Brain, Behavior, and Immunity 25 (2011) 6–13

Contents lists available at ScienceDirect

Brain, Behavior, and Immunity

journal homepage: www.elsevier.com/locate/ybrbi

Invited Review

A short review on the psychoneuroimmunology of posttraumatic stress

disorder: From risk factors to medical comorbidities
Thaddeus W.W. Pace ⇑, Christine M. Heim
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA

a r t i c l e i n f o a b s t r a c t

Article history: Posttraumatic stress disorder (PTSD) is a serious and debilitating condition with a prevalence rate of
Received 20 July 2010 approximately 8% in the United States. Given the number of veterans returning from conflicts around
Received in revised form 2 October 2010 the globe with PTSD, and the substantial number of civilians experiencing traumas, new perspectives
Accepted 4 October 2010
on the biology of PTSD are needed. Based on the concept that PTSD is a disorder of stress response sys-
Available online 8 October 2010
tems, numerous studies have suggested changes in hypothalamic–pituitary–adrenal (HPA) axis and sym-
pathetic–adrenal–medullary (SAM) system function in patients with PTSD. Given that both
Keywords:
glucocorticoids and catecholamines exert powerful effects on the immune system, it is surprising that
PTSD
Immune system
relatively few studies have examined immune changes in patients with PTSD. Moreover, patients with
Inflammation PTSD are known to have increased rates of comorbidity with somatic disorders that involve immune
Catecholamines and inflammatory processes. Patients with PTSD have been found to exhibit a number of immune
Glucocorticoids changes including increased circulating inflammatory markers, increased reactivity to antigen skin tests,
Neuroendocrine–immune interactions lower natural killer cell activity, and lower total T lymphocyte counts. Studies with humans and rodents
PTSD risk factors suggest that certain proinflammatory cytokines are able to induce neurochemical and behavioral changes
that resemble some key features of PTSD. This short article reviews immune alterations in PTSD, and con-
siders possible mechanisms by which such changes may be related to neuroendocrine alterations and
medical comorbidities of PTSD.
Ó 2010 Elsevier Inc. All rights reserved.

1. Introduction 2. History and central features of PTSD

Although neuroendocrine systems have been studied exten-
sively in posttraumatic stress disorder (PTSD), relatively few pa-
pers have explored immune alterations in patients with PTSD.
Given that neuroendocrine systems are known to regulate immune
function, it is reasonable to predict that patients with PTSD may
show immune changes. This expectation is bolstered by the fact
that PTSD is often comorbid with medical disorders that involve
inflammatory or autoimmune dysregulation. This short article dis-
cusses studies that have indentified changes in inflammatory
markers and lymphocyte function in patients with PTSD compared
to controls. We also consider whether immune changes may play a
role in the development and severity of PTSD symptoms as op-
posed to being merely epiphenomena of PTSD. Possible mecha-
nisms by which the described immune changes take place are
discussed. Finally, a psychoneuroimmunological model is pre-
sented in which immune alterations serve as mediators between
PTSD and medical disease.
⇑ Corresponding author. Address: Department of Psychiatry and Behavioral
Sciences, Emory University School of Medicine, 1365-B Clifton Rd., Rm B5105,
Atlanta, GA 30322, USA. Fax: +1 404 778 3965.
E-mail address: thaddeus.pace@emory.edu (T.W.W. Pace).
PTSD was first introduced as a diagnosis in 1980. At the time,
traumatic events sufficient to produce clinical PTSD symptoms
were thought to be relatively rare (Vieweg et al., 2006). However,
subsequent investigations revealed that 50–90% of people in the
civilian population are exposed to events that may produce PTSD,
and some 8% go on to develop the disorder in their lifetime (View-
eg et al., 2006; Yehuda and LeDoux, 2007). The nature of the trau-
ma is important for understanding the risk for developing the
disorder, as PTSD may be more likely to develop after repeated
trauma such as torture or abuse (as high as 65%) compared to sin-
gle incident exposures involving accidents such as car crashes and
natural disasters (10–15%) (Bichescu et al., 2005). Traumas experi-
enced early in life have also been shown to increase the risk for
developing PTSD following subsequent stressors (Keane et al.,
2006). Finally, women appear to be more likely than men to devel-
op PTSD after traumatic events (Kessler et al., 1995).
PTSD is especially a concern for combat veterans or individuals
exposed to war. Although the exact numbers are a matter of de-
bate, between 1.4% and 31% of military personnel deployed to Iraq
and Afghanistan develop PTSD upon returning home (Sundin et al.,
2010). This variability in prevalence rates likely stems from differ-
ences in trauma exposure and differences in methodologies used to

0889-1591/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.bbi.2010.10.003
 T.W.W. Pace, C.M. Heim / Brain, Behavior, and Immunity 25 (2011) 6–13
study PTSD in military personnel. Differences in deployed popula-
tions may also contribute to this variability in prevalence rates.
Individuals living with PTSD bear a large burden. Patients with
PTSD are six times more likely to commit suicide, have increased
risk of dropping out of high school or college, and are more likely
to experience marital instability (Kessler, 2000). Financial penalties
are significant, as work and family lives are severely interrupted.
Indeed, the overall work impairment suffered by PTSD patients is
comparable to that found for individuals with major depression,
highlighting the devastating nature of the disorder. In 2000, Kess-
ler estimated that the annual loss in productivity because of PTSD
in the United States was some $3 billion (Kessler, 2000), which
equates to $3.8 billion (EUR 2.9 billion) today. This estimate does
not take into account the increased number of veterans suffering
from PTSD as a result of conflicts in Iraq and Afghanistan, which
would likely increase the annual loss in productivity.
The Diagnostic and Statistical Manual for Mental Disorders
(DSM)-IV requires that a person has been exposed to an extraordi-
nary traumatic event in order to make a diagnosis of PTSD. Trau-
matic events involve actual or threatened death or serious injury
of the patient, or a threat to other persons such as friends and loved
ones. The diagnosis also requires that key symptoms are present
from three distinct clusters: the first symptom cluster involves
reexperiencing the traumatic event with flashbacks, dreams, or
recollections, and/ or psychological or physical distress when
encountering cues of the trauma. The second symptom cluster in-
volves hypervigilance for danger and/or the expression of in-
creased arousal manifested as difficulties sleeping, concentrating,
and controlling anger. The third symptom cluster includes persis-
tent avoidance of cues that evoke memories of the traumatic event.
The avoidance cluster also includes features such as emotional
numbing, decreased interest in activities, a sense of a foreshort-
ened future, and a lack of positive emotions including love, con-
tentment, or happiness.
3. Neuroendocrine alterations in PTSD
Over the last three decades, biological PTSD research has fo-
cused on two major hormone systems that form the backbone of
the physiological response to stress: the hypothalamic–pituitary–
adrenal (HPA) axis and the sympathetic–adrenal–medullary
(SAM) system. Attention on these systems stemmed from the facts
that (1) PTSD develops subsequent to exposure to a traumatic and
stressful event and (2) glucocorticoids and catecholamines are
‘‘stress hormones’’ that may regulate responses to trauma. In the
1990’s, it became clear that PTSD is not a normative response to
extreme stressors, as only a subset of people exposed to trauma
go onto develop the disorder. Yehuda therefore reconceptualized
PTSD as a disorder of stress response systems, leading to maladap-
tive responses and a failure to cope with the stressor (Yehuda,
2009). A search of the literature reveals multiple papers document-
ing changes of the HPA axis and the SAM system in PTSD patients.
Although a comprehensive discussion of HPA axis and SAM system
changes in PTSD is beyond the scope of this review, we will briefly
consider the highpoints of the literature, in order to set the stage
for considering the possible origins of immune changes in PTSD pa-
tients. Readers are referred to thorough reviews on the topic (e.g.
