Stress and immune regulation
The paper by Olgart Höglund and colleagues published in this issue examines the association between examination stress, systemic immunological, local inflammatory and functional airway responses to stress in healthy and atopic undergraduate students [1]. It brings a careful analysis of various components of immune regulation to the study of psychological influences of asthma, which one of us previously described as having a long and chequered history [2]. Examination stress has been used to study various aspects of immune activation [3, 4] but this study represents the first description of an increased number of regulatory T cells in peripheral blood, observed in both atopic and non-atopic students, as well as a skewed Th1/Th2 ratio and reduced natural killer (NK) cell numbers that were unique to atopic students.
Interestingly, Olgart Höglund and colleagues noted that the group of students characterized by high perceived stress levels at baseline had higher numbers of CD4+CD45RO+CD25bright than the group with low perceived stress at the baseline (non-exam) period, suggesting that numbers of regulatory T cells increase with increased stress levels. NK cells were decreased in atopics in response to stress, but the techniques used to quantitate these, while specific for NK cells as stated by the authors, do not address the numbers of NKT cells. A future study might offer some further interesting insights into the respective roles of these latter cells which may contribute to either the pathogenic or protective processes underlying asthma, with some studies showing that NKT cells are essential for development of allergic asthma but others reporting that treatment with specific NKT ligands inhibits airway hyper-reactivity, eosinophilia and IgE production [5]. Furthermore, the relations between baseline stress levels, changes in stress from the no-exam to the exam period and immune or pulmonary function parameters were complex. For example, there were no differences in any investigated parameters when the group of students with a large increase in perceived stress or cortisol levels from baseline to exam period was compared with a group of students with minimal changes in perceived stress or cortisol. This calls into question whether the visual analogue scale used to assess perceived stress is sensitive to change and whether the group was adequately powered to support analyses by subgroups. This is not a trivial issue when we consider that only 41 students had to be divided into several subgroups. A lack in description of the statistics used enhanced the challenge of sorting out main effects from interactions in this report.
Although a modest number of studies such as this one by Olgart Höglund have examined the impact that the activity of the stress system may have on immune activation and asthma symptoms, fewer studies have considered whether immune activation and the experience of having asthma, particularly during childhood, influences the long-term responsiveness of the HPA axis. Furthermore, few have considered what the impact of this long-term dysregulation of the HPA axis could mean to the course and severity of asthma and other immune-related diseases. Kean et al. [6] recently reported rates of post-traumatic stress, presumably analogous to post-traumatic stress disorder (PTSD, associated with chronic alterations in HPA axis function), in adolescents with life-threatening asthma. Twenty percent of adolescents with life-threatening asthma had PTS, compared with 8% of healthy controls. Provocatively, almost 1/3 (29%) of the parents of adolescents with life threatening asthma had PTS compared with only 2% of the parents of healthy controls. Parental rates of PTS were elevated (14%) for parents of children with non-life-threatening asthma as well. If the reported rates of PTS are roughly equivalent to a PTSD diagnosis in these subjects, then the rates of PTSD are comparable to those observed in populations exposed to the most challenging and chronically stressful conditions such as war. Kean et al. [6] also found a relation between PTS symptoms and asthma morbidity, highlighting a potential reciprocal and plastic relation between stress activation and asthma symptoms or severity. That is, alterations in HPA axis responsiveness might contribute to vulnerability to asthma after which the experience of asthma may lead to further dysregulation of the HPA axis. Further HPA axis dysregulation in turn increases vulnerability to exacerbation or severity of asthma, which results in further stress and HPA axis dysregulation in a form of biological vicious circle. In apparent contrast, given the potent anti-inflammatory effect of glucocorticoids, investigators have suggested that inflammatory autoimmune diseases as well as asthma may be associated with attenuated HPA axis activity [7, 8]. A possible resolution to this paradox may be found in some, although not all, studies finding that people with PTSD have lower than expected basal cortisol levels, despite exaggerated responses to acute stress. A decrease in basal HPA axis activity might provide a permissive environment for immune activation.
It is possible therefore that children with asthma and their parents have a pre-disposition to alterations of the HPA axis that contributes to vulnerability to asthma and partially accounts for the strikingly high rates of PTS observed by Kean et al. [6] in the parents of youth with asthma. This possibility sounds less far-fetched when one considers recent data showing that there is decreased diurnal variation in cortisol of infants whose mothers or fathers had asthma [9]. Ball and colleagues concluded that the alterations in both basal and stress levels of endogenous cortisol in infants predisposed to allergic disease might affect the development of immune responses early in life through interactions with inflammatory mediators. Wright [10] also recently emphasized the importance of critical developmental periods, including the in utero environment, during which the influence of stress on immune regulation might be particularly prominent; Meaney and Szyf [11] further discuss environmental programming of the HPA axis. Several years ago, Shanks and Lightman [12] reviewed the potential of this multi-directional programming of immune, endocrine and central nervous systems, which can occur during critical windows of developmental plasticity and contribute to emergence and course of illness much later in life.
A new direction for advancing studies on asthma, immune and central nervous system regulation was impressively mapped in a recent report describing the use of functional MRI during antigenic challenge to examine regional brain activation in people with mild allergic asthma [13]. Activity in the anterior cingulate cortex (ACC) and insula in response to asthma-associated emotional words (e.g., Wheeze) was associated with markers of inflammation and airways obstruction. Notably, the observed effects were highly specific to asthma content and were distinguishable from the general experience of airways obstruction induced by a methacholine challenge. The study was not able to dissociate whether the activation reflected afferent modulation of neural activity by signals from the lung or efferent processes modulating the pulmonary response to antigenic challenge, but the study provides a paradigm for future studies of the communication pathways – neural and humoral – that link these systems. It should be possible to conduct similar studies on patients with asthma under various states of HPA axis activity. The tendency of the subjects to be primed by asthma-related words is interesting, although it may not be a homogenous feature among people with asthma. We previously performed a double-blind, crossover study in which subjects were identified as being suggestible or suggestion-resistant. Five of eight suggestible subjects compared with one of nine suggestion-resistant subjects showed a significant decline in forced expiratory volume in 1 s in response to inhaled saline and suggestion of bronchoconstriction [14]. Furthermore, the ACC and insula are implicated in the processing of emotion and appear to have different activity states in patients who are depressed, a condition strongly associated with stress and HPA axis dysregulation.
Based on studies to date, it is unfortunately still difficult to translate this knowledge of the interconnectedness of the nervous, immune and endocrine milieu into clinical relevance. A systematic review of studies assessing the efficacy of psychological interventions for children and adolescents with asthma was recently attempted. Although 12 studies were identified, a meta-analysis could be conducted on only two studies, and study quality was generally judged as poor [15]. Data such as those presented here may spur further investigation of the ways in which behavioural interventions may be used to modulate the stress response and minimize expression of atopic symptoms. Despite the paucity of data supporting the utility of targeting either the stress response as an intervention for asthma, there is emerging recognition of the potential for this strategy. Chetta et al. [16] recently noted that, ‘the evaluation of breathlessness perception, psychological disturbances and the recording of any stressful events should be considered as relevant as the physical and functional assessment of respiration’. Further multi-disciplinary, technically challenging studies are needed to increase our understanding of the ways in which stress is transduced into physical symptoms and ultimately, the ways in which this can be manipulated to reduce the burden of a host of inflammation-driven illnesses.
