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Vulnerable Caregivers of Patients With Alzheimer’s Disease Have a Deficit in Circulating CD62L^- T Lymphocytes

From the Departments of Psychiatry (P.M., H.Y., T.P., I.G.) and Medicine (M.Z.), University of California, San Diego, and Veterans Administration Medical Center (T.P., I.G.), La Jolla, California.

Address reprint requests to: Paul J. Mills, UCSD Medical Center, 200 West Arbor Drive, San Diego, CA. 92103-0804; pmills{at}ucsd.edu

	ABSTRACT

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OBJECTIVE: The cell adhesion molecule, L-selectin (CD62L), serves a crucial role in the migration of naive T lymphocytes and is typically shed on cell activation. The objective of this study was to determine the effects of chronic stress on L-selectin expression on peripheral lymphocytes in elderly spousal caregivers of patients with Alzheimer’s disease.

METHODS: Twenty caregivers (mean age, 73.5 years) had their lymphocytes and catecholamine levels sampled at rest and in response to an acute psychological stressor. Ten of the caregivers were classified as susceptible or "vulnerable" based on the large amount of care required by the patient relative to the amount of respite the caregiver received during the previous 6 months.

RESULTS: At rest, vulnerable caregivers had 60% fewer L-selectin negative CD8⁺ T cells (CD8⁺CD62L^-) (p = .01) but no difference in CD8⁺CD62L⁺ cells. Vulnerable caregivers also showed significantly fewer CD4⁺CD62L^- T lymphocytes (p = .04) but no difference in CD4⁺CD62L⁺ lymphocytes. Resting plasma epinephrine levels were 44% higher in vulnerable caregivers as compared with nonvulnerable caregivers (p = .01). The acute stressor increased circulating levels of CD8⁺CD62L^- and CD8⁺CD62L⁺ lymphocytes and catecholamines similarly in both groups.

CONCLUSIONS: The findings suggest that caregivers who are more vulnerable to the chronic stress of caregiving show a decrement in circulating CD62L^- T lymphocytes, possibly by adrenomedullary activation. The data also suggest the identity of lymphocyte subsets that may underlie prior observations of immunologic decrements associated with the chronic stress of caregiving.

Key Words: Alzheimer caregivers, • L-selectin, • epinephrine, • chronic stress.

Abbreviations: SAM = sympathoadrenomedullary;; FACS = fluorescence-activated cell sorter;; FITC = fluoresceine isothiocyanate;; PE = phycoerythrin;; ANOVA = anaylsis of variance.

	INTRODUCTION

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Lymphocytes circulate throughout the body as part of routine immune surveillance and to mount inflammatory responses to foreign antigens. The trafficking of lymphocytes between the blood and lymphoid and nonlymphoid tissue depends on the expression of specific adhesion molecules, including the membrane glycoprotein L-selectin (1, 2, for review). L-selectin (CD62L) is constitutively expressed on all classes of leukocytes, including naïve T lymphocytes, which utilize L-selectin to migrate through lymph nodes and other secondary lymphoid tissue (3, 4). The transition from a naïve to an activated memory T cell is generally accompanied by a shedding of L-selectin (4–6). CD8⁺ memory T cells, for example, then acquire a distinct profile of other adhesion molecules that permit them to preferentially migrate through the tissue in which they were activated (3, 6, 7). A deficiency in L-selectin has been associated with alterations in both lymphocyte migration and reduced immune responsiveness (8).

Stress affects the number of circulating T lymphocytes as well as their function. Acute stressors activate the sympathetic nervous activation (9–11), causing a substantial lymphocytosis (12, 13, for review). More chronic stress, on the other hand, may lead to a selective reduction in lymphocyte subsets (14, 15 for review). Functional immune studies indicate that both acute and chronic stress lead to a reduction in T lymphocyte-mediated immunity (15–18). For example, the chronic stress associated with caregiving for a spouse with Alzheimer’s disease leads to poorer Con A-stimulated blastogenesis and poorer antibody response after vaccination (16, 17). Recent studies suggest that sympathetic activation, whether via psychological stress, exercise, or adrenergic agonist infusion, preferentially affects CD62L^- vs. CD62L⁺ T lymphocytes (19–21).

