Psychosomatics 40:222-225, June 1999
© 1999 The Academy of Psychosomatic Medine
Phenotype of Blood Lymphocytes in PTSD Suggests Chronic Immune Activation
Scott N. Wilson, M.D.,
Bessel van der Kolk, M.D.,
Jennifer Burbridge, M.A.,
Rita Fisler, Ed.M., and
Richard Kradin, M.D.
Received June 15, 1998; revised October 20, 1998; accepted November 3, 1998. From the Massachusetts General Hospital, Harvard Medical School, and The Trauma Center at Human Resource Institute, Boston, Massachusetts. Address correspondence and reprint requests to Dr. Wilson, Five Longfellow Place, Ste. 213, Boston, MA 02114.
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ABSTRACT
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Patients with posttraumatic stress disorder (PTSD) have a past history of extremely stressful experience and often present with somatic complaints. Peripheral blood lymphocytes (PBL) of patients with PTSD associated with a history of childhood sexual abuse were examined for changes in immune phenotype. The ratio of CD45RO-positive to CD45RA-positive lymphocytes (CD45RO/CD45RA), an index of lymphocyte activation, was higher (P=0.04) in the PTSD subjects than in the normal subjects. No differences were observed for the number of PBL or the representation of major T, B, or NK lymphocyte subsets. These findings suggest the presence of increased lymphocyte activation in the PBL of patients with PTSD.
Key Words: Posttraumatic Stress Disorder • Psychoimunology • Lymphocytes
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INTRODUCTION
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The concept of homeostasis has failed to help us understand the hidden toll of chronic stress on the body. Rather than maintaining constancy, physiologic systems, instead, adapt to meet the demands of external stressors, a process termed "allostasis." Allostatic load represents the cost of repeated exposures to fluctuating or heightened neuroendocrine responses that result from repeated stressful environmental challenges. In addition, different types of stress can yield distinct patterns of central nervous system-neuroendocrine activation, so that sustained stress yields neuroendocrine alterations that are opposed to those seen in acute stress.1,2
Evidence suggests that the immune system is primarily autoregulated, so that its role in discriminating "self from non-self" does not appear to require the supraordinate input of the central nervous system. Nevertheless, crosstalk does occur between the neuroendocrine and immune systems in vivo and may contribute to the fine regulation of immune reactivity.3,4 For example, at high concentrations adrenal steroids have a profound suppressive effect on the immune system, and stressors that activate the hypothalamic-pituitary-adrenal (HPA) axis can potentially suppress certain immune activities. Conversely, diminished activation of HPA may potentiate activities that are normally suppressed within the immune system.
Immunologic dysfunction can accompany psychiatric disorders; however, the observed changes have often been subtle and at times contradictory. Nevertheless, a recent meta-analysis has concluded that depression is significantly associated with reduced cellular immunity.5 Manfro and co-workers6 found an increase in CD45RA+ "naive" lymphocytes and relative hypercortisolemia in patients with panic disorder and suggested that decreased immune activation might account for this finding.
Patients with PTSD have experienced extreme stress in the past. In the majority of cases, PTSD is accompanied by major depression. Whereas the comorbidity between PTSD and depression is common, activation of the HPA axis in PTSD is more readily suppressed by dexamethasone than in depression. Currently, it is not known whether patients with PTSD develop changes in immune activities that primarily resemble those observed with major depression or other forms of stress.7,8
Chronic central down-regulation of the HPA axis occurs in patients with PTSD, in contrast to the transient hypercortisolemia that typically accompanies acute stress. Compared with normal subjects, patients with PTSD have lower urinary cortisol levels,9 serum cortisol levels that are more readily suppressed by dexamethasone than in purely depressed patients,10 and increased lymphocyte cortisol receptors.11 As cortisol antagonizes a wide spectrum of immune activities, patients with PTSD and decreased cortisol levels might be expected to develop evidence of increased immune activation in vivo. In this regard, Watson et al.12 have previously demonstrated enhanced cutaneous reactivity to antigens in combat veterans with PTSD.
In the present study, conducted in 1996, markers of immune activation expressed the surface membrane of peripheral blood lymphocytes (PBL), and serum cortisol levels, from 10 patients with PTSD secondary to childhood sexual trauma were compared with those of normal control subjects.