Wessa and Rohleder, 2007; Yehuda, 2009; Heim and Nemeroff,
2009).
3.1. HPA axis alterations and glucocorticoid sensitivity in PTSD
While cerebrospinal fluid (CSF) levels of corticotropin
releasing hormone (CRH) are increased in patients with PTSD
(e.g. Bremner et al., 1997), many studies have found that peripheral
7
concentrations of cortisol are decreased (for a review, see Wessa
and Rohleder, 2007; Heim and Nemeroff, 2009). Reduced cortisol
levels in PTSD patients have been reported most often when the
hormone has been assessed in urine or saliva (Wessa and Rohleder,
2007). The disagreement between indicators of HPA axis activity in
central versus peripheral components suggests that endocrine
glands downstream of the hypothalamus are either downregu-
lated, inhibited by glucocorticoid negative feedback, or insensitive
to the increased activity of stress response systems in the brain.
However, it must be noted that not all studies have reported lower
circulating concentrations of cortisol in patients with PTSD (Mee-
wisse et al., 2007). This variability of results may be due to various
factors including comorbid depression, current versus lifetime
PTSD, severity of PTSD symptoms, time since the traumatic event,
duration of trauma exposure, and whether or not control groups
have a history of trauma (Wessa and Rohleder, 2007; Meewisse
et al., 2007). It may also be more likely to find an association be-
tween lower cortisol and PTSD when studies involve women, peo-
ple with a history of physical or sexual abuse, or when samples are
collected in the afternoon (Meewisse et al., 2007).
In addition to decreased cortisol at specific points over the
course of the day, patients with PTSD may exhibit a ‘‘flattening’’
of the cortisol slope. More specifically, patients with PTSD have
been found to display less of a cortisol ‘‘spike’’ upon awakening
and higher circulating concentrations of cortisol in the evening
(Wessa and Rohleder, 2007). Interestingly, flattening of the daily
cortisol rhythm has been associated with a number of chronic
medical illnesses including CVD and insulin resistance, as well as
other psychiatric disorders including major depression and chronic
fatigue syndrome (e.g. Nater et al., 2008).
With respect to HPA axis function, several studies suggest that
PTSD patients may exhibit enhanced glucocorticoid sensitivity.
This has been assessed by the low-dose dexamethasone suppres-
sion test (DST). Yehuda and colleagues were the first to demon-
strate that patients with PTSD showed enhanced sensitivity to
glucocorticoids during the DST, especially when a low dose of
dexamethasone was used (Yehuda, 2009). However, later studies
using the DST have found little or no differences between PTSD pa-
tients and trauma-exposed controls without PTSD (Wessa and
Rohleder, 2007). Thus, it is somewhat unclear if PTSD patients con-
sistently display enhanced glucocorticoid sensitivity during the
DST. Heim and colleagues found lower cortisol levels during the
DEX–CRH test in men with abuse-related PTSD, which is consistent
with the idea of enhanced feedback suppression under conditions
of additional challenge (Heim et al., 2008).
Glucocorticoid sensitivity can also be measured in circulating
immune cells. Several original reports suggest that circulating im-
mune cells from patients with PTSD may be more sensitive to glu-
cocorticoids compared to immune cells from healthy individuals
(reviewed in Rohleder et al., 2010). For example, lysozyme activity
has been found to be more sensitive to dexamethasone in bulk leu-
kocytes collected from PTSD patients compared to cells obtained
from healthy controls. In addition, lipopolysaccharide (LPS)-in-
duced cytokine production from whole blood, a measure of mono-
cyte responsiveness, has been reported to be more sensitive to
dexamethasone in samples collected from PTSD patients compared
to samples collected from controls (Rohleder et al., 2010). How-
ever, not all findings point to enhanced glucocorticoid sensitivity
in immune tissues from PTSD patients: de Kloet and colleagues
compared the sensitivity of various immune parameters to dexa-
methasone in cell samples collected from patients with PTSD, trau-
ma exposed controls, and controls not exposed to trauma (de Kloet
et al., 2007). While they found that the sensitivity of LPS-induced
cytokine production to dexamethasone did not vary as a function
of PTSD or trauma exposure, the sensitivity of phytohemagglutinin
(PHA)-induced T cell proliferation to dexamethasone was actually
8 T.W.W. Pace, C.M. Heim / Brain, Behavior, and Immunity 25 (2011) 6–13
reduced in samples collected from PTSD patients versus those ob-
tained from controls with or without trauma exposure (de Kloet
et al., 2007). The disagreement between measures of glucocorticoid
sensitivity when using LPS-induced cytokines as an endpoint may
be explained by differences in assay protocols or control conditions
(de Kloet et al., 2007). The finding of decreased sensitivity of T cell
proliferation to glucocorticoids may not necessarily conflict with
studies using LPS-induced cytokines or lysozyme activity end-
points, as each explores different aspects of immune function. In
other words, there is the intriguing possibility that PTSD involves
decreased glucocorticoid sensitivity in some immune tissues and
increased glucocorticoid sensitivity in others.
There is also a lack of clarity with respect to changes of GR den-
sity in immune cells as a correlate of PTSD. While a number of
studies have reported increased expression of GR in circulating im-
mune cells, other reports suggest that GR density may actually be
decreased (for a review, see Gill et al., 2009). As with measures of
glucocorticoid sensitivity, this disagreement in GR expression in
patients with PTSD could involve clinical differences between stud-
ies regarding patient groups. Methodological difference could also
be important, including different techniques to assess GR density
or expression levels, as well as assessments of these parameters
in different subpopulations of immune cells.
3.2. SAM system alterations in PTSD
Central and peripheral concentrations of norepinephrine appear
to be elevated in patients with PTSD. One study found increased
CSF concentrations of norepinephrine in veterans with the disorder
(Geracioti et al., 2001). And seven studies have found increased ur-
ine norepinephrine levels in PTSD patients exposed to various
types of trauma including domestic abuse, childhood abuse, com-
bat, automobile accidents, and exposure to war as a refugee (re-
viewed in Wessa and Rohleder, 2007). Urinary epinephrine
concentrations are also increased in patients with PTSD (Wessa
and Rohleder, 2007). Only one study has attempted to measure
norepinephrine levels in blood (Yehuda et al., 1998). Beyond cate-
cholamines, studies investigating cardiovascular variables in PTSD
patients support the notion of increased SAM reactivity. Thus, pa-
tients with PTSD exhibit increased heart rate, blood pressure, and
tremor responses when presented with reminders of traumatic
events (Bedi and Arora, 2007).
3.3. Is neuroendocrine dysregulation a risk factor for the development
of PTSD?
While most studies conceptualized neuroendocrine changes as
correlates of the disease state of PTSD, several studies now suggest
that neuroendocrine dysregulation may in fact be a risk factor that
predicts the development of the disorder upon exposure to ex-
treme stress. Some studies have evaluated whether altered neuro-
endocrine responses observed in the immediate aftermath of a
trauma predict PTSD. SAM and HPA axis responses to traumatic
events have been shown to predict later development of PTSD.
According to Yehuda’s model, PTSD develops because key aspects
of the biological response to trauma interfere with recovery after
the trauma ends (Yehuda, 2009). Indeed, low plasma concentra-
tions of cortisol and elevated plasma catecholamines in the period
of time immediately after trauma have been found to predict PTSD
development (for a review of original studies, see Yehuda, 2009). If
cortisol responses to trauma normally facilitate containment of
catecholamine responses to the same event, then reduced cortisol
following a trauma may promote an excessive catecholamine re-
sponse. This enhanced sympathetic activity may amplify encoding
of traumatic memories, which would encourage expression of key
PTSD features (Yehuda, 2009).