This study sought to determine whether the chronic stress associated with caregiving would be similarly associated with preferential alterations in CD62L^- T cells. Many studies suggest that caregivers to patients with Alzheimer’s disease report high levels of psychological distress (22, for review). Inconsistencies in the literature linking caregiving stress and physical health changes (16, 17, 22, 23) led our group to develop criteria that allow us to identify a subset of caregivers who are potentially more susceptible or "vulnerable" to the chronic stress of caregiving. Based on animal research on chronic stress, we posited that caregiving for a relative with Alzheimer’s disease produces a background level of chronic psychological and physiological stress in elderly spouses. However, whether such stress eventuates in an adverse health outcome depends on the superimposition of added severe stressors. We speculated that the most important such stressor consists of a serious "mismatch" between the amount of care required by the patient with Alzheimer’s and the amount of respite available to the caregiver (24). The presence of such a circumstance would identify the caregiver that is vulnerable to expressing the physiological and psychological effects of chronic stress. In this study, we examined a group of 20 elderly spousal caregivers to patients with Alzheimer’s disease under resting conditions and after a period of acute psychological stress. Ten of the caregivers were classified as vulnerable and the other 10 as nonvulnerable. We wished to determine whether vulnerable caregivers showed a relative reduction in CD62L^- T lymphocytes, whether this reduction was related to higher plasma catecholamine concentrations, suggesting chronic sympathoadrenomedullary (SAM) activation, and if the superimposition of an added acute experimental stressor further differentiated the chronically stressed vulnerable caregiver.

	METHODS

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Subjects
Subjects were selected from a cohort of 41 men and women caregivers participating in a longitudinal physiologic and psychosocial study of caregivers of patients with Alzheimer’s disease. The caregivers were spouses of patients with Alzheimer’s disease who were living at home; they were recruited from the University of California, San Diego (UCSD) Alzheimer’s Disease Research Center or local community support groups (mean age, 73.5 years, SD = 7). The UCSD Institutional Review Board approved the protocol. All subjects gave written consent.

Vulnerability Classification
The vulnerability classification was based on responses to an interview, which probed two dimensions: "How many hours a day does your relative require you to care for them?" and "How often do you get respite?" We classified as vulnerable those caregivers who responded that they were required to provide care for their relative more than 12 hours per day, every day, and who at the same time, received respite less than once per month. Using this classification method, 10 caregivers of the total 41 caregivers were classified as vulnerable, based on the mismatch between the amount of care required by the patient and the amount of respite the caregiver received during the previous 6 months (ie, vulnerable caregivers reported that their spouse required constant care and they did not have adequate respite from the caregiving role). The remaining 31 caregivers were identified as nonvulnerable because they reported that either their patient did not require constant care or they received adequate respite from the caregiver role. Of the 31 nonvulnerable caregivers, 10 were matched on age and gender to the vulnerable caregivers and served as controls. All subjects also answered questions on illness and medical symptoms, alcohol consumption, smoking, and exercise.

Procedure
Testing was conducted at the home of the caregiver between the hours of 8:00 and 10:00 AM. A catheter was placed in a antecubital vein and the subject then sat quietly for approximately 20 minutes. Subjects were then given instructions for two impromptu speaking tasks in a fixed order. For the first, subjects were told to prepare and then give a speech on the topic of defending oneself from being falsely accused of shoplifting. The second involved preparing and giving a speech on the topic of the most difficult caregiving situation they had encountered in the past 2 weeks. Each task contained a 3-minute preparation period and a 3-minute speaking period. This back-to-back speaking task design provides a stressor duration suitable for eliciting a lymphocytosis, is highly standardized, and has been used in previous studies examining the effects of acute psychological stress on immune parameters (15, 20). The speeches were given in the presence of two nurses and were tape recorded. Blood was collected after the 20-minute rest and after the completion of the speaking tasks.

Assays
CD8 T-cytotoxic and CD4 T-helper lymphocytes and L-selectin (CD62L) expression were determined as previously described (21). Briefly, whole blood was preserved with EDTA and maintained at room temperature (23°C). Dual-color flow cytometry (FACScan, Becton Dickinson, San Jose, CA) using SimulSET software with CD45 (FITC, Becton Dickinson) gating was used to yield the following cell types: CD8⁺CD62L^-, CD8⁺CD62L⁺, CD4⁺CD62L^-, and CD4⁺CD62L^-. Blood was processed within 3 hours of collection, and whole blood was stained with antibody before lysis (FACS Brand Lysing Solution). Cells were detected by mouse monoclonal antibodies conjugated to either FITC (Becton Dickinson) or PE (Coulter Products, Buffalo, NY). Fluorochromes were conjugated to primary antibodies. Optimal amounts of antibodies were used, and 8,000 to 15,000 events were analyzed per tube. Isotype controls (IgG₁-FITC/IgG_2a-PE) were used for each assay to determine nonspecific staining. Assay volumes were 100 µl.

