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Differential Immune Cell Chemotaxis Responses to Acute Psychological Stress in Alzheimer Caregivers Compared to Non-caregiver Controls

From the Department of Psychiatry, University of California, San Diego.

Address correspondence and reprint requests to Laura Redwine, PhD, VA San Diego Healthcare System, 9–151, 3350 La Jolla Village Dr., La Jolla, CA 92161. E-mail: lredwine{at}vapop.ucsd.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
OBJECTIVE: Caregiving for a spouse with Alzheimer’s disease is associated with alterations in various immune cell responses. Chemotaxis of immune cells to chemokines is an important factor involved in lymphocyte migration, which plays an essential role in inflammatory responses to infection and may also be involved in atherogenesis. However, the effects of chronic stress on chemotaxis have not been investigated. The objective of this study was to examine lymphocyte chemotaxis to chemokines, stromal cell-derived factor-1 (SDF-1), N-formyl-methionyl-leucyl-phenylalanine (FMLP), and a beta-adrenergic agonist, isoproteronol (ISO), in response to an acute stressor in Alzheimer’s caregivers. Correlations between immune cell chemotaxis and epinephrine and norepinephrine levels were also examined.

METHODS: Caregivers (n = 18) and noncaregiver controls (n = 9) completed a public speaking task. Blood was drawn before and immediately after the task for changes in chemotaxis to FMLP, SDF-1, and ISO, and for epinephrine and norepinephrine levels.

RESULTS: Caregivers had reduced chemotaxis to FMLP, SDF-1, and ISO in response to the speech task, compared with non-caregivers. Also, the direction of the correlations between chemotaxis to FMLP, SDF-1, and ISO and epinephrine levels differed between groups.

CONCLUSIONS: These findings suggest that immune cells released into circulation in response to acute stress are altered in caregivers. Group differences in immune responses may be due to sympathetically mediated alterations, which may have implications for caregivers’ ability to successfully mount viable immune responses, as well as, atherogenesis.

Key Words: Alzheimer’s disease, • caregivers, • stress, • immunity, • chemotaxis, • catecholamines.

Abbreviations: AD = Alzheimer’s disease;; ANOVA = analysis of variance;; FMLP = N-formyl-methionyl-leucyl-phenylalanine;; ISO = isoproterenol;; PBMC = peripheral blood mononuclear cell;; SAM = sympathetic-adrenal medullary;; SDF-1 = stromal cell-derived factor-1;; UCSD = University of California, San Diego.

	INTRODUCTION

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Caring for a spouse with Alzheimer’s disease (AD) is an arduous task that can last for many years (1). With an increase in longevity in industrialized countries AD is becoming far more prevalent, affecting approximately 4 million patients and their caregivers in the United States alone (2). There are many reports of psychological and physical health consequences of spousal caregiving of patients with dementia (3,4). The effects of increased stress on the immune system may be one factor in increased morbidity in this chronically stressed population.

Caregiving for spouses with AD is associated with immune changes such as lower percentages of total T lymphocytes and helper T lymphocytes and higher antibody titers to Epstein-Barr virus (presumably reflecting poorer cellular immune system control to the latent virus in caregivers) (5), reduced natural killer cell responses to cytokines (6), and poorer concanavalin A-stimulated lymphocyte proliferation (3). Kiecolt-Glaser et al. (7) and Vedhara et al. (8) also reported poorer antibody response to influenza vaccine, which is suggested to have implications for vulnerability to infection among older adults. There is some evidence that caregiving alters cellular expression of adhesion molecules on leukocytes with deficits in circulating CD62L(-) T lymphocytes (9). Cellular adhesion molecules allow immune cells to adhere to sites of inflammation to aid in cell migration, which is important for the accumulation of immune cells at sites of infection.