These results raised the intriguing possibility that neuroendo-
crine dysregulation may be a pre-existing risk factor that is present
well before and independent of the traumatic event that elicits
PTSD. Several prospective studies have now assessed neuroendo-
crine changes prior to trauma exposure. Indeed, increased PBMC
glucocorticoid binding before deployment has been found to pre-
dict the development of PTSD 6 months after deployment in army
personnel (van Zuiden et al., 2010). In addition, exaggerated startle
responses in police academy cadets, measured prospectively, have
also been found to predict the development of PTSD (Pole et al.,
2009). This suggests that healthy people who show enhanced star-
tle responses are at increased risk for developing PTSD.
Risk for PTSD may also be transmitted across generations. Low-
er plasma concentrations of cortisol have been found in children of
Holocaust survivors (who also displayed enhanced HPA axis sensi-
tivity during the DST), and in babies from mothers who developed
PTSD after the World Trade Center attack in New York City (Yehu-
da, 2009).
4. Comorbidity with somatic illness
Chronic sympathetic activation in PTSD may have important
implications for the individual risk to develop cardiovascular dis-
ease (CVD) as well as other chronic medical illnesses. Indeed, pa-
tients with PTSD have increased rates of comorbidity with CVD
and other chronic somatic conditions (Boscarino, 2004, 2008; Ki-
bler, 2009). A recent study by Heppener and colleagues reported
that PTSD severity predicted the presence of metabolic syndrome
(Heppner et al., 2009). However, PTSD does not appear to be asso-
ciated with diabetes mellitus (Qureshi et al., 2009) or waist-to-hip
ratio (Heppner et al., 2009). This suggests that PTSD may enhance
the risk for insulin resistance, especially in the context of obesity.
PTSD has also been linked to rheumatoid arthritis (Qureshi et al.,
2009), independent of genetic and familial factors (Boscarino
et al. 2010). Other chronic medical conditions that have been asso-
ciated with PTSD include psoriasis and thyroid disease (Boscarino,
2004). Interestingly, each of these chronic somatic disorders has
inflammatory or autoimmune underpinnings. It is therefore rea-
sonable to suspect that patients with PTSD may display immune
alterations in addition to neuroendocrine changes.
5. Immune alterations in PTSD
5.1. Central and peripheral inflammatory markers
In 1997, Spivak and colleagues were the first to measure plasma
cytokine levels in PTSD patients. They discovered that compared to
healthy, non-trauma exposed controls, veterans with PTSD dis-
played increased circulating concentrations of interleukin IL-1b
that were also correlated with the duration of PTSD symptoms
(Spivak et al., 1997). This finding has been bolstered by subsequent
studies. Higher tumor necrosis factor (TNF)-a was found in PTSD
patients with mixed trauma experience versus non-PTSD controls
(von Känel et al., 2007). In addition, higher plasma IL-6 levels
and soluble IL-6 receptors were found in victims of an automobile
accident or a hotel fire compared to healthy controls (Maes et al.,
1999). Higher IL-6 levels have also been reported in patients with
PTSD subsequent to myocardial infarction (MI) as compared to MI
patients who did not develop PTSD, when controlling for depres-
sive symptoms (von Känel et al. 2010). And refugees with PTSD fol-
lowing Hurricane Katrina exhibited higher circulating IL-6
concentrations compared to refugees without PTSD (Tucker et al.,
2010). Alterations in inflammatory markers are evident not just
in the peripheral circulation, but in the central nervous system as
well. Hence, elevated IL-6 concentrations have been measured in
 T.W.W. Pace, C.M. Heim / Brain, Behavior, and Immunity 25 (2011) 6–13
CSF of PTSD patients with combat trauma exposure compared to
healthy controls (Baker et al., 2001). Given that IL-6 is thought to
drive C-reactive protein (CRP) production from the liver, several re-
cent studies have also examined CRP levels in patients with PTSD.
In one of these studies, PTSD patients were found to have a nearly
twofold higher chance of having elevated CRP levels, even after
controlling for possible confounds including sex, age, and alcohol
use (Spitzer et al., 2010).
Despite multiple reports of increased circulating and central
nervous system cytokines in PTSD patients, two studies have found
decreased inflammatory markers. Most recently, von Känel and
colleagues found lower CRP in patients with PTSD subsequent to
MI (von Känel et al., 2007). Lower CRP was also found in Iraqi ref-
ugees with PTSD (Sondergaard et al., 2004). The lack of agreement
between these studies may involve unique participant characteris-
tics. For example, Sondergaard and colleagues noted that control
participants in their study may have been more likely than PTSD
patients to have infections (Sondergaard et al., 2004), leading to
higher circulating CRP concentrations in the control group. Results
from studies with MI patients should be interpreted carefully as
well, given the complicated medical status of these individuals.
Finally, a recent report suggests that trauma exposure and PTSD
may instill epigenetic changes that impact long-term inflammatory
function (Uddin et al., 2010). In that study, patients with PTSD
were found to exhibit a greater number of unmethylated genes re-
lated to innate immune and inflammatory function compared to
healthy controls, which could eventually encourage the expression
of altered immune function and enhanced inflammatory activity.
5.2. Monocyte and natural killer cells
Several studies have examined natural killer cell activity
(NKCA) in patients with PTSD using in vitro approaches. On the
whole, it appears that NKCA is impaired in PTSD. The most recent
report in this area examined NKCA in Croatian veterans with com-
bat-related PTSD and found that patients had reduced NKCA com-
pared to healthy controls (Gotovac et al., 2010). Earlier studies
have reported the same finding in patients with non-combat re-
lated PTSD, such as male workers with PTSD who were victims of
an earthquake in Japan and residents with PTSD exposed to Hurri-
cane Andrew (Inoue-Sakurai et al., 2000; Kawamura et al., 2001;
Ironson et al., 1997). In contrast, negative findings have been re-
ported in a small sample of Vietnam veterans with PTSD versus
Vietnam veterans without PTSD (Laudenslager et al., 1998). How-
ever, in that study scores on the Beck Depression Inventory were
positively correlated with NKCA, suggesting that NKCA alterations
may have been more related to comorbid depression than to PTSD
in those patients.
In vitro mitogen-stimulated cytokine tests have also been con-
ducted in PTSD patients. Samples containing immune cells (most
often whole blood) are removed from participants and treated with
a mitogen such as LPS. LPS stimulates cytokine production primar-
ily from monocytes. These tests provide information about im-
mune responsiveness, without exposing participants to mitogens.
Only three studies have been performed using this approach, and
two have found increased production of proinflammatory cyto-
kines in samples from PTSD patients. In the first, Rohleder and col-
leagues reported increased LPS-induced IL-6 and TNF-a production
in whole blood collected from Bosnian war refugees with PTSD
compared to healthy controls (Rohleder et al., 2004). In the second
study, enhanced LPS-induced production of interferon (IFN)-gam-
ma was found in domestic abuse victims with PTSD (Woods
et al., 2005). However, a study by de Kloet and colleagues did not
find enhanced cytokine responses after LPS challenge in samples
from veterans with PTSD (de Kloet et al., 2007).
9
Proportions of natural killer (NK) cells and monocytes in the cir-
culation have also been examined in patients with PTSD using flow
cytometry. Skarpa and colleagues found increased proportions of
CD16+ positive cells in PTSD patients who were prisoners of war
(Skarpa et al., 2001). All other studies (e.g. Laudenslager et al.,
1998) have failed to detect enumerative differences in NK cells be-
tween PTSD and control participants. Monocytes also appear un-
changed in patients with PTSD (Rohleder et al., 2004). Thus, it
remains unclear whether or not the number of circulating NK cells
or monocytes is altered in patients with PTSD.
5.3. T and B cell function
The function of T and B cells has been examined in patients with
PTSD using a number of techniques including vaccine response, la-
tent virus antibody titers, delayed-type hypersensitivity (DTH)
tests, and cell proliferation assays.
