endothelial dysfunction and atherosclerosis. The finding provides one possible mechanism linking non-dipping with cardiovascular disease.

Age and Ethnicity Differences in Short-Term Heart-Rate Variability

Objective: Hypertension is more frequent and more severe in older individuals and in African Americans. Differences in autonomic nervous system activity might contribute to these differences. Autonomic effects on the heart can be studied noninvasively through analysis of heart rate variability (HRV). We examined the effects of age and ethnicity on HRV. Methods: We studied 135 subjects (57 African Americans and 78 Caucasian Americans), aged 23 to 54 years. Using their surface electrocardiogram (ECG) data, we calculated the HRV indices with spectral analyses. High frequency (HF) power was used to index parasympathetic activity, whereas the ratio of low to high frequency power (LF/HF) was used to index sympathovagal balance. Results: Three HRV indices (HF, LF power, and LF/HF) were significantly related to age in Caucasian Americans but not in African Americans. The effect of age, ethnicity, and the age-by-ethnicity interaction on HF and LF power was significant, even after controlling for gender, body mass index, and blood pressure. Conclusions: Young African Americans manifested a pattern of HRV response similarly to older Caucasian Americans. These results suggest that young African American individuals might show signs of premature aging in their autonomic nervous system. HRV = heart rate variability; HF = high frequency; LF = low frequency; AA = African Americans; CA = Caucasian Americans; BP = blood pressure; ECG = electrocardiogram; BMI = body mass index; ARIC = Atherosclerosis Risks in Communities.

The association between interleukin-6, sleep, and demographic characteristics.

We examined the relationship between the pro-inflammatory cytokine IL-6 and sleep architecture in 70 healthy men and women. Blood was drawn in the early morning for assessment of IL-6 followed by nocturnal sleep monitoring with polysomnography. Sleep records were scored for sleep stages using standard criteria. Morning IL-6 levels were positively correlated with REM latency after sleep onset [rho = .31, p = .01], percent (%) stage 1 sleep [rho = .23, p = .053], % wake after sleep onset (WASO) [rho = .29, p<.05]. IL-6 levels were negatively correlated with sleep efficiency [rho = -.36, p<.01] and slow wave sleep (SWS) [rho = -.26, p<.05]. After controlling for demographic variables including race, gender, age, and BMI, multiple hierarchical regression analyses revealed that morning IL-6 levels accounted for a significant portion of the variance of REM latency (p<.01), sleep efficiency (p<.01), and % WASO (p = .01). IL-6 was no longer associated with % stage 1 sleep, SWS, and total sleep time after controlling for the demographic characteristics. These findings suggest that the inflammatory marker IL-6 is associated with sleep quality and that certain individual characteristics such as race, gender, and age modify that relationship. Higher IL-6 levels were associated with lower quality of sleep among healthy asymptomatic men and women.

Effects of an exercise challenge on mobilization and surface marker expression of monocyte subsets in individuals with normal vs. elevated blood pressure.

High blood pressure (BP) and monocyte activation are associated with atherogenic processes. Especially, CD16 expressing monocytes are shown to be activated in many inflammatory conditions but their characteristics in hypertension is unknown. We compared CD16(++), CD16(+) and CD16(-) monocyte populations and their cellular adhesion molecule (CAM), chemokine receptor, and activation marker expression in response to a moderate 20-min treadmill exercise bout at 65-70% V O(2peak) in 44 participants with elevated (EBP) or normal BP (NBP). Blood was drawn before, immediately after, and 10min after exercise. Phenotyping of monocytes and detection of surface markers were done by flow cytometry. Monocyte subset by exercise [pre, post, 10-min post] repeated measures ANOVA and group [EBP vs. NBP] by exercise repeated measures of ANCOVA with age, BMI, and fitness as covariates were employed. Circulating numbers of all the three monocyte subsets increased after exercise (p<0.001), with the largest % increase for CD16(+)CD14(++). Percents of CD16(++)CD14(+) and CD16(+)CD14(++) increased, whereas % CD16(-)CD14(++) decreased (p<0.001). Also, pre to post exercise changes in CD62L, CD11b, CXCR2, and HLA-DR expression were different among the monocyte subsets (ps<0.001). BP status did not significantly affect monocyte subset trafficking, although post-exercise changes in CD62L and CXCR2 levels were greater in EBP individuals (p<0.05). We conclude that exercise leads to a different mobilization among monocyte subsets based on CD16 expression. Individuals with high BP showed greater responses to a physical challenge in some monocyte chemokine receptors and selectins, but its clinical implications need further examination.