Although chemotaxis of immune cells to chemokines is also important in lymphocyte migration, at this time there are no reported studies examining chemotaxis in a chronic stress model in humans. In response to foreign antigens, leukocytes migrate from the blood to other organs in the body in order to mount immune responses. Chemokines provide specific signaling to leukocytes for extravasation from the blood, and direct locomotion and microenvironmental homing of leukocytes within tissues (10). "Misdirected" locomotion may result in atherogenesis, since atherosclerosis is considered to be mediated by immune components such as chemokines, cytokines, and cellular adhesion molecules that may be involved in adherence and migration of immune cells into aortic intima (11). Once within the aortic intima macrophages can engulf ox-LDLs, causing fatty streaks and atherogenic lesions (12).

By using an acute stress task in a chronically stressed population, variations in immune activity may be unmasked. One study found differences in immune activity between chronic stressed persons and controls in response to an acute stress task, but not at baseline (13). Natural killer cell activity increased in the control subjects (nonchronic stress) in response to an arithmetic task but not in the chronic stress group. However, few studies have addressed how chronically stressed populations respond in acutely stressful situations. This type of research may be important for determining potential mechanisms through which chronic stressors such as caregiving could lead to negative health effects.

In addition to immune changes, caregiving is associated with altered sympathetic activity reflected by elevated epinephrine (14,15) and neuropeptide Y levels (16), and elevated heart rate and blood pressure (17). Although it is thought that acute psychological stress induced sympathetic nervous system changes are linked with alterations in immunoregulatory cell number and function in humans (18–22), few studies have investigated the relationship between immune activity and sympathetic hormones in chronic stress groups. Mills et al. (23) found that in caregivers there is an inverse relationship between epinephrine and CD62L(-) cells following an acute stressor. Thus, sympathetic-adrenal medullary (SAM) activation may down regulate immune responses to acute stress in a chronically stressed population. Recent data from our group supports this conjecture. We found that stressed Alzheimer caregivers had reduced beta2-adrenergic receptor sensitivity and density on lymphocytes as compared with nonstressed caregivers and to controls (24). A decrease in beta2-adrenergic receptor sensitivity and density diminishes the degree of susceptibility of the immune cells to be stimulated by sympathetic hormones. In turn, this loss of beta-receptor function could have consequences for immune cell trafficking and migration.

Given the important role of immune cell recruitment and migration in inflammation and the role of stress in mediating leukocyte trafficking, this study examined the effects of caregiving on chemotaxis to chemokines. Stromal cell-derived factor-1 (SDF-1) and N-formyl-methionyl-leucyl-phenylalanine (FMLP) were used as chemoattractants, since SDF-1 attracts B cells, monocytes (25), and T cells (26), and FMLP is a bacterial peptide that is a general chemoattractant and attracts various immune cells (27). Also, since prior studies have observed that beta-adrenergic receptors on lymphocytes increase in response to acute stress (28) and that epinephrine levels are elevated in caregivers (14), chemotaxis to isoproteronol was measured in order to examine differences in peripheral blood mononuclear cell (PBMC) sensitivity to catecholamines in caregivers versus controls. In addition, epinephrine and norepinephrine levels were measured and the relationships between these sympathetic hormones and chemotaxis were examined.

	METHODS

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Subjects
The subjects were 18 spouses of patients with AD who were being cared for at home by the spousal caregiver and 9 control subjects whose spouses were relatively healthy. Caregivers and controls were similarly aged (72.1 vs. 67.6, t = –1.75, p = .09), did not differ in gender (89% vs. 90% females in caregivers vs. controls respectively (x² = 0.008, p = .927), and socioeconomic status (29) (36 vs. 32, t = –0.70). Caregivers had been caring for their spouse for an average of 3 to 5 years, and Alzheimer’s patients had an average Clinical Dementia Rating of "moderate" dementia. Subjects were participating in a longitudinal study of physiological and psychosocial adaptation to caregiving. One aspect of the parent study explored physiological responses of caregivers and non-caregiving controls to acute stressors (speech tasks). Subjects were recruited from the University of California, San Diego (UCSD) Alzheimer’s Disease Research Center, local community support groups, or the community at large. The UCSD Institutional Review Board approved the protocol. All subjects gave written consent.