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METHODS
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Ten female subjects with childhood sexual trauma who met DSM-IV diagnostic criteria for PTSD and 10 age- and sex-matched control subjects were recruited from an outpatient psychiatric trauma clinic. After complete description of the study to the subjects, written informed consent was obtained. Male subjects were excluded to control for possible effects of sexual dimorphism on lymphocyte antigen expression. Subjects were excluded if they were medically ill, taking medication, actively smoking, currently abusing alcohol or drugs, or pregnant. Control subjects were staff volunteers who were free of significant psychiatric disease and met exclusion criteria. A Hamilton Depression Scale (Ham-D) score was obtained from subjects and control subjects.
Peripheral blood (30 ml) was obtained by venipuncture between 9:00 and 11:00 AM from the subjects and paired control subjects; samples were analyzed blindly under identical conditions. Leukocyte counts were performed, and PBL were separated on Ficoll-hypaque and immunostained with fluorescein isothiocyanate-conjugated murine anti-human antibodies that react with cell surface lymphocyte antigens, including CD3, CD4, CD8, CD19, CD25, CD45RA, CD45RO, Leu8, CD56, and CD16, and analyzed in a FACscanTM cytofluorimeter (Becton-Dickinson, San Jose, California). Serum cortisol levels were measured in parallel by 125I radioimmunoassay (GammaCoatTMKit, INCSTAR Corporation, Stillwater, Minnesota).
A dependent (paired) T-test was used to compare the PTSD subjects with control subjects. Data were analyzed by using StatViewTM for MacintoshTM (SAS Institute, Cary, NC).
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RESULTS
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The Ham-D scores for the PTSD group were higher than the control subjects (14.1± 9.5 vs. 1.2±1.5; P=0.0015). There were no differences in total lymphocyte counts or in percentages of lymphocyte subsets. Table 1 shows that there was no difference in levels of acute lymphocyte activation, as judged by expression of CD25 (IL2-R) between groups. The ratio of CD45RO+ to CD45RA+ lymphocytes (CD45RO/CD45RA) was higher in the PTSD than the control subjects (P=0.04). Serum cortisol levels in the PTSD subjects were not different from the control subjects (6.8±2.8 vs. 9.4±6.7; P=0.18).
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TABLE 1. Lymphocyte subset analysis of peripheral blood lymphocytes in posttraumatic stress disorder (PTSD) vs. normal subjects
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DISCUSSION
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The increased CD45RO/CD45RA ratios in PTSD associated with a history of childhood sexual abuse suggest increased levels of lymphocyte immune activation in vivo. Normally, following antigen activation, T-lymphocytes show decreased expression of the CD45RA isoform and sustained neo-expression of the CD45RO isoform.13 Expression of CD45RO is linked to the acquisition of immunologic memory, defined as the ability of T-lymphocytes to mediate an anamnestic response to antigen. However, the absence of increased IL-2R expression indicates that PBL in PTSD were not acutely activated at time of study.
A recent field trial of DSM-IV has confirmed an association between somatization and PTSD.14 However, it is not known whether somatic complaints in PTSD have a basis in immune dysregulation.15 Although the PTSD patients in the present study claimed to be free of medical illnesses, we cannot exclude subclinical illness as a cause of the increase in CD45RO/CD45RA.
The PTSD patients had higher Ham-D scores than the control subjects, and we cannot fully exclude depression as a factor in the increased CD45RO/CD45RA ratios. However, the weight of evidence from other studies suggests that depression is accompanied by immune suppression rather than immune activation.5 Alternatively, it is possible that patients with past sexual trauma represent a subset of "atypical" depressed patients who do not develop decreased cellular immune activation.
Other studies have linked abnormalities in the immune response to changes of PTSD. Ironson et al. showed changes in immune function in subjects who had lived through the natural trauma of Hurricane Andrew.16 In these patients, the natural killer (NK) cell cytotoxic activities and CD4+ and CD8+ lymphocytes were diminished, and these changes correlated with the response to loss. Mosnaim et al. showed that NK activities were altered following a methionine-enkephalin challenge in PTSD.17
In the present study, we have demonstrated that a history of childhood sexual trauma is associated with markers of increased immune activation in vivo. The interpretation of the results are limited by the small number of patients in this pilot study. In addition, the possible mechanisms in vivo that might account for this change have not yet been rigorously addressed. Future studies with larger numbers of subjects will focus on how markers of increased immune activation that accompany PTSD are regulated in vivo, whether an increased CD45RO/CD45RA index is a stable phenotypic finding in PTSD, and whether this finding correlates with the somatic complaints in this population.
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ABSTRACT
INTRODUCTION
