Module 4: Acupuncture for the Treatment of HPA Axis Dysfunction in Autoimmunity

Stress is inevitable and pervasive; we encounter stress – consciously and subconsciously – in untold ways and forms throughout each day. Traffic jams, work deadlines, relationship issues, environmental toxicants, climactic fluctuations, poor diet and inappropriate exercise are all common triggers for stress. A healthy, resilient body is equipped with stress response mechanisms that allow it adapt to stressful situations and though perhaps not without enduring some unsavory yet transient side effects, the body ultimately returns to baseline. Individuals with autoimmune disease, on the other hand, have impaired stress response systems, which may contribute to their susceptibility to initial disease onset as well as to the preservation of disease states and periodic symptomatic exacerbations.

Stress And Immunity

As the immune, nervous and endocrine systems work in concert to maintain health, what affects one system will necessarily impact the others. Ongoing imbalance in any or multiple systems alters the internal landscape, presenting a obstacle to the maintenance of homeostasis. To that end, the link between stress and immunity is well established; chronic stress can trigger an acute phase response, which stimulates an inflammatory cascade through the innate immune system, indicating the potential for stress to give rise to inflammation.44 Even among healthy individuals, stress can lead to immune system impairment, decreasing the proliferative capacity of lymphocytes, and reducing levels of circulating B cells and T cells, specifically helper T cells and cytotoxic T cells, leaving the body ill-equipped to fight off potential immune infection or insult.45

Stress And Autoimmunity

While there is no conclusive or categorical cause for autoimmunity, stress is generally accepted as a potent trigger for the neuroendocrine and immune dysfunction that partake in the pathogenesis of autoimmune disease. The ubiquity of stress in our fast-paced, productivity-driven culture has made it both a readily accessible scapegoat for any harm that befalls us and an easily dismissible facet of modern living; the importance of stress as it relates to autoimmunity, however, cannot be overstated. Disease states, including autoimmune conditions, are inherently stressful. As we’ve seen, the inflammatory burden of autoimmunity is itself a stress; coupled with the pain, gut dysbiosis, energy and mood imbalances and hormonal dysregulation that autoimmune disease patients typically suffer, it is easy to appreciate how the state of disease places significant strain on the body. Furthermore, many autoimmune patients face unique challenges that amplify their stress, including difficulty in obtaining a diagnosis, juggling multiple healthcare providers, managing complicated treatment regimens and their attendant side effects, and accepting physical and functional limitations imposed by their conditions. Overcoming the stress burden of autoimmunity is made more difficult as the continual bombardment of internal and external stressors creates a self perpetuating cycle that favors the maintenance of disease and further distances the patient from both symptomatic relief and disease remission.

Though the precise interactions of the stress response with autoimmunity appear to vary between autoimmune diseases, as we will see later, it is clear that stress plays an important role in the onset of disease, with up to 80% of autoimmune disease patients reporting significant emotional stress prior to onset of autoimmune disease in a retrospective study.52  Further underscoring the influence of stress on autoimmune disease, a meta analysis of fourteen studies found a significant association between stressful life events in the twelve month pre-diagnostic period and autoimmune disease.46  As retrospective studies are particularly prone to recall bias (a sort of revisionist history that happens naturally with the passage of time, particularly in the context of a subjective topic such as stress), it is important to include various study types and designs in evaluating the effects of a given trigger on disease. To that end, a prospective study of MS patients bolstered the above-mentioned findings in uncovering an association between stress and disease, and furthermore pointed to a cumulative effect of stress on autoimmune disease states, as the presence of three or more stressful life events was associated with a five fold increased risk of MS exacerbation.47

Stress Mechanisms

Before diving further into the role of stress in autoimmunity, let’s back up and take a look at the physiological mechanisms of stress. While the body enacts multiple mechanisms to respond with stress, the Sympathetic Nervous System and in particular the Hypothalamic Pituitary Adrenal (HPA) axis form the basis of our discussion relating to autoimmunity.

The Sympathetic Nervous System

When the body encounters acute stress, be it physical, emotional or mental, the sympathetic nervous system is first to spring into action, releasing the catecholamines epinephrine and norepinephrine that help the body quickly adapt to changing circumstances and prime it for action: heart rate increases, blood flow is shunted from the viscera to the musculature, and pupils dilate, among other effects. Importantly, catecholamines released from sympathetic nerve terminals can influence lymphocyte traffic, proliferation, and local function.45 That catecholamines are capable of inhibiting the production of Th1 cytokines but do not directly affect the production of Th2 cytokines indicates their tendency to encourage a shift towards Th2 dominance.45 Ultimately, though, the effects of sympathetic activation are short-lived, and the body typically resumes its baseline state without suffering undue damage.