Procedure
Research nurses gathered data in the study participant’s homes between 8:00 AM and 10:00AM. Before testing, a catheter was placed in an antecubital vein and the subject then sat quietly for 20 minutes, followed by blood pressure, heart rate measures, and a baseline blood draw. Subjects were then given instructions for an impromptu speaking task. The speech task contained a 3-minute preparation period and a 3-minute speaking period. Subjects were randomly assigned to give a speech on one of two topics. They were either told to give a speech on defending oneself from being falsely accused of shoplifting, or on being taken advantage of by a used car dealership that they purchased a car from. These types of standardized speaking tasks provide a stressor duration sufficient for eliciting heart rate and blood pressure changes, epinephrine flux and lymphocytosis, and have been used in previous studies examining the effects of acute psychological stress on immune measures and have been found to elicit comparable reactivity (30). Heart rate and blood pressure were taken and blood was drawn immediately after the task.

Chemotaxis of Peripheral Blood Mononuclear Cells Assay
Ten ml of blood was collected into heparinized tubes for each time point and processed within 3 hours. PBMCs were separated from whole blood using Ficoll-Hypaque sedimentation and resuspended in RPMI 1640 with 20 mmol/L HEPES (serum free media). Cells were incubated for 45 minutes at room temperature in the dark, shaking lightly with 0.1 uM calcein-AM (acetomethyl ester)/ 2 x 10⁶ cells per ml serum (31). Cells were then washed and resuspended to 3 x 10⁶ cell/ml RPMI 1640 with 20 mmol/L HEPES, L-glutamine, and 0.1% bovine serum albumin (chemotaxis buffer). In a modified Boyden chamber (Neuroprobe, Gaithersburg, MD) 29.5 uL/ of chemokines or chemotaxis buffer were pipeted into each well at the bottom of the chamber. SDF-1, FMLP, and isoproteronol were used as chemoattractants in this study. SDF-1 binds to CXCR4 receptors, strongly attracts B cells, but also attracts monocytes (25). CXCR4 receptors are also present on T cells (26). FMLP is a bacterial peptide that is a general chemoattractant and attracts various immune cells (27). In order to examine catecholamine sensitivity of PBMCs in caregivers versus controls, and since pilot laboratory studies indicated that PBMCs chemotax to catecholamines, isoproteronol was used as a chemoattractant. Chemokines were used at optimal doses that were determined following a series of pilot studies; the following chemokine concentrations were used, SDF-1 (25 and 100 ng/ml) (Biosource, Camarillo, CA), FMLP (1 and 10 nM) (Sigma), and isoproteronol (1 and 100 nM). After the pipetting of chemokines the membrane was snapped on top of the plate and 20uL of cell suspension was added to the top of each well. Cells were incubated for 2 hours at 37°C and then the top of the membrane was gently rinsed with phosphate buffer saline (PBS) and nonmigrated cells were scraped away using PBS dampened cotton swabs. The membrane was removed from the plate and briefly submerged in PBS. Once dry, the membrane was read by a fluorescence plate reader (CytoFluor) at an excitation of 485 nm and emission of 530 nm.

Norepinephrine and Epinephrine Measures
Blood samples for catecholamines were collected on ice and separated in a refrigerated centrifuge, and plasma was stored at –80°C until assay. Norepinephrine and epinephrine were determined by radioenzymatic assay (32). The intra- and interassay coefficients of variation for the assay were 6.5% and 11% respectively. Blood was drawn for catecholamines at baseline and immediately after the speech task.

