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Psychosomatic Medicine 69:40-46 (2007)
© 2007 American Psychosomatic Society

ORIGINAL ARTICLES

Attachment Security and Immunity in Healthy Women

Angelo Picardi, MD, Francesca Battisti, MD, Lorenzo Tarsitani, MD, Maurizio Baldassari, MD, Alfredo Copertaro, MD, Eugenio Mocchegiani, MD and Massimo Biondi, MD

From the Center of Epidemiology and Health Surveillance & Promotion (A.P.), Italian National Institute of Health, Rome, Italy; Department of Psychiatric Science and Psychological Medicine (F.B., L.T., M.Biondi), University "La Sapienza" of Rome, Italy; Occupational Health Unit (M.Baldassari), United Hospitals of Ancona and Politechnic University of Marche, Ancona, Italy; Healthcare Workers Service (A.C.), Regional Health Administration, Ancona, Italy; Immunology Center, Section Nutrition, Immunity and Aging, Research Department (E.M.), Istituto Nazionale Riposo e Cura Anziani, Ancona, Italy.

Address correspondence and reprint requests to Angelo Picardi, Italian National Institute of Health, Center of Epidemiology and Health Surveillance & Promotion, Mental Health Unit, Viale Regina Elena, 299-00161 Rome, Italy. E-mail: angelo.picardi{at}iss.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Background: Attachment security is associated with health and possibly autonomic and endocrine reactivity to stress, however the relationship between attachment style and immune function has not yet been investigated.

Methods: A random sample of 61 female nurses provided a blood sample and completed the Perceived Stress Scale, the Multidimensional Scale of Perceived Social Support, the 20-item Toronto Alexithymia Scale, and the Experiences in Close Relationships questionnaire. Immune measures included immunophenotypic analysis, lymphocyte proliferative response to Phytohemagglutinin, and NK cell cytotoxicity (NKCC). Statistical analysis focused on the relationship between attachment-related anxiety or avoidance and immune measures. Multiple regression was used to control for perceived stress and support, alexithymia, health-related behaviors possibly influencing immunity, and use of anti-inflammatory drugs, tobacco or alcohol.

Results: Attachment-related anxiety was not associated with any immune parameter. Attachment-related avoidance was associated with lower NKCC. This association was independent from the number of circulating NK cells, which suggests a change in cell functionality. Perceived stress was also associated with lower NKCC.

Conclusions: This study suggests a link between attachment security and immunity. While our findings should be interpreted with great caution and need replication, they are consistent with previous work suggesting that insecure attachment may be a risk factor for health and may relate to biological processes relevant to health.

Key Words: attachment • stress • support • emotion regulation • immunity

Abbreviations: PSS = Perceived Stress Scale; MSPSS = Multidimensional Scale of Perceived Social Support; TAS-20 = 20-item Toronto Alexithymia Scale; ECR = Experiences in Close Relationships questionnaire; PHA = Phytohemagglutinin; NKCC = Natural Killer Cell Cytotoxicity; BMI = body mass index.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
There is evidence that stress can affect immunity (1,2). However, people respond differently to stressful events and situations. Personality characteristics are associated with variability in the neural processing of threatening stimuli (3) and influence how an individual interprets and responds to stressors. Therefore, individual differences have a potentially important role in modulating the immune system (4,5).

Compared with the literature linking stress (1,2) and social support (6) with immune function, relatively few studies investigated the relationship between individual differences and immunity. Natural Killer cell cytotoxicity (NKCC) was found to be negatively associated with neuroticism or ‘emotional instability’ (7–9), positively related to hardiness (10), and variably associated with extraversion (7,11). Also, sense of coherence was found to moderate the relationship between stress and NKCC (12). Other studies suggested that dispositional optimism is negatively related to measures of cellular immunity when stressors are difficult, but positively related when stressors are easy (13).