The HPA Axis

The primary stress response system of interest, the hypothalamic pituitary adrenal (HPA) axis, has significant implications for autoimmunity, as impaired HPA axis responsiveness has been posited as a major contributing factor in the onset of autoimmune disease, the premise of its contribution being that impaired HPA axis function renders the body incapable of releasing adequate cortisol to suppress aberrant immune activity, potentiating the misrecognition of self proteins that constitutes autoimmune disease.48

Faced with an acute stressor, the hypothalamus releases corticotropin releasing factor (CRH), which signals to the pituitary to release adrenocorticotropic hormone (ACTH), which stimulates the adrenals to release glucocorticoids, the human form of which is called cortisol. In animals, glucocorticoids are referred to as corticosterone; for the purposes of this discussion, which is informed by both human and animal research, the term CORT will be used in reference to glucocorticoids. CORT has many functions in the body; as it pertains to stress and the immune system specifically, CORT modulates immune responses. An important distinction exists between endogenous CORT and exogenous forms administered as pharmacological therapy: while endogenous CORT can upregulate or downregulate immune system activity, exogenous CORT has strictly immunosuppressive effects.45,49 Importantly, CORT and the glucocorticoid receptors it binds to in order to exert its functions, operate in a feedback loop that serves to regulate the HPA axis, ultimately preventing or attenuating the excess HPA axis excitation that leads to maladaptive stress responses and contributes to systemic inflammation.50 As is the case for many hormones, cytokines and other immunomodulatory cells, optimal activity and concentrations lie within a range – a sort of physiological sweet spot in which not too much and not too little is necessary to achieve the desired physiological effect. While too much CORT can lead to glucocorticoid resistance (more on that below), not enough can exacerbate disease, as blocking CORT production can lead to flares in Rheumatoid Arthritis (RA), while surgical removal of the adrenal glands triggers disease exacerbations in Cushings patients.46

In the case of both the sympathetic nervous system and the HPA axis under healthy conditions, responses to acute stress are quick and easily recovered from. Chronic activation of the stress response systems, by contrast, creates another picture entirely.

Acute vs Chronic Stress

While acute stress can actually have a protective effect – acute stressors have been shown in animal models to shift immune phenotypes from autoimmune disease susceptibility towards autoimmune disease resistance46 – chronic stress hinders the body’s ability to maintain resilience against disease. Specifically, acute stress inhibits Th1 activity and induces Th2 cytokine production, lowering the potential for Th1 dominance and increasing the threshold for activation of self-reactive T cells, while chronic stress impairs CORT release over time, allowing inflammatory cytokine activity to go unchecked, ultimately leading to heightened immune reactivity.7

Chronic HPA axis activation leading to HPA axis dysfunction has been cited in a number of autoimmune conditions, including Crohn’s Disease, Colitis, Rheumatoid Arthritis and Multiple Sclerosis, among others.48 Because CORT plays an important role in regulating homeostasis – influencing metabolism, immune system function and behavior – the dysregulation of CORT resulting from HPA Axis impairment has unsurprisingly also been implicated in the development of allergic conditions such as asthma and dermatitis, somatic disorders such as Chronic Fatigue Syndrome and Fibromyalgia, and psychiatric disorders such as PTSD and depression, underscoring its far-reaching and profound effects on health.51

Worth noting is that stress hormones such as CORT have diurnal rhythms that determine their circulating concentrations at various points throughout the day. A loss in the natural diurnal rhythm of hormones and cytokines features in a number of diseases, and the capacity to recuperate normal rhythms has been tied to better outcomes, as cancer patients able to maintain healthy CORT rhythms had increased survival time relative to cancer patients whose CORT rhythms were blunted.48 An autoimmune disease that illustrates this point is Rheumatoid Arthritis (RA), in which case the characteristic worsening of symptoms in the morning may be attributable to the effect of dysregulated CORT on the immune system. RA patients tend to altered ACTH and cortisol patterns, as well as increased  levels of pro-inflammatory cytokines IL-6, IL-1, IL-12, IFN-γ, and TNF-α relative to healthy controls; the earlier peaks in CORT and later peaks in IL-6 seen in RA patients are thought to contribute to increased symptom severity experienced in the morning.48 Interestingly, in moderate to severe cases of RA, ACTH and CORT rhythms shift so that concentrations peak earlier in the night, whereas advanced cases of RA indicate a blunting of the rhythm altogether48, suggesting that the window of opportunity in which therapeutic interventions are most likely to benefit patients is limited, and underscoring the importance of early detection and treatment.