Blood samples for catecholamines were collected on ice, separated in a refrigerated centrifuge, and the plasma stored at -80°C until assay. Epinephrine and norepinephrine were determined by radioenzymatic assay (25). Data analysis included analysis of variance (ANOVA) [one-way ANOVA of the resting data and two-way (group x time) repeated measures ANOVA of the resting and acute poststressor data] and Pearson product moment correlation was performed using BMDP Statistical Software (Los Angeles, CA).

	RESULTS

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Table 1 shows the characteristics of the subjects. As a result of subject matching, both groups had the same number of women and men and were of similar age. Both groups reported a similar amount of smoking, alcohol consumption, and rates of exercise. As compared with the nonvulnerable caregivers, vulnerable caregivers reported a slightly greater frequency, and a three-fold greater duration of health and medical problems over the previous 6 months, although these differences were not statistically significant.

View larger version (52K): [in this window] [in a new window]   Fig. 1. In both groups, acute psychological stress led to a significant increase over rest in circulating levels of CD8+CD62L- (top) and CD8+CD62L+ (bottom) T cells (p<.001). Compared with nonvulnerable caregivers, vulnerable caregivers had lower levels of CD8+CD62L- cells at rest and following the task (p=.01) but no difference in CD8+CD62L+ cells (mean,±SEM).

View larger version (54K): [in this window] [in a new window]   Fig. 2. Neither CD4+CD62L- (top) or CD4+CD62L+ (bottom) T cells increased significantly over baseline following the acute stressor. Vulnerable caregivers, however, had significantly lower levels of CD4+CD62L- T cells at both time points (p=.01) but not CD4+CD62L+ T cells (mean,±SEM).

Repeated measures ANOVA revealed that in response to the speeches, CD8⁺CD62L^- counts (F_1,18 = 23, p < .001), CD8⁺CD62L⁺ counts (F_1,18 = 12, p < .01), and plasma epinephrine (F_1,18 = 13.5, p = .001) and norepinephrine (F_1,18 = 6.1, p = .025) levels increased significantly. In contrast, neither CD4⁺CD62L^- or CD4⁺CD62L⁺ counts increased significantly. The vulnerable and nonvulnerable caregivers showed similar relative increases in CD8⁺CD62L^- and CD8⁺CD62L⁺ counts and in catecholamine levels in response to the acute stressor, ie, there were significant main effects of time and group, but no significant interaction effects for these variables.

	DISCUSSION

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This study examined CD62L expression on CD8⁺ T-cytotoxic and CD4⁺ T-helper lymphocytes in two groups of elderly caregivers of patients with Alzheimer’s disease. At rest, vulnerable caregivers had only 40% as many circulating CD8⁺ and CD4⁺ T lymphocytes not expressing CD62L as compared with their respective nonvulnerable counterparts. This deficit was seen also after exposure to an acute psychological stressor, implying that the vulnerable caregivers were unable to mount a lymphocytosis adequate to overcome the CD62L^- T cell deficit seen at rest (12). For comparison, we recently reported values of 254 cells/µl (SD = 214) and 124 cells/µl (SD = 177) for CD8⁺CD62L^- and CD4⁺ CD62L^- cells, respectively, in a group of healthy, young, nonchronically stressed volunteers (mean age, 33 years) (21). These values are comparable with the nonvulnerable caregivers (279 cells/µl [SD = 175] and 115 cells/µl [SD = 77], respectively) but higher than the vulnerable caregivers (113 cells/µl [SD = 73] and 47 cells/µl [SD = 63], respectively). The vulnerable and nonvulnerable caregivers were found to be similar in terms of rates of exercise, smoking, and alcohol consumption.