Attachment theory (14) is attracting increasing interest from psychosomatics (15). It postulates an innate, evolutionarily grounded motivational system including cognitive, emotional, and behavioral components, designed to promote and maintain some key relationships from infancy to old age. In infancy and childhood the parent-child relationship is the primary attachment bond, while in adulthood this place is taken by committed romantic relationships. Attachment style develops in childhood, beginning in infancy, based on the child’s relationship with his or her primary caregiver, and affects an individual’s close relationships throughout life. It is postulated to be the result of inner representations of self and attachment partner, called ‘internal working models’, that guide affects and behavior in close relationships. Attachment style is related to various psychological and social phenomena including perceptions of and beliefs about self and others, emotion regulation, and quality of close relationships. Secure attachment is characterized by relatively low levels of two dimensions underlying attachment style, named attachment-related anxiety and avoidance. Securely attached individuals tend to see themselves as being valued and worthy of affection, and to see their partner as being trustworthy, reliable, and available for support if needed. Insecure attachment is characterized by high attachment-related anxiety, avoidance, or both. Individuals with high attachment-related anxiety tend to be preoccupied with their romantic relationships, to feel unappreciated, and to worry about insufficient love or abandonment. Individuals with high attachment-related avoidance have difficulty trusting or depending on others, feel uncomfortable with emotional closeness and intimacy, and are reluctant to ask their partner for support. In adults, the convergent and discriminant validity of the dimensions underlying attachment style is supported by many studies showing that they are not redundant, despite being related in a theoretically meaningful way, to constructs such as temperament, character, the ‘Big Five’ factors, coping strategies, support seeking, self-esteem, self-efficacy, verbal intelligence, social desirability, physical attractiveness, and relationship satisfaction (16,17).

Recent studies suggested intriguing links between attachment security and health. Attachment insecurity was found to be associated with several mental disorders (18) and physical illnesses (15,19,20). Also, studies in infants (21,22) and adults (23) suggested a link between attachment insecurity and altered autonomic and endocrine reactivity to stress. However, to our knowledge, the relationship between attachment style and immune function has not yet been investigated.

This study explored the relationship between attachment style and both enumerative and functional immune parameters in healthy women. Given its association with poorer health and altered psychophysiological reactivity, we hypothesized that attachment insecurity would be associated with lower immunity. We controlled for psychosocial factors associated with immunity or health (perceived stress, social support, alexithymia), and various health-related behaviors possibly influencing immunity (physical exercise, quality of sleep, use of tobacco, alcohol or anti-inflammatory drugs).


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Participants and Procedure
The study was performed in Ancona, Italy, from January to November 2004 on a random sample of female nurses from the local National Health Service Unit. As the study was performed as part of the periodic occupational health examinations, it needed no formal approval by the local ethical committee, which was nevertheless consulted and gave informal authorization. Participants were fully informed of the study aims and procedures, were offered the opportunity to ask questions, and gave their written informed consent to participate. Inclusion criteria were age less than 60 years, at least two years in current job, absence of infectious diseases and chronic medical diseases, no history of major psychiatric disorders, and no current or recent treatment with drugs affecting the immune system (eg, corticosteroids, cytostatics, immunosuppressors, immunomodulators).

Participants were scheduled for a baseline assessment session between 8:30 and 9:30 AM in a quiet and comfortable room. They were asked to refrain from exercising, smoking, eating, drinking alcohol, and taking medication for at least 12 hours before the session. After participants had rested for at least 5 minutes in the sitting position, a blood sample was taken from a forearm vein and processed as described below or stored at –20°C for subsequent analyses. Then, participants had breakfast and were administered a standardized form to collect information about health-related habits, and several self-completed questionnaires with established validity and reliability in counterbalanced order. Follow-up evaluations were scheduled and will be the subject of future papers.

Assessment
Psychometric Instruments
The Experiences in Close Relationships (ECR) questionnaire is a self-report instrument with documented validity and reliability (17,24) which includes 36 items, each scored on a 7-point scale, and yields scores on two scales, named Avoidance and Anxiety. Higher scores indicate greater attachment-related avoidance and anxiety, respectively.

The 20-item Toronto Alexithymia Scale (TAS-20) is a self-report questionnaire with demonstrated reliability and validity (25) which comprises 20 items, each scored on a 5-point scale. It measures the difficulty identifying and describing feelings, and the tendency to focus on the concrete details of external events rather than on one’s own feelings and fantasies. Higher scores denote higher alexithymic characteristics.

The Perceived Stress Scale (PSS) (26) is a well-known self-report questionnaire that has been thoroughly validated and widely used. The items are scored on a 5-point scale and summed to yield a total score. Higher scores reflect greater perceived stress. We used the 10-item version.

The Multidimensional Scale of Perceived Social Support (MSPSS) is a validated self-report questionnaire (27) which comprises 12 items, each scored on a 7-point scale. Higher scores indicate greater perceived adequacy of support from family, friends, and significant others.