Only one study has examined vaccine responses in patients
with PTSD. In that report, patients with combat-related PTSD did
not differ from healthy controls regarding antibody titers and sero-
conversion rates after influenza vaccination (Kosor Krnic et al.,
2007). This result suggests that B cell function is not impaired in
PTSD. Interestingly, the same study found that patients with PTSD
had significantly lower numbers of T cells positive for human leu-
kocyte antigen-A*0201-restricted influenza A haemagglutinin anti-
gens before vaccination (Kosor Krnic et al., 2007), indicating that
patients may have had greater pre-vaccination vulnerability to
influenza infection.
Immune function related to latent virus infection in patients
with PTSD has also been examined by only one study. In that re-
port, physically or psychologically abused women with increased
PTSD symptoms (but who were not diagnosed with syndromal
PTSD according to DSM-IV criteria) were compared to healthy con-
trols. Physically abused women exhibited significantly lower her-
pes simplex virus 1 (HSV-1) viral neutralization compared to
healthy controls and psychologically abused women. The physi-
cally abused women also tended to have lower HSV-1 specific anti-
body levels (Garcia-Linares et al., 2004). This suggests that in vivo
cellular immunity may be impaired in PTSD patients. A search of
the literature for studies on the relationship between PTSD and Ep-
stein–Barr antibody titers, another common latent virus, did not
yield any findings.
Several investigations have measured DTH responses in pa-
tients with PTSD. The majority of these suggest that antigen-spe-
cific T cell function is enhanced in PTSD. Altemus and colleagues
found that women with PTSD who were victims of early life phys-
ical and sexual abuse had enhanced DTH responses compared to
healthy controls (Altemus et al., 2006). Similarly, Boscarino and
Chang reported enhanced DTH in PTSD patients that served during
the Vietnam War compared to healthy veterans who also served in
Vietnam (Boscarino and Chang, 1999). These studies suggest that
patients have enhanced T cell responses, and they may explain in-
creased rates of autoimmune conditions such as psoriasis or atopic
dermatitis in individuals suffering from PTSD.
Besides DTH, T cell function has also been examined in PTSD pa-
tients using in vitro mitogen-induced cytokine or proliferation as-
says. These techniques involve treating whole blood or PBMCs with
the T cell mitogen PHA, or more recently with anti-human CD3
monoclonal antibody. On the whole it appears that PTSD patients
display attenuated T cell responses when using these in vitro tests.
For example, patients with non-combat related PTSD demon-
strated lower IFN-gamma and IL-4 responses to PHA (Kawamura
et al., 2001). In another study, women displaced by the Bosnian
war who had increased fear and anxiety features displayed re-
duced PHA-induced lymphocyte proliferation compared to non-
displaced controls (Sabioncello et al., 2000). Finally, greater T cell
10 T.W.W. Pace, C.M. Heim / Brain, Behavior, and Immunity 25 (2011) 6–13
proliferation was found in PBMCs collected from refugees with
PTSD and stimulated with the anti-CD3 monoclonal antibody
(measured with a carboxyfluorescein succinimidyl ester [CFSE]-
based assay), indicating enhanced T cell responsiveness (Sommers-
hof et al., 2009). Taken together, these studies suggest that patients
with PTSD exhibit enhanced T cell function.
5.4. T and B cell counts
Several studies have examined circulating lymphocytes num-
bers in PTSD patients. Results are extremely mixed, and general
conclusions cannot be drawn. However, a brief review of the topic
is still warranted given recent interest in the role that T cells may
play in other psychiatric disorders, including major depression
(Miller, 2010). In general, T cells may play important neuroprotec-
tive roles in situations of stress and inflammation. Along with func-
tional changes described above, changes in T cell subsets may
encourage the development and maintenance of psychiatric ill-
nesses like major depression (Miller, 2010), and possibly PTSD.
Total lymphocytes do not appear to be altered in patients with
PTSD, as measured in women with childhood sexual abuse-related
PTSD (Wilson et al., 1999), in Croatian war veterans with PTSD
(Vidovic et al., 2007), in Bosnian refugees with PTSD (Rohleder
et al., 2004), or in Dutch veterans with PTSD (de Kloet et al.,
2007). These negative results with the lymphocyte population as
a whole encourage examination of lymphocytes subsets.
Findings from two studies suggest that B cell counts do not dif-
fer as a function of PTSD. Specifically, B cells were not different be-
tween Vietnam era veterans with and without PTSD (Boscarino and
Chang, 1999), or traumatized Dutch veterans with and without
PTSD (de Kloet et al., 2007).
Mixed results have been found for T cell counts. Vietnam veter-
ans with PTSD were found to have higher total T cells compared to
veterans without PTSD (Boscarino, 2004; Boscarino and Chang,
1999). However, fewer T cells were found in non-combat related
PTSD (Kawamura et al., 2001). For T helper (CD4+) cells, one study
reported increased proportions in combat veterans with PTSD
(Boscarino and Chang, 1999), while others have reported decreased
proportions in patients with different types of trauma history
(Ironson et al., 1997; Kawamura et al., 2001). With respect to cyto-
toxic T (CD8+) cells, some studies have reported lower counts
(Ironson et al., 1997; Kawamura et al., 2001), while others have
found no differences between participants with and without PTSD
(Altemus et al., 2006; de Kloet et al., 2007; Laudenslager et al.,
1998; Vidovic et al., 2007; Wilson et al., 1999).
A recent article by Sommershof and colleagues suggested that it
may be important to consider T cell activation and differentiation
states when performing enumerative tests of T cells (Sommershof
et al., 2009). For this approach, T cells are categorized according to
the lineage markers CD45RA and CCR7, which identifies naive T
cells. This assumes a model in which naive T cells (CD45RA+
CCR7+) become activated with antigen exposure, differentiate into
T memory cells, and then partly develop into effector/T cytolytic
cells.
Sommershof and colleagues found that compared to a healthy
controls, war refugees with PTSD had reduced percentages of
CD3+ naive T cells along with an increased percentage of central
and effector memory T cells. Among CD8+ T cells, PTSD patients
displayed reduced naive and increased effector memory cells
(Sommershof et al., 2009). CD4+ cells of all lineages were not sig-
nificantly altered between groups. PTSD patients also had reduced
regulatory T cells compared to healthy participants. Along with
functional alterations in patients with PTSD (i.e. enhanced re-
sponses to anti-CD3 monoclonal antibody discussed above), these
shifts in T cells might be related to increased comorbidities with
PTSD such as CVD and autoimmune disorders.
5.5. Are immune changes risk factors for the development of PTSD?
As discussed above, decreased concentrations of cortisol and in-
creased sympathetic activation in the immediate aftermath of a
trauma have been relatively consistently associated with the
development of PTSD. Interestingly, immune responses to a trauma
may also be a risk factor for developing subsequent PTSD. Pervan-
idou and colleagues found that increased circulating concentra-
tions of IL-6 measured 24 hours after an automobile accident
predicted the development of PTSD 6 months later in children (Per-
vanidou et al., 2007). This is the first and only study to examine the
relationship between an immune endpoint at the time of trauma
and the later development of PTSD. To date no prospective studies
have examined immune variables recorded well before and sepa-
rate from a traumatic event. Immune risk factors for PTSD may also
be governed by genetic influences, as inflammatory responsiveness
may be inherited (e.g. Danik and Ridker, 2007).
Insight into how altered cytokine levels may be related to the
development of PTSD is provided by a study by Reichenberg and
colleagues, in which participants were acutely treated with LPS.
Feelings of anxiety were increased in the LPS group compared to
vehicle controls, and the severity of anxiety was positively corre-
lated with the magnitude of the TNF-a response to LPS treatment
(Reichenberg et al., 2001). These results suggest that proinflamma-
tory cytokines may exert anxiogenic effects. Of note, LPS also led to
an increase in both core body temperature and depressive features.
The latter suggests that proinflammatory cytokines, or mitogens
that induce inflammatory responses, have the ability to induce a
diverse set of behavioral changes, including anxiety. However, it
is also important to point out that not all cytokines or mitogens in-
duce behavioral changes.