Statistical Analyses
To evaluate changes in norepinephrine, epinephrine, systolic blood pressure, diastolic blood pressure, and heart rate a 2 (groups = caregivers and controls) x 2 (time points = baseline and post task) repeated measures analysis of variance (ANOVA) was used. To evaluate changes in PBMC migration to chemokines a 2 (groups = caregivers and controls) x 2 (time points = baseline and post task) x 2 (doses of chemokine or isoproteronol) repeated measures ANOVA were used. In order to examine the relationship between sympathetic hormones and immune cell chemotaxis in the two groups (caregivers and controls), a test was performed where correlation coefficients generated from chemotaxis and catecholamine levels were compared between the two subject groups using a Fisher r to z transformation (33).

	RESULTS

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Figures 1, 2 and 3 show the resting and post-speech chemotaxis of PBMCs to chemoattractants. At baseline, caregivers did not differ from control subjects for chemotaxis to SDF-1, FMLP, and ISO. However, in response to the speech task, repeated measures ANOVA revealed that for chemotaxis to FMLP there was a significant dose effect (F = 5.3(1,25), p = .03), time effect (F = 8.07(1,25), p < .01) and dose x time x group interaction (F = 5.1(1,25), p = .03). Figure 1 shows that while the control group increased in chemotaxis to FMLP (10 nM) in response to the task, the caregivers had a reduced response at both concentrations. For chemotaxis to SDF-1 there was a significant time effect (F = 6.02 (1,24), p = .02) and time x group interaction (F = 4.2(1,24), p = .05), but not a significant dose effect. Figure 2 reveals that again in response to the speech tasks the control group increased in chemotactic responses to SDF-1, while the caregivers had a markedly reduced response. Chemotaxis to ISO was examined by repeated measures ANOVA, revealing a significant time effect (F = 4.5(1,25), p = .04) but not a significant dose or group x time effect. However, chemotaxis to ISO at 100 nM showed a trend toward a group x time interaction (F = 3.6(1,25), p = .07, (2) = 0.087). Figure 3 suggests a reduction in chemotaxis to the higher dose of ISO in the caregiver group following the speech task, indicative of altered sensitivity to sympathetic hormones with prolonged caregiving.

View larger version (10K): [in this window] [in a new window]   Figure 1. Chemotaxis of peripheral blood mononuclear cells from Alzheimer’s caregivers to 1 nM () and 10 nM () FMLP or noncaregivers to 1 nM (•) and 10 nM () FMLP. Data are presented as cells migrating to FMLP divided by random migration of cells to media ± SEM. Blood was drawn at baseline and following the speech tasks. There was a differential change across the session with a significant dose x group x time interaction (F (1,25) = 5.1, p = .03).

View larger version (11K): [in this window] [in a new window]   Figure 2. Chemotaxis of peripheral blood mononuclear cells from Alzheimer’s caregivers to 25 pg/ml () and 100 pg/ml () SDF-1 or noncaregivers to 25 pg/ml (•) and 100 pg/ml () SDF-1. Data are presented as cells migrating to SDF-1 divided by random migration of cells to media ± SEM. Blood was drawn at baseline and following the speech tasks. There was a differential change across the session with a significant group x time interaction (F (1,24) = 4.2, p = .05).

View larger version (10K): [in this window] [in a new window]   Figure 3. Chemotaxis of peripheral blood mononuclear cells from Alzheimer’s caregivers to 1 nM () and 100 nM () ISO or noncaregivers to 1n M (•) and 100 nM () ISO. Data are presented as cells migrating to ISO divided by random migration of cells to media ± SEM. There were no significant interactions.

Tests were performed where coefficients were established from correlations between chemotaxis and catecholamine levels and compared between the caregiver and control subjects. Findings are presented in Table 1. At baseline there were group differences for correlations between chemotaxis to ISO (100 nM) and epinephrine levels (z = –3.07, p < .01). While there was a negative correlation between chemotaxis to ISO (100 nM) and epinephrine levels in the control group, there was a positive correlation for the caregivers (see Figure 4A). However, immediately following the speech task the slopes of the correlations for ISO (100 nM) and epinephrine levels appeared to change in the opposite direction from those at baseline, suggesting stress-related sympathetically mediated redistribution of immune cells (see Figure 4B). Although the groups did not have significantly different correlations after the speech, there was a trend toward group differences (z = 1.7, p = .089). There were also significant group differences in correlations between chemotaxis to FMLP (10 nM and 100 nM) and epinephrine levels following the speech task (z = 2.09, p < .05 and z = 2.66, p < .01, respectively), which may further suggest a dysregulation of sympathetic mediated immune activity in response to acute stress in caregivers.