Cytotoxicity Assay
The K562 tumor cell line was used as the target. NKCC was assayed using a fluorimetric method described previously (28). Briefly, a stock solution (20 mg/ml acetone stored at –20°C) of carboxyfluorescein diacetate (c’FDA; Molecular Probes, USA) was diluted in phosphate-buffered saline (PBS) to a final concentration of 75 µg/ml. K562 cells were washed twice with PBS and then labeled with c’FDA by incubation at 37°C in a humidified 5% CO2 incubator for 30 minutes. They were then washed 3 times in PBS containing 1% bovine serum albumin and resuspended at a final concentration of 1 x 105 cells/ml. c’FDA-labeled K562 cells (1 x 104) were incubated with effector cells in 200 µl total volume per well of a round microtiter plate. Effector target cell ratios from 100:1 to 12.5:1 were tested in triplicate. The plates were kept at 37°C in a humidified 5% CO2 incubator for 3 hours and then centrifuged at 1500 rpm for 5 minutes. The supernatant was separated by rapidly inverting the plate and flicking the supernatant out. Then, 100 ml of 1% Triton X-100 in 0.05 M borate buffer, pH 9.0, was added to each well. The plate was kept for 20 hours at 4°C to allow for solubilization and then read for fluorescence with a Titertek Fluoroskan II (Flow Laboratories, USA). The proportion of specific lysis was calculated as follows:

% Specific Lyses = F med – F exp/F med

where F is the fluorescence of solubilized cells after the supernatant has been removed, med = F from target cells incubated in culture medium alone, and exp = F from target cells incubated with effector cells.

Results were then normalized by conversion to lytic units, calculated as the number of effector cells required to lyse 20% of target cells and reported as the number of lytic units contained in 107 cells (29).

Lymphocytes Proliferative Response
Ficoll-Hypaque enriched peripheral blood mononuclear cells at the concentration of 1 x 106/ml in Roswell Park Memorial Institute medium (GIBCO, USA) containing 10% fetal calf serum (GIBCO), penicillin (100 U/ml) and streptomycin (10 µg/ml), were used. Aliquots of 0.1 ml were distributed in microwells (Nunc, Denmark). Phytohemagglutinin (PHA) (Difco, USA) to reach the final concentrations of 0.0125 µg/ml and 0.05 µg/ml was added in the amount of 10 µL/well. After 48 hours of incubation in a 5% CO2-air environment at 37°C, H3-Td (Amersham, UK: specific activity, 2 Ci/ml) was added in the amount of 1 µCi/well. After additional 18 hours of incubation in CO2 atmosphere, cultures were killed by means of a cell harvester (Skatron, Norway) and radioactivity was measured by a scintillator counter (Packard, Italy). All cultures were performed in quadruplicate. The results, referring to the highest responses regardless of the mitogen concentration used, are expressed in counts per minute (cpm) per culture (30).

Immunophenotypic Analysis
Immunophenotypic analysis was carried out on fresh whole blood within 2 hours after collection, using a direct immunofluorescence cytofluorimetric assay. Samples were collected into evacuated blood collection tubes containing ethylenediamenetetraacetic acid (Becton Dickinson Vacutainer Systems). Lymphocyte surface antigens were identified by the following monoclonal antibodies (mAbs): antihuman CD3 (APC), antihuman CD4 (FITC), antihuman CD8 (APC), antihuman CD19 (PE), antihuman CD16 (PE), and antihuman CD56 (FITC), all from Becton Dickinson, San Jose, CA, USA. After a 30-minute incubation at 4°C with monoclonal antibodies, fresh whole blood specimens were treated with lysing reagent (FACS Lyse, Becton Dickinson) for flow cytometry.

Four-color flow cytometric acquisition was performed on FACScalibur (Becton Dickinson), using MultiSet software (Becton Dickinson). At least 10,000 events/sample were acquired. Percentages of cells expressing CD3+CD4+(Helper T lymphocytes), CD8+(cytotoxic/suppressor T lymphocytes), CD19+(B cells), CD3–CD16+CD56+(NK cells) were calculated, and absolute values were obtained based on lymphocyte count provided by an automated Hematology Analyzer (Gen-S, Beckman-Coulter, Fullerton, CA, USA).

Statistical Analysis
Analysis was performed with SPSS 13.0 for Windows (SPSS Inc., Chicago, IL). All tests were two-tailed, with alpha set at 0.05.

First, participants scoring in the highest quartile on the ECR Avoidance or Anxiety scales were classified as characterized by high attachment-related avoidance or anxiety, respectively. In most cases, scores in this range would likely reflect attachment insecurity.

Then, the {chi}2 test (with Yates’ correction for 2 x 2 tables) or Fisher’s exact test was used as appropriate to analyze differences between participants with and without high attachment-related anxiety or avoidance in categorical variables, while the t test was used to analyze differences in continuous variables. Although we performed several such comparisons, we did not adjust the alpha level because any form of correction to control the potential increase in type I error rate would probably have been excessively conservative given the exploratory nature of this study (31).