Studies with rodents suggest that cytokines may have actions in
the brain that promote changes in the neurocircuitry that is in-
volved in the mediation of anxiety. IL-6 has been shown to increase
dopamine levels in the hippocampus and prefrontal cortex in mice
(Zalcman et al., 1994). Change in these regions can have powerful
effects on the amygdala, which is central to the neurocircuitry of
the fear response and overactive in PTSD (Yehuda and LeDoux,
2007). Interestingly, the frequency and severity of PTSD symptoms
(reexperiencing, avoidance, and arousal) are correlated with circu-
lating concentrations of TNF-a (von Känel et al., 2007). Taken to-
gether, these results may suggest that cytokine actions are
causally linked to PTSD symptoms, possibly by way of limbic
circuits.
5.6. The hippocampus and immune function in PTSD
Multiple studies have reported reduced hippocampal volumes
in patients with PTSD (Bremner et al., 2008). Twins without trauma
or PTSD have been found to have the same reduced hippocampal
volume as siblings with PTSD (Yehuda and LeDoux, 2007). Child-
hood adversity, a known risk factor for PTSD, has also been associ-
ated with reduced hippocampal volume (Stein et al., 1997;
Vythilingam et al., 2002). This suggests that reduced hippocampal
volume may be a preexisting risk factor for PTSD.
Interestingly, proinflammatory cytokines have been shown to
mediate chronic stress-induced impairments in hippocampal neu-
rogenesis (Goshen et al., 2008), and this effect has been shown to
depend on NF-jB (Koo et al., 2010). Given that early life adversity
(i.e. childhood abuse) has been associated with elevated circulating
concentrations of CRP in childhood (Danese et al., 2010), it is
possible that increased inflammation subsequent to childhood
adversity impairs neurogenesis via NF-jB at critical periods
throughout development. This may ultimately encourage
decreased hippocampal volume in adulthood. Reduced hippocam-
pal volume may then promote malfunction of the fear response
 T.W.W. Pace, C.M. Heim / Brain, Behavior, and Immunity 25 (2011) 6–13
circuit in context-dependent situations (Yehuda and LeDoux,
2007), with the eventual development of PTSD symptoms.
Of course, neither early life adversity nor reduced hippocampal
volume are prerequisites for PTSD, and many patients with the dis-
order will not have these risk factors. In addition, early life adver-
sity is not the only factor that may promote increased
inflammation. For example, elevated circulating inflammatory
markers have also been associated with personality traits such as
hostility (e.g. Graham et al., 2006). Individual traits should there-
fore be considered along with adverse early life experiences when
attempting to understand the relationship between inflammation
and PTSD.
6. Neuroendocrine–immune interactions in PTSD
Neuroendocrine studies suggest that PTSD is not exclusively
dependent on exposure to trauma. Instead, the onset and course
of the disorder may involve a number of biological variables
including altered cortisol levels, enhanced glucocorticoid sensitiv-
ity, altered GR numbers on immune cells, altered startle responses,
and increased SAM system activity (Fig. 1). As discussed above, evi-
dence suggests that immune risk factors, and in particular the
inflammatory system, may play important roles as well. Thus,
atypical interactions between immune and neuroendocrine
Fig. 1. A psychoneuroimmunological model of PTSD. Psychosocial risk factors join
and synergize with biological risk factors for PTSD. Immune system changes
identified in PTSD include increased delayed-type hypersensitivity (DTH),
decreased natural killer cell activity (NKCA), and increased in vitro lipopolysac-
charide (LPS)-induced cytokine responses. Major biological alterations already
known to exist in PTSD engage in a complex interplay, which is hypothesized to
contribute to immune alterations found in the disorder. Immune changes associ-
ated with PTSD are hypothesized to increase the risk for developing medical
illnesses.
11
systems may help to explain the inflammatory excess found in a
portion of patients with PTSD.
Because glucocorticoids are well known for their anti-inflam-
matory effects, it is reasonable to theorize that reduced circulating
concentrations of cortisol seen in some patients with PTSD may be
responsible for increased inflammation in the same individuals.
While we are unaware of studies directly relating cortisol and
inflammatory markers in PTSD, attenuated cortisol responses have
been associated with enhanced IL-6 and IL-1b responses to stress
in healthy individuals (Kunz-Ebrecht et al., 2003). This suggests
that low circulating concentrations of cortisol may foster a hyper-
inflammatory state, especially in the context of stress.
But the actions of hormones are not determined solely as a
function of circulating concentrations. Instead, hormone effects
also depend on tissue sensitivity, which is determined by receptor
density and receptor function. As discussed above, PTSD patients
have been found to exhibit altered glucocorticoid sensitivity in
endocrine tissues and immune cells. In addition, multiple studies
suggest that GR density may be increased on immune cells. Assum-
ing that patients with PTSD exhibit enhanced glucocorticoid sensi-
tivity, especially of inflammatory processes, and higher GR density,
if anything patients with the disorder should have ‘‘normal’’ con-
centrations of circulating inflammatory markers despite low corti-
sol. One may even predict that patients with PTSD would have
reduced inflammatory markers. And yet multiple studies suggest
that PTSD involves enhanced inflammatory activation. How can
this apparent paradox be explained?
First, it is possible that enhanced inflammation in patients with
PTSD may not be the direct result of low circulating concentrations
of cortisol. Instead, increased inflammation may be driven by en-
hanced SAM system activity found in PTSD patients. Increased
sympathetic activity in patients with PTSD could be secondary to
reduced cortisol, especially in the context of stress challenge (Yeh-
uda, 2009). Increased SAM system activity may then enhance the
activity of inflammatory pathways, including NF-jB (Bierhaus
et al., 2003). With this possibility, low circulating concentrations
of cortisol would indirectly influence inflammatory function via
the SAM system.
Second, it also may be possible that the low circulating concen-
trations of cortisol found in a portion of patients with PTSD may
fall below critical thresholds needed to maintain normal inflamma-
tory function, even in the presence of enhanced glucocorticoid sen-
sitivity. If this hypothesis is correct, inflammatory excess in these
patients should respond rapidly to glucocorticoid therapy without
altering SAM system activity. Regardless of the exact nature of the
mechanisms involved, it is possible that reduced cortisol, enhanced
sympathetic activity, and enhanced inflammation influence one
another in the context of PTSD (Fig. 1).
It is also important to point out that inflammatory alterations in
patients with PTSD may develop independently of reduced cortisol
levels. As discussed above, increased inflammation may be a pre-
existing risk factor that results from personality traits or genetic
factors. If reduced cortisol is not involved, or if patients with PTSD
have normal circulating concentrations of cortisol (Meewisse et al.,
2007), it is possible that enhanced glucocorticoid sensitivity of im-
mune cells may be unable to overcome this inflammation.
7. From PTSD to medical comorbidities, via immune
dysfunction
As discussed in Section 4, PTSD is often comorbid with a num-
ber of chronic medical illnesses that have immune underpinnings.
Could inflammatory and autoimmune changes that appear with
the onset of PTSD encourage later development of the same comor-
bid medical illnesses? Although short-lived inflammation may be
12 T.W.W. Pace, C.M. Heim / Brain, Behavior, and Immunity 25 (2011) 6–13
beneficial for combating pathogen exposure or tissue damage,
long-term inflammation is well known to increase the risk for
chronic medical illnesses. In this section, we will briefly illustrate
a psychoneuroimmunological model of PTSD (Fig. 1), by focusing
on two disease states that are often comorbid with the disorder:
CVD and insulin resistance.