The dangers of chronic stress, and its accompanying elevations in CORT levels, are many. Not only can prolonged exposure to CORT inhibit both innate and adaptive immune responses, but it has also has been shown to impair neural plasticity and cognition, decrease neurogenesis, reduce spine density and induce dendritic atrophy.49 Higher basal levels of CORT have been associated with increases in pro-inflammatory cytokines in animal studies, and chronic stress has been shown to decrease glucocorticoid receptor numbers and function, weakening the response to CORT’s immunoregulatory actions.47,49 This decreased responsiveness of glucocorticoid receptors to CORT is termed glucocorticoid (GC) resistance, which can amplify inflammatory responses.52

With GC resistance, increased CORT levels induced by chronic stress downregulate glucocorticoid receptors (GR’s) in immune cells, permitting the spread of inflammation. Because GR’s play a critical role in determining the function and availability of CORT in the body, the HPA axis’ regulatory effects on the immune system are therefore weakened as immune cells become less responsive to CORT.47 

As the HPA Axis is a complex multi-organ system, impairment at any level – that of the hypothalamus, the pituitary, or the adrenals – can potentiate the downstream effect of altering CORT secretion and function, enumerating the ways in which GC resistance can develop. Furthermore, genetic polymorphisms and environmental factors such as preexisting inflammation, toxicant exposure and prolonged administration of exogenous glucocorticoids, as well as psychological stress, can give rise to GC resistance.51 GC resistance serves as an important piece in the stress-and-autoimmunity puzzle; while chronic elevations in CORT would theoretically suppress immune responses, the decreased responsiveness of GR’s to CORT illustrates a mechanism by which inflammation is allowed to spread, contributing to the development of disease.

Acupuncture

We’ve seen that acupuncture can reduce the stress burden on the body by attenuating inflammatory responses and regulating imbalanced cytokine profiles characteristic of autoimmune disease. When it comes to the actual mechanisms of acupuncture’s effects on the stress response system, however, a clear argument emerges for the inclusion of this therapeutic modality in treating patients with autoimmune disease.

A number of animal studies have investigated the role of acupuncture in relieving excess excitation of the HPA axis – i.e. the stress response system. A rat model of depression in which rats were subjected to ‘chronic unpredictable mild stress’ for a period of 21 days demonstrated a significant reduction in ACTH and CRH levels, as well as mRNA expression of CRH among acupuncture-treated rats relative to stressed and untreated controls, indicating the capacity for acupuncture to blunt the stress response.53 The study also evaluated 5-HT (serotonin) mRNA expression and concentrations, as serotonin activity is known to be impaired in depression, a common comorbidity of autoimmune disorders. Relative to controls, acupuncture-treated rats showcased significant elevations in mRNA expression and levels of serotonin; the behavioral correlates of acupuncture’s effects on stress hormones and serotonin manifested in decreased ‘depression behavior’ in the form of enhanced activity indices such as exploratory behavior and increased time to immobility (an indicator of despair), illustrating the potential for acupuncture to ameliorate maladaptive behavioral changes stemming from inflammatory conditions.53

A series of studies performed by the same research group explored the effects of acupuncture on the stress response system, with an initial study administering acupuncture pre-stress and another, post-stress. In the former study, acupuncture given once daily for 4 days followed by ten days of cold stress attenuated the impact of cold stress: ACTH and CORT levels were unchanged in the acupuncture group, whereas un-stressed and un-treated rats indicated elevations in these stress markers. While protein expression of CRH in the hypothalamus was elevated in response to cold stress, acupuncture lowered levels similar to that of un-stressed and un-treated controls, while stressed and un-treated and stressed and sham acupuncture rats indicated significantly higher levels.54 Though these findings highlight the capacity for acupuncture to disrupt the stress response, the application of acupuncture in anticipation of stress is not a likely real-world scenario. To that end, the second study in this series administered acupuncture immediately following cold stress exposure, achieving the same stress hormone preventing effects as the former study.55 The HPA axis hormones in acupuncture-treated rats were unchanged by cold stress, remaining similar to that of un-stressed and un-treated controls for 4 days after acupuncture treatment had stopped, despite the continuation of cold stress exposure.55 The long lasting effects demonstrated in this study are particularly enticing for a patient population predisposed to stress susceptibility, such as autoimmune disease patients. On the behavioral front, depressive and anxious behavior was unseen in the acupuncture-treated rats, while stressed and un-treated rats display significant depressive and anxious behavior following stress exposure, again emphasizing the capacity for acupuncture to address not only physical but also psycho-emotional aspects of health.55

Another animal model of stress demonstrated similar effects of acupuncture, with acupuncture treatment alleviating chronic stress-induced overexcitation of the HPA axis.52 Beyond these effects, acupuncture increased protein expression of the glucocorticoid receptor (GR) in the hippocampus, pituitary and hypothalamus, thereby promoting functional connectivity between GR and CORT, permitting GR’s regulatory effects on the HPA axis. Acupuncture-induced GR activation resulted in decreases in CORT elevations, reduced HPA hyperexcitation, and a diminished stress response.52 Furthermore, the study looked at ACTH receptor (ACTHR) gene