View larger version (17K): [in this window] [in a new window]   Figure 4. (A) Correlations between chemotaxis to ISO (100 nM) and epinephrine at baseline. (B) Correlations between chemotaxis to ISO (100 nM) and epinephrine immediately following the speech task.

	DISCUSSION

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Two doses were used for each chemokine in order to determine whether there were alterations in chemotactic sensitivity in response to acute stress and/or to chronic stress (ie, caregiving). One relatively high dose and one physiologically relevant lower dose were chosen for each chemokine. We observed dose effects for FMLP but not for SDF-1 or ISO. One of the limitations of the study may be the lack of more doses included, particularly to SDF-1 since the two doses, 100 ng/ml and 25 ng/ml, may not have been different enough to determine alterations in sensitivity, leading to the absence of a dose effect.

Group differences seen only after stress, but not at rest, may have been due to alterations in sympathetically mediated redistribution of immune cells expressing chemokine receptors, SDF-1, and FMLP in response to the task. There appeared to be an alteration in sensitivity to sympathetic hormones, with a decrease in chemotaxis to ISO (100 nM) in response to the speech task in the caregiver group. Although, this finding was only marginally significant, the effect size (² = 0.087) suggested that the lack of significance may have been due to the small sample size. The observation is however consistent with our data showing caregivers have reduced beta-adrenergic receptor function compared with noncaregivers.

The similarity in norepinephrine, epinephrine, heart rate, and blood pressure responses between the groups to the speech task suggests that the groups likely engaged in the tasks to the same degree. Thus, the immune differences were not likely due to differences in engagement or effort exerted on the tasks. Although there were no differences between the caregiver and control subjects in cardiovascular responses to the speech task, differences between the groups emerged in the correlations between sympathetic hormones and immune cell chemotaxis, further suggesting differential sympathetic mediated immune responses to stress. However, these findings are still preliminary and need to be replicated with a larger sample size. At baseline, control subjects had a negative relationship between chemotaxis to ISO and epinephrine levels, which changed to a positive relationship post-task, suggesting that epinephrine may switch from being inhibitory during rest to stimulatory following acute stress. This switch may be adaptive in order to fight pathogens in situations of acute stress. However, in the caregivers a completely different pattern was generated. At baseline there was a positive relationship between chemotaxis to the higher concentration of ISO and epinephrine levels and a negative relationship following the speech task. Similarly, the caregivers had positive relationships between chemotaxis to FMLP (1 nM) and epinephrine levels, and SDF-1 (100 ng/ml) and epinephrine levels at baseline and negative relationships following the speech task. This was in contrast to the control subjects. These findings may suggest that the caregivers’ sympathetic mediated immune responses may be dysregulated.

The findings from this study may have implications for health. A positive relationship between chemotaxis to chemokines and epinephrine levels in caregivers at baseline may suggest that elevations in basal epinephrine levels may lead to increased infiltration of immune cells to the intima of blood vessels, contributing to atherosclerosis. Chemotaxis to SDF-alpha may be involved in this process, since SDF-alpha receptors are found to increase by 3 to 4 times on macrophage-derived foam cells compared with other endothelial cells (35). On the other hand, reduced chemotaxis following acute stressors in the caregivers may be deleterious for their ability to mount an immune response to infectious disease during stress. However, studies are needed to make a more definitive connection between in vitro immune measures such as chemotaxis and clinical implications.

	ACKNOWLEDGMENTS

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This work was supported in part by award 5R01AG015301 to 14 from the National Institutes of Health, National Institute on Aging.

Received for publication February 4, 2004.

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