Connections between PTSD, immune function and CVD may be-
gin with increased concentrations of proinflammatory cytokines in
the circulation that appear with the onset of PTSD. Circulating
cytokine changes then persist for months, and perhaps years, along
with ongoing PTSD symptoms. Although prospective studies are
yet to demonstrate that the onset of PTSD symptoms is associated
with increased circulating inflammatory markers, as noted above
increased plasma levels of IL-6 at the time of trauma have been
associated with later development of PTSD (Pervanidou et al.,
2007). In addition, acute and chronic stressors are well known to
increase inflammatory markers (Segerstrom and Miller, 2004). Of
note, PTSD has already been prospectively associated with the
development of heart disease 15 years later in veterans who were
free of heart disease at baseline (Boscarino, 2008).
Along with increased lipoproteins, inflammation within the
wall of blood vessels fosters the atherosclerotic process (Sprague
and Khalil, 2009). Increased circulating concentrations of proin-
flammatory cytokines associated with PTSD may eventually acti-
vate inflammatory signaling pathways (e.g. NF-kB) in vascular
cells that make up the vessel wall. Inflammatory pathway activa-
tion in these cells encourages increased cell adhesion, increased
vessel permeability, and apoptosis. Monocytes are then able to at-
tach more readily to vessel walls, and eventually mature into mac-
rophages. These macrophages then amplify the proinflammatory
message in the vascular wall by secreting additional IL-1b and
TNF-alpha, as well as other factors, which furthers expression of
adhesion molecules such as vascular cell adhesion molecule-1.
Macrophages eventually become large foam cells, forming ‘‘fatty
streaks’’ inside vessels that can develop into atherosclerotic le-
sions. Proinflammatory cytokines would also draw smooth muscle
cells to the lesion, forming fibrous capsules over these lesions. Fi-
nally, circulating proinflammatory cytokines have been shown to
potentiate thromboses, or rupture of atherosclerotic lesions, lead-
ing to MI or ischemic stroke (Tousoulis et al., 2006). Although
CVD depends on a number of factors, including dietary habits,
smoking, and exercise, it is conceivable that increased inflamma-
tion begun by trauma and PTSD may eventually push PTSD pa-
tients into comorbid CVD.
Inflammation has also been implicated in the pathophysiology
of insulin resistance and metabolic syndrome. Multiple studies
have found that chronic activation of inflammatory signaling
pathways can lead to obesity-related insulin resistance. In the psy-
choneuroimmunological model of PTSD, elevated circulating con-
centrations of proinflammatory cytokines associated with PTSD
would potentiate activation of macrophages in adipose tissue and
the liver that are central to insulin resistance. These activated mac-
rophages are the main generators of inflammatory products, such
as TNF-alpha, that go onto induce inflammatory signaling path-
ways within insulin target cells. Increased inflammatory signaling
activity within insulin target cells is then able to antagonize nor-
mal insulin receptor signaling (Olefsky and Glass, 2010). Although
increased inflammation as a result of trauma and PTSD may not be
sufficient to induce insulin resistance alone, the model predicts
that inflammatory changes induced by PTSD would synergize with
other factors, including waist-to-hip ratio and exercise habits, to
encourage development of insulin resistance and metabolic
syndrome.
Although work to date supports an immune component in
mechanisms linking PTSD and chronic medical illness, more infor-
mation is needed. Prospective studies will need to demonstrate
that immune changes subsequent to trauma and the onset of PTSD
predict disease development. As mentioned above, one prospective
study has already found that PTSD predicts the development of
heart disease (Boscarino, 2008).
8. Conclusions
PTSD is a debilitating disorder that strikes some, but not all peo-
ple after exposure to extreme stress. The pathophysiological
underpinnings of the disorder are complicated. Moreover, as with
other psychiatric disorders, it is very likely that not all cases of
PTSD share the same underlying mechanistic ‘‘nuts and bolts’’. This
complicates attempts to understand the disorder, as well as efforts
to develop new treatment approaches. Although research on the
biology of PTSD has been historically dominated by studies with
neuroendocrine endpoints, it is now clear that PTSD pathophysiol-
ogy may also involve the immune system. Given the close relation-
ship between the immune and neuroendocrine systems, as well as
how immune alterations are thought to play a central role in other
neuropsychiatric disorders, it is reasonable to hypothesize that the
immune system plays a central role in PTSD pathophysiology as
well as in medical illnesses found along with PTSD.
References
Altemus, M., Dhabhar, F.S., Yang, R., 2006. Immune function in PTSD. Ann. NY Acad.
Sci. 1071, 167–183.
Baker, D.G., Ekhator, N.N., Kasckow, J.W., Hill, K.K., Zoumakis, E., Dashevsky, B.A.,
Chrousos, G.P., Geracioti, T.D., 2001. Plasma and cerebrospinal fluid interleukin-
6 concentrations in posttraumatic stress disorder. NeuroImmunoModulation 9,
209–217.
Bedi, U.S., Arora, R., 2007. Cardiovascular manifestations of posttraumatic stress
disorder. J. Natl. Med. Assoc. 99, 642–649.
Bichescu, D., Schauer, M., Saleptsi, E., Neculau, A., Elbert, T., Neuner, F., 2005. Long-
term consequences of traumatic experiences: an assessment of former political
detainees in Romania. Clin. Pract. Epidemiol. Ment. Health 1, 17.
Bierhaus, A., Wolf, J., Andrassy, M., Rohleder, N., Humpert, P.M., Petrov, D., Ferstl, R.,
von Eynatten, M., Wendt, T., Rudofsky, G., Joswig, M., Morcos, M., Schwaninger,
M., McEwen, B., Kirschbaum, C., Nawroth, P.P., 2003. A mechanism converting
psychosocial stress into mononuclear cell activation. Proc. Natl Acad. Sci. USA
100, 1920–1925.
Boscarino, J.A., 2004. Posttraumatic stress disorder and physical illness: results from
clinical and epidemiologic studies. Ann. NY Acad. Sci. 1032, 141–153.
Boscarino, J.A., 2008. A prospective study of PTSD and early-age heart disease
mortality among Vietnam veterans: implications for surveillance and
prevention. Psychosom. Med. 70, 668–676.
Boscarino, J.A., Chang, J., 1999. Higher abnormal leukocyte and lymphocyte counts
20 years after exposure to severe stress: research and clinical implications.
Psychosom. Med. 61, 378–386.
Boscarino, J.A., Forsberg, C.W., Goldberg, J., 2010. A twin study of the association
between PTSD symptoms and rheumatoid arthritis. Psychosom. Med. 72, 481–
486.
Bremner, J.D., Licinio, J., Darnell, A., Krystal, J.H., Owens, M.J., Southwick, S.M.,
Nemeroff, C.B., Charney, D.S., 1997. Elevated CSF corticotropin-releasing factor
concentrations in posttraumatic stress disorder. Am. J. Psychiatry 154, 624–629.
Bremner, J.D., Elzinga, B., Schmahl, C., Vermetten, E., 2008. Structural and functional
plasticity of the human brain in posttraumatic stress disorder. Prog. Brain Res.
167, 171–186.
Danese, A., Caspi, A., Williams, B., Ambler, A., Sugden, K., Mika, J., Werts, H.,
Freeman, J., Pariante, C.M., Moffitt, T.E., Arseneault, L., 2010. Biological
embedding of stress through inflammation processes in childhood. Mol.
Psychiatry, in press.
Danik, J.S., Ridker, P.M., 2007. Genetic determinants of C-reactive protein. Curr.
Atheroscler. Rep. 9, 195–203.
de Kloet, C.S., Vermetten, E., Bikker, A., Meulman, E., Geuze, E., Kavelaars, A.,
Westenberg, H.G., Heijnen, C.J., 2007. Leukocyte glucocorticoid receptor
expression and immunoregulation in veterans with and without post-
traumatic stress disorder. Mol. Psychiatry 12, 443–453.
Garcia-Linares, M.I., Sanchez-Lorente, S., Coe, C.L., Martinez, M., 2004. Intimate male
partner violence impairs immune control over herpes simplex virus type 1 in
physically and psychologically abused women. Psychosom. Med. 66, 965–972.