Finally, the association between attachment security and selected immune variables was further tested with multiple linear regression, to adjust for possible confounders. Before regression analysis, Mahalanobis distance was computed to screen for multivariate outliers. Also, the residual plot was examined to screen for outliers in the solution. In both cases, a criterion of p < .001 was used to define outliers. No outliers were found.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
Of 70 nurses who accepted to participate, 61 returned a complete ECR and were included in this study. Their mean age was 36.5±7.3 years (range 24–58), while their mean score on the ECR Anxiety and Avoidance scales was 64.8±20.9 and 41.0±17.1, respectively. These figures are closely similar to those of females in this age range who participated in the Italian ECR validation study on 746 subjects (32). Attachment-related anxiety correlated with alexithymia, r (59) = 0.48, p <. 001, and perceived stress, r (58) = 0.45, p < .001, whereas attachment-related avoidance correlated with alexithymia, r (59) = 0.27, p = .03, but not perceived stress, r (58) = 0.14, p = .29. The results of immunophenotypic analysis were available for all participants, whereas the results of the NKCC assay and lymphocyte proliferative response were available for 58 and 53 participants, respectively.

In univariate analysis, NK cell cytotoxicity and number were the only immune variables showing a trend toward an association with attachment security (Table 1). Thus, we focused on NK function in multiple regression analysis, which included 57 participants with complete data for all independent variables. Two regression models were built. In each model, NKCC served as the dependent variable, whereas either attachment-related anxiety or avoidance served as the independent variable. Also, we included as independent variables NK cell number (closely linked with NKCC); psychosocial factors associated with immunity or health (perceived stress, social support, alexithymia); health-related behaviors possibly influencing immunity [regular physical exercise, sleeping well, use of nonsteroidal anti-inflammatory drugs (NSAIDS), tobacco, alcohol]. We did not include caffeine and tranquilizers use (unlikely to be confounders as they were used by most or only a few participants, respectively), or age and body mass index (hardly confounders in a sample of young-to-middle aged healthy women, and not associated with attachment security in univariate analysis). For each model, Tables 2 and 3 display R, R2, adjusted R2, standardized regression coefficients (Beta), and squared semipartial correlations which express the unique contribution of an independent variable to the total variance in the dependent variable.


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  		TABLE 1. Comparison Between Participants With and Without High Attachment-related Anxiety or Avoidance on Age, Health-related Habits, Psychological Characteristics, and Immune Variables

 

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  		TABLE 2. Multiple Regression of NK Cell Cytotoxicity on Attachment-related Anxiety, NK Cell Number, Psychosocial Factors Associated With Immunity or Health, and Health-related Behaviors Possibly Influencing Immunity (N = 57)

 


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  		TABLE 3. Multiple Regression of NK Cell Cytotoxicity on Attachment-related Avoidance, NK Cell Number, Psychosocial Factors Associated With Immunity or Health, and Health-related Behaviors Possibly Influencing Immunity (N = 57)

 
In the first model including attachment-related anxiety, R2 = 0.29 (adjusted 0.14), F (10, 46) = 1.9, p = .07, the only significant predictors were NK cell number and perceived stress.

In the second model including attachment-related avoidance, R2 = 0.36 (adjusted 0.22), F(10, 46) = 2.5, p ≤ .01, the significant predictors were NK cell number, attachment-related avoidance, and perceived stress. Importantly, if attachment-related anxiety were included in the model, attachment-related avoidance remained a significant predictor, ß = –0.29, t (1) = –2.2, p < .05. If attachment-related avoidance were broken down into five categories based on quintiles and four dummy variables were used as indicators for each category (median quintile as reference), the model fit increased, R2 = 0.43 (adjusted 0.26), F(13, 43) = 2.5, p = .01, and the pattern of regression coefficients suggested a possible threshold effect (ß = –0.06, t (1) = –0.4, p = .68; ß = –0.03, t (1) = –0.2, p = .86; ß = 0.06, t (1) = 0.4, p = .70; ß = –0.40, t (1) = –2.5, p = .01 for the first, second, fourth, and highest quintile, respectively).