We are attributing the deficit in CD62L expression to CD3⁺ T cell subsets. A limitation of this study, however, is our use of dual-color flow cytometry. Because CD8 is also expressed on a portion of natural killer (NK) cells, it could be that a percentage of the CD62L^- cells were also NK cells. Although we did not ascertain CD62L expression on NK cells, we did determine the CD3^-CD16⁺56⁺ NK subset and found no difference between the vulnerable and nonvulnerable caregivers, either at rest (274 cells/µl [SD = 152] vs. 243 cells/µl [SD = 117], respectively) or at post-task (393 cells/µl [SD = 261] vs. 335 cells/µl [SD = 101], respectively) (two-way repeated measures ANOVA). Another limitation of this study is that we sampled at only one time point after the acute stress period. It is possible that the kinetics of the stress response is different in chronically stressed caregivers, and consequently, we may have missed detecting such a difference. Such a differential effect of chronic stress has not been previously demonstrated.

What mechanism(s) might underlie these adhesion observations in vulnerable caregivers? Naïve CD8⁺ T lymphocytes typically lose CD62L expression as the cell transitions to a postantigen-presented memory T lymphocyte (5, 8, 26). Memory CD8⁺ T cells use other adhesion molecules such as LFA-1 (CD11a/18), HCAM (CD44), and Tp44 (CD28) for their migration through primarily nonlymphoid tissue (26, 27). Memory CD4⁺ T cells, on the other hand, can be more readily divided according to both CD62L^- and CD62L⁺ subsets (7, 28). The phenotypic variation in CD62L expression among memory T cells may depend on the initial site of first encountered antigen, as well as the dose and physical properties of the antigen (26). CD62L expression is not static, however, and can be down- or upregulated, respectively, on T lymphocytes depending whether the cells are actively responding to antigen or in a quiescent state (7, 8, 26).

We are proposing that the chronically high epinephrine levels in the vulnerable caregivers led to a reduction of circulating CD62L^- T cell numbers as well as possibly a partial downregulation of CD62L expression per cell. Acute sympathetic activation via both psychologic stress and exercise is associated with a preferential mobilization of circulating CD62L^- but not CD62L⁺ T lymphocytes (19, 29), as well as a partial downregulation of CD62L expression (19). Although in vitro studies report catecholamine effects on the surface expression of some adhesion molecules, there have not been reports on L-selectin expression (30, 31). We recently demonstrated that infusion of a ß-adrenergic agonist (isoproterenol) results in a similar preferential mobilization of CD8⁺CD62L^- T cells (21). A fairly consistent pattern in the literature illustrates that the lymphocyte subsets that are most responsive to acute sympathetic activation, such as the CD8⁺ and natural killer cell subsets, are the very same subsets that show a deficit with more chronic stress (15, 18).

T_H1 and T_H2 cells can be differentiated according to CD62L expression, with the T_H1 subset being CD62L^- and the T_H2 subset being CD62L⁺ (32). Studies suggest that epinephrine leads to a suppression of the T_H1 phenotype of CD4⁺ cells (33–34). Given these observations, it may be that the higher epinephrine levels in vulnerable caregivers are leading to a suppression of the CD62L^-, T_H1 subset.

Kiecolt-Glaser et al. (17) showed that caregivers, as compared with matched control subjects, had poorer antibody response to vaccination and lower levels of IL-2 and IL-1ß, both T_H1 subset-associated cytokines. This same group of investigators also demonstrated slower rates of skin wound healing in caregivers (35), an observation consistent with L-selectin-deficient T lymphocyte homing to the skin (36). In this study, the vulnerable caregivers reported that their illnesses lasted three times longer than the nonvulnerable caregivers. Studies are beginning to examine possible direct relationships between lymphocyte L-selectin expression and illness (37, 38). In a different group of caregivers, we recently reported that chronically stressed caregivers were more likely to become hypertensive, more likely to receive unhealthy medical ratings by a nurse, and more likely to be hospitalized (39, 40). Our future caregiver studies will examine directly L-selectin expression and illness ratings in vulnerable caregivers.

In summary, those caregivers of patients with Alzheimer’s disease who were classified as vulnerable showed reduced levels of circulating CD4⁺ and CD8⁺ CD62L^- T lymphocytes, possibly a result of increased sympathomedullary activation. In general, the findings seem consistent with prior studies demonstrating functional immune deficits in elderly caregivers of patients with Alzheimer’s disease and suggest the identity of specific lymphocyte subsets related to this phenomenon.

	ACKNOWLEDGMENTS

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This work was supported by Grants MH42840, MO1RR-00827, and HL57265 from the National Institutes of Health. The authors are grateful to Sharyn Wilenski, RN, and Carolyn Swenerton, RN, for their assistance.

Received for publication July 7, 1998.

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