Geracioti, T.D., Baker, D.G., Ekhator, N.N., West, S.A., Hill, K.K., Bruce, A.B., Schmidt,
D., Rounds-Kugler, B., Yehuda, R., Keck Jr., P.E., Kasckow, J.W., 2001. CSF
norepinephrine concentrations in posttraumatic stress disorder. Am. J.
Psychiatry 158, 1227–1230.
Gill, J.M., Saligan, L., Woods, S., Page, G., 2009. PTSD is associated with an excess of
inflammatory immune activities. Perspect. Psychiatr. Care 45, 262–277.
 T.W.W. Pace, C.M. Heim / Brain, Behavior, and Immunity 25 (2011) 6–13
Goshen, I., Kreisel, T., Ben-Menachem-Zidon, O., Licht, T., Weidenfeld, J., Ben-Hur, T.,
Yirmiya, R., 2008. Brain interleukin-1 mediates chronic stress-induced
depression in mice via adrenocortical activation and hippocampal
neurogenesis suppression. Mol. Psychiatry 13, 717–728.
Gotovac, K., Vidovic, A., Vukusic, H., Krcmar, T., Sabioncello, A., Rabatic, S., Dekaris,
D., 2010. Natural killer cell cytotoxicity and lymphocyte perforin expression in
veterans with posttraumatic stress disorder. Prog. Neuropsychopharmacol. Biol.
Psychiatry 34, 597–604.
Graham, J.E., Robles, T.F., Kiecolt-Glaser, J.K., Malarkey, W.B., Bissell, M.G., Glaser, R.,
2006. Hostility and pain are related to inflammation in older adults. Brain
Behav. Immun. 20, 389–400.
Heim, C., Mletzko, T., Purselle, D., Musselman, D.L., Nemeroff, C.B., 2008. The
dexamethasone/corticotropin-releasing factor test in men with major
depression: role of childhood trauma. Biol. Psychiatry 63, 398–405.
Heim, C., Nemeroff, C.B., 2009. Neurobiology of posttraumatic stress disorder. CNS
Spectr. 14, 13–24.
Heppner, P.S., Crawford, E.F., Haji, U.A., Afari, N., Hauger, R.L., Dashevsky, B.A., Horn,
P.S., Nunnink, S.E., Baker, D.G., 2009. The association of posttraumatic stress
disorder and metabolic syndrome: a study of increased health risk in veterans.
BMC Med. 7, 1.
Inoue-Sakurai, C., Maruyama, S., Morimoto, K., 2000. Posttraumatic stress and
lifestyles are associated with natural killer cell activity in victims of the
Hanshin–Awaji earthquake in Japan. Prev. Med. 31, 467–473.
Ironson, G., Wynings, C., Schneiderman, N., Baum, A., Rodriguez, M., Greenwood, D.,
Benight, C., Antoni, M., LaPerriere, A., Huang, H.S., Klimas, N., Fletcher, M.A.,
1997. Posttraumatic stress symptoms, intrusive thoughts, loss, and immune
function after Hurricane Andrew. Psychosom. Med. 59, 128–141.
Kawamura, N., Kim, Y., Asukai, N., 2001. Suppression of cellular immunity in men with
a past history of posttraumatic stress disorder. Am. J. Psychiatry 158, 484–486.
Keane, T.M., Marshall, A.D., Taft, C.T., 2006. Posttraumatic stress disorder: etiology,
epidemiology, and treatment outcome. Annu. Rev. Clin. Psychol. 2, 161–197.
Kessler, R.C., 2000. Posttraumatic stress disorder: the burden to the individual and
to society. J. Clin. Psychiatry 61 (Suppl. 5), 4–12. Discussion 13–14.
Kessler, R.C., Sonnega, A., Bromet, E., Hughes, M., Nelson, C.B., 1995. Posttraumatic
stress disorder in the National Comorbidity Survey. Arch. Gen. Psychiatry 52,
1048–1060.
Kibler, J.L., 2009. Posttraumatic stress and cardiovascular disease risk. J. Trauma
Dissociation 10, 135–150.
Koo, J.W., Russo, S.J., Ferguson, D., Nestler, E.J., Duman, R.S., 2010. Nuclear factor-
kappaB is a critical mediator of stress-impaired neurogenesis and depressive
behavior. Proc. Natl. Acad. Sci. USA 107, 2669–2674.
Kosor Krnic, E., Gagro, A., Kozaric-Kovacic, D., Vilibic, M., Grubisic-Ilic, M.,
Folnegovic-Smalc, V., Drazenovic, V., Cecuk-Jelicic, E., Gjenero-Margan, I.,
Kuzman, I., Jeren, T., Sabioncello, A., Kerhin-Brkljacic, V., Kaic, B., Markotic, A.,
Gotovac, K., Rabatic, S., Mlinaric-Galinovic, G., Dekaris, D., 2007. Outcome of
influenza vaccination in combat-related post-traumatic stress disorder (PTSD)
patients. Clin. Exp. Immunol. 149, 303–310.
Kunz-Ebrecht, S.R., Mohamed-Ali, V., Feldman, P.J., Kirschbaum, C., Steptoe, A., 2003.
Cortisol responses to mild psychological stress are inversely associated with
proinflammatory cytokines. Brain Behav. Immun. 17, 373–383.
Laudenslager, M.L., Aasal, R., Adler, L., Berger, C.L., Montgomery, P.T., Sandberg, E.,
Wahlberg, L.J., Wilkins, R.T., Zweig, L., Reite, M.L., 1998. Elevated cytotoxicity in
combat veterans with long-term post-traumatic stress disorder: preliminary
observations. Brain Behav. Immun. 12, 74–79.
Maes, M., Lin, A.H., Delmeire, L., Van Gastel, A., Kenis, G., De Jongh, R., Bosmans, E.,
1999. Elevated serum interleukin-6 (IL-6) and IL-6 receptor concentrations in
posttraumatic stress disorder following accidental man-made traumatic events.
Biol. Psychiatry 45, 833–839.
Meewisse, M.L., Reitsma, J.B., de Vries, G.J., Gersons, B.P., Olff, M., 2007. Cortisol and
post-traumatic stress disorder in adults: systematic review and meta-analysis.
Br. J. Psychiatry 191, 387–392.
Miller, A.H., 2010. Depression and immunity: a role for T cells? Brain Behav. Immun.
24, 1–8.
Nater, U.M., Youngblood, L.S., Jones, J.F., Unger, E.R., Miller, A.H., Reeves, W.C., Heim,
C., 2008. Alterations in diurnal salivary cortisol rhythm in a population-based
sample of cases with chronic fatigue syndrome. Psychosom. Med. 70, 298–305.
Olefsky, J.M., Glass, C.K., 2010. Macrophages, inflammation, and insulin resistance.
Annu. Rev. Physiol. 72, 219–246.
Pervanidou, P., Kolaitis, G., Charitaki, S., Margeli, A., Ferentinos, S., Bakoula, C.,
Lazaropoulou, C., Papassotiriou, I., Tsiantis, J., Chrousos, G.P., 2007. Elevated
morning serum interleukin (IL)-6 or evening salivary cortisol concentrations
predict posttraumatic stress disorder in children and adolescents six months
after a motor vehicle accident. Psychoneuroendocrinology 32, 991–999.
Pole, N., Neylan, T.C., Otte, C., Henn-Hasse, C., Metzler, T.J., Marmar, C.R., 2009.
Prospective prediction of posttraumatic stress disorder symptoms using fear
potentiated auditory startle responses. Biol. Psychiatry 65, 235–240.
Qureshi, S.U., Pyne, J.M., Magruder, K.M., Schulz, P.E., Kunik, M.E., 2009. The link
between post-traumatic stress disorder and physical comorbidities: a
systematic review. Psychiatr. Q. 80, 87–97.
Reichenberg, A., Yirmiya, R., Schuld, A., Kraus, T., Haack, M., Morag, A., Pollmacher,
T., 2001. Cytokine-associated emotional and cognitive disturbances in humans.
Arch. Gen. Psychiatry 58, 445–452.
Rohleder, N., Joksimovic, L., Wolf, J.M., Kirschbaum, C., 2004. Hypocortisolism and
increased glucocorticoid sensitivity of pro-Inflammatory cytokine production in
Bosnian war refugees with posttraumatic stress disorder. Biol. Psychiatry 55,
745–751.
13
Rohleder, N., Wolf, J.M., Wolf, O.T., 2010. Glucocorticoid sensitivity of cognitive and
inflammatory processes in depression and posttraumatic stress disorder.
Neurosci. Biobehav. Rev. 35, 104–114.
Sabioncello, A., Kocijan-Hercigonja, D., Rabatic, S., Tomasic, J., Jeren, T., Matijevic, L.,
Rijavec, M., Dekaris, D., 2000. Immune, endocrine, and psychological responses
in civilians displaced by war. Psychosom. Med. 62, 502–508.
Segerstrom, S.C., Miller, G.E., 2004. Psychological stress and the human immune
system: a meta-analytic study of 30 years of inquiry. Psychol. Bull. 130, 601–630.
Skarpa, I., Rubesa, G., Moro, L., Manestar, D., Petrovecki, M., Rukavina, D., 2001.
Changes of cytolytic cells and perforin expression in patients with
posttraumatic stress disorder. Croat. Med. J. 42, 551–555.
Sommershof, A., Aichinger, H., Engler, H., Adenauer, H., Catani, C., Boneberg, E.M.,
Elbert, T., Groettrup, M., Kolassa, I.T., 2009. Substantial reduction of naive and
regulatory T cells following traumatic stress. Brain Behav. Immun. 23, 1117–
1124.
Sondergaard, H.P., Hansson, L.O., Theorell, T., 2004. The inflammatory markers C-
reactive protein and serum amyloid A in refugees with and without
posttraumatic stress disorder. Clin. Chim. Acta 342, 93–98.
Spitzer, C., Barnow, S., Volzke, H., Wallaschofski, H., John, U., Freyberger, H.J., Lowe,
B., Grabe, H.J., 2010. Association of posttraumatic stress disorder with low-
grade elevation of C-reactive protein: evidence from the general population. J.
Psychiatr. Res. 44, 15–21.
Spivak, B., Shohat, B., Mester, R., Avraham, S., Gil-Ad, I., Bleich, A., Valevski, A.,
Weizman, A., 1997. Elevated levels of serum interleukin-1 beta in combat-
related posttraumatic stress disorder. Biol. Psychiatry 42, 345–348.
Sprague, A.H., Khalil, R.A., 2009. Inflammatory cytokines in vascular dysfunction
and vascular disease. Biochem. Pharmacol. 78, 539–552.
Stein, M.B., Koverola, C., Hanna, C., Torchia, M.G., McClarty, B., 1997. Hippocampal
volume in women victimized by childhood sexual abuse. Psychol. Med. 27,
951–959.
Sundin, J., Fear, N.T., Iversen, A., Rona, R.J., Wessely, S., 2010. PTSD after deployment
to Iraq: conflicting rates, conflicting claims. Psychol. Med. 40, 367–382.
Tousoulis, D., Antoniades, C., Koumallos, N., Stefanadis, C., 2006. Pro-inflammatory
cytokines in acute coronary syndromes: from bench to bedside. Cytokine
Growth Factor Rev. 17, 225–233.
Tucker, P., Jeon-Slaughter, H., Pfefferbaum, B., Khan, Q., Davis, N.J., 2010. Emotional
and biological stress measures in Katrina survivors relocated to Oklahoma. Am.
J. Disaster. Med. 5, 113–125.
Uddin, M., Aiello, A.E., Wildman, D.E., Koenen, K.C., Pawelec, G., de Los Santos, R.,
Goldmann, E., Galea, S., 2010. Epigenetic and immune function profiles
associated with posttraumatic stress disorder. Proc. Natl. Acad. Sci. USA 107,
9470–9475.
van Zuiden, M., Heijnen, C.J., Geuze, E., Willemen, H., Maas, M., Vermetten, E.,
Kavelaars, A., 2010. Increased glucocorticoid binding to peripheral blood
mononuclear cells before military deployment in individuals developing PTSD
symptoms 6 months after deployment. Brain Behav. Immun. 24, S9–S10.
Vidovic, A., Vilibic, M., Sabioncello, A., Gotovac, K., Rabatic, S., Folnegovic-Smalc, V.,
Dekaris, D., 2007. Circulating lymphocyte subsets, natural killer cell
cytotoxicity, and components of hypothalamic–pituitary–adrenal axis in
Croatian war veterans with posttraumatic stress disorder: cross-sectional
study. Croat. Med. J. 48, 198–206.
Vieweg, W.V., Julius, D.A., Fernandez, A., Beatty-Brooks, M., Hettema, J.M.,
Pandurangi, A.K., 2006. Posttraumatic stress disorder: clinical features,
pathophysiology, and treatment. Am. J. Med. 119, 383–390.
von Känel, R., Begre, S., Abbas, C.C., Saner, H., Gander, M.L., Schmid, J.P., 2010.
Inflammatory biomarkers in patients with posttraumatic stress disorder caused
by myocardial infarction and the role of depressive symptoms.
NeuroImmunoModulation 17, 39–46.
von Känel, R., Hepp, U., Kraemer, B., Traber, R., Keel, M., Mica, L., Schnyder, U., 2007.
Evidence for low-grade systemic proinflammatory activity in patients with
posttraumatic stress disorder. J. Psychiatr. Res. 41, 744–752.
Vythilingam, M., Heim, C., Newport, J., Miller, A.H., Anderson, E., Bronen, R.,
Brummer, M., Staib, L., Vermetten, E., Charney, D.S., Nemeroff, C.B., Bremner,
J.D., 2002. Childhood trauma associated with smaller hippocampal volume in
women with major depression. Am. J. Psychiatry 159, 2072–2080.
Wessa, M., Rohleder, N., 2007. Endocrine and inflammatory alterations in post-
traumatic stress disorder. Expert Rev. Endocrinol. Metab. 2, 91–122.
Wilson, S.N., van der Kolk, B., Burbridge, J., Fisler, R., Kradin, R., 1999. Phenotype of
blood lymphocytes in PTSD suggests chronic immune activation.
Psychosomatics 40, 222–225.
Woods, A.B., Page, G.G., O’Campo, P., Pugh, L.C., Ford, D., Campbell, J.C., 2005. The
mediation effect of posttraumatic stress disorder symptoms on the relationship
of intimate partner violence and IFN-gamma levels. Am. J. Community Psychol.
36, 159–175.
Yehuda, R., 2009. Status of glucocorticoid alterations in post-traumatic stress
disorder. Ann. NY Acad. Sci. 1179, 56–69.
Yehuda, R., LeDoux, J., 2007. Response variation following trauma: a translational
neuroscience approach to understanding PTSD. Neuron 56, 19–32.
Yehuda, R., Siever, L.J., Teicher, M.H., Levengood, R.A., Gerber, D.K., Schmeidler, J.,
Yang, R.K., 1998. Plasma norepinephrine and 3-methoxy-4-
hydroxyphenylglycol concentrations and severity of depression in combat
posttraumatic stress disorder and major depressive disorder. Biol. Psychiatry
44, 56–63.
Zalcman, S., Green-Johnson, J.M., Murray, L., Nance, D.M., Dyck, D., Anisman, H.,
Greenberg, A.H., 1994. Cytokine-specific central monoamine alterations
induced by interleukin-1, -2 and -6. Brain Res. 643, 40–49.