Despite being sufficient to detect medium-to-large-size relationships between the independent variables and the dependent variable (33), the ratio of subjects to independent variables was less than desirable, and thus the model may have produced some unreliable regression estimates. To address this concern, we first performed a completely unadjusted analysis and then an analysis adjusting only for the four most theoretically important variables in our opinion, i.e., NK cell number, perceived stress, social support, and alexithymia. Though not all concerns were resolved, the regression estimates showed reasonable consistency across models. In the first analysis, attachment-related avoidance did not significantly predict NKCC if modeled as a continuous variable, ß = –0.15, t (1) = –0.1.1, p = .26, although it was a borderline significant predictor if modeled as four dummy variables based on quintile distribution (ß = –0.31, t (1) = –1.9, p = .06 for the highest quintile). In the second analysis, attachment-related avoidance was a borderline significant predictor when modeled as a continuous variable, ß = –0.24, t (1) = –1.9, p = .06, and a significant predictor when modeled as four dummy variables (ß = –0.35, t (1) = –2.3, p = .03 for the highest quintile).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
In this study, lower NKCC was found to be associated with attachment-related avoidance and greater perceived stress. The latter association was not unexpected given previous similar findings (34) and the documented relationship between decreased NKCC and naturally occurring stressors (35). The association between NKCC and attachment-related avoidance was independent of many biological and psychological factors that may affect immunity, and was likely due to a change in cell functionality because we controlled for the number of circulating NK cells. Given that NK cells are critical to host defense against virally infected cells and neoplastic transformation through cytolytic activity and release of cytokines (36), a reduction in NKCC may have clinical relevance and may be associated with poorer health (37).

No association emerged between attachment security and the other immune parameters studied. This may represent a truly negative finding or be due to other factors possibly obscuring associations with these parameters. As for lymphocyte subsets count, enumerative assays are less strongly and reliably related to psychological variables compared with functional assays (38). Regarding lymphocyte proliferative response, we used only a particular mitogen, whereas other mitogens may have yielded different results. Also, our reliance on a single estimate of immune parameters may have weakened the analysis because immune parameters are often relatively volatile and two measures cannot correlate more highly than their reliabilities (5).

Although many studies suggest that early life factors such as quality of maternal care may have long-term effects on physiology (39,40), interpreting our results as consistent with this literature would be overly speculative. It is more prudent to place our findings in the context of psychoimmunology literature and point out some characteristics of individuals with high attachment-related avoidance that may be associated with impaired immunity. First, positive expectations about specific life domains may reduce the impact on immunity of stressors occurring in that domain (13), whereas these individuals have negative expectations about their partner’s availability for support. Also, self-disclosure is associated with better cellular immune function and health (41), whereas these individuals are reluctant to share their thoughts and feelings with the partner. Further, increased stress and lower support in close relationships are associated with poorer health and decreased cellular immunity (42,43); notably, attachment- related avoidance is related to ineffective support seeking and lower perceived support from the partner (44). Finally, attachment-related avoidance may predispose to social isolation, a major risk factor for health (45) associated with reduced NKCC (46).

Several psychobiological pathways may account for the association between attachment-related avoidance and reduced NK function. Attachment style is related to brain activation in regions associated with emotion, memory, and emotion regulation (47). Attachment insecurity may affect stress regulation (15) and is related to altered autonomic and endocrine reactivity to stress (21–23). Possible mediators of the association between attachment-related avoidance and reduced NK function are cortisol, which inhibits NK-mediated lysis of target cells (48,49), proinflammatory cytokines, and stress-related proteins such as metallothioneins and alpha-2 macroglobulin, which may induce cellular death and reduce the bioavailability of zinc which is crucial for the normal development and function of NK cells (50,51).

Our study has several limitations, the most serious being the single estimate of immune parameters and the resulting suboptimal measurement reliability. We also relied on participants’ self-reports of sleep and health-related behaviors, which may have lower reliability than observer-rated measures. The cross-sectional design does not allow causal inferences, and the relatively small sample size increases the risk of both Type I and II errors. Further, the inclusion of only well-educated, young-to-middle-aged healthy women may reduce generalizability.

While our findings should be interpreted with great caution and need replication, they are consistent with previous investigations pointing out the importance of stable individual difference factors as correlates of tonic levels of specific immune parameters (4), and with previous work suggesting that insecure attachment may be a risk factor for health and may relate to biological processes relevant to health (15). The integration of attachment theory into psychoimmunology may be a promising avenue for future research.

We thank Mrs. Nazzarena Gasparini and Dr. Mario Muzzioli for their valuable help with immunological assays, and Mr. Luca Latini for his precious help with data input.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 
Received for publication December 23, 2005; revision received July 26, 2006.

DOI:10.1097/PSY.0b013e31802dd777


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 

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