Cardiac-related hospitalization and/or death associated with immune dysregulation and symptoms of depression in heart failure patients

Objective: Congestive heart failure (CHF) patients with depressive symptoms have a greater risk of morbidity and mortality. Immune activity such as inflammation is increasingly implicated as underlying this relationship. However, it is unknown whether there is a broader spectrum of immune dysregulation beyond inflammatory activity. This study examined in CHF patients the relationship of depressive symptoms with cellular immune activity measured by Th1/Th2 ratios and cardiac rehospitalization and/or death. Method: Eighteen patients with CHF (mean age = 62, NYHA classes II–IV) were enrolled and depressive symptoms were measured with interviewer ratings using the Hamilton Rating Scale-Depression. For the determination of Th1/Th2 ratios, intracellular cytokine expression of interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) CD4+ T cells were measured by flow cytometry. Plasma interleukin-6 levels were measured to ascertain circulating inflammatory cytokine activity. Patient records were examined for cardiac related rehospitalization or cardiac related death over a two-year period after baseline depression and immune measures were taken. Results: Higher depression scores were associated with a prospective increase in incidence of cardiac related hospitalizations and/or death (p = .037). Lesser IFN-gamma/IL-10 expressing CD4+ T cell ratios were related to higher depressive symptom scores at baseline (p = .005) and a prospective increased incidence of cardiac related hospitalization or death over a two-year period (p = .05). Conclusions: A shift in the Th1/Th2 ratio may play a role in the association between depressive symptoms and morbidity and mortality in CHF patients, suggesting broader immune dysregulation than previously considered. CHF = congestive heart failure; IFN = interferon; IL = interleukin; NYHA = New York Heart Association; BNP = B-type natriuretic peptide; HAM-D = Hamilton Depression Scale; EF = ejection fraction; BMI = body mass index.

Immune cell CD62L and CD11a expression in response to a psychological stressor in human hypertension.

This study examined the effects of hypertension and an acute psychological stressor on white blood cells and their expression of CD62L and CD11a. Seventeen mild hypertensive and 23 normotensive volunteers were studied prior to and following a standardized laboratory public speech. In response to the speech, all subjects increased the number of circulating leukocyte populations (ps<.01). Patients with hypertension increased the number of circulating white blood cells more than normotensives (p<.01). Hypertensives also showed a greater increase in the number of circulating CD3(+)CD8(+) T cells (p<.02) in response to the speech. Only hypertensives increased the number of circulating CD8(+)CD62L(high) T cells (p=.001). The density of CD11a on lymphocytes was increased in all subjects following the speech (p<.001). Hypertensives showed a greater mean density of CD11a on lymphocytes (p<.01). Coupled with observations of increased expression of the endothelial CD11a ligand ICAM-1 in hypertension, these findings are consistent with the notion that patients with hypertension exhibit a circulatory environment conducive to increased leukocyte adhesion. Exposure to repeated psychological stressors may further augment this potentially adverse circulatory environment.

Stress, exercise, and Alzheimer's disease: a neurovascular pathway.

Genetic factors are known to play a role in Alzheimers disease (AD) vulnerability, yet less than 1% of incident AD cases are directly linked to genetic causes, suggesting that environmental variables likely play a role in the majority of cases. Several recent human and animal studies have examined the effects of behavioral factors, specifically psychological stress and exercise, on AD vulnerability. Numerous animal studies have found that, while stress exacerbates neuropathological changes associated with AD, exercise reduces these changes. Some human studies suggest that psychological stress can increase the risk of developing AD, while other studies suggest that exercise can significantly reduce AD risk. Most animal studies investigating the mechanisms responsible for the effects of these behavioral factors have focused on neuronal processes, including the effects of stress hormones and neurotrophic factors on the neuropathological hallmarks of AD, namely amyloid-beta (Aβ) deposition and tau-phosphorylation. However, cumulative evidence indicates that, in humans, AD is associated with the presence of cerebrovascular disease, and cardiovascular risk factors are associated with increased risk of developing AD. There is an extensive literature demonstrating that behavioral factors, particularly stress and exercise, can powerfully modulate the pathophysiology of vascular disease. Thus, the following model proposes that the influence of stress and exercise on AD risk may be partially due to the effects of these behavioral factors on vascular homeostasis and pathology. These effects are likely due to both indirect modification of AD risk through alterations in vascular risk factors, such as hypertension, diabetes, and aortic stiffening, as well as direct influence on the cerebrovasculature, including changes in cerebral blood flow, angiogenesis, and vascular disease. Future studies examining the effects of behavioral factors on AD risk should incorporate measures of both peripheral and cerebral vascular function to further our understanding of the mechanisms by which behavior can modify AD susceptibility. Greater knowledge of the molecular mechanisms behind these behavioral effects would further our understanding of the disease and lead to innovative treatment and preventive approaches.

Effects of regular exercise on lymphocyte subsets and CD62L after psychological vs. physical stress

OBJECTIVE To examine the effects of regular physical activity on lymphocyte responses to a speech stressor and an exercise challenge. METHODS We assessed lymphocyte subsets and CD62L expression pre, immediately after and 15 min after a speech task vs. exercise in 24 high vs. 24 low physically active subjects. Catecholamine levels were determined by radioenzymatic assay, and enumeration of cells was assessed by flow cytometry. RESULTS Both tasks induced significant increases in plasma epinephrine (EPI; P<.05) and norepinephrine (NE; P<.001) levels. Similarly, both tasks led to increases in the numbers of lymphocyte subsets (P<.05). Physically active individuals showed attenuated responses to the speech stressor in numbers of CD62L(+), CD45RA(+), CD45RO(+) CD8(+), CD45RO(+) T(H) and CD62L(-) natural killer (NK) cells (Ps<.05). In contrast, physical activity level had no significant effect on lymphocyte subsets or CD62L expression in response to exercise. CONCLUSION The findings suggest that physical fitness affects immune responses to a psychological but not a physical stressor. It is an interesting but open question whether attenuated lymphocyte trafficking responses to stress in regular exercisers might have clinical implications regarding host defense by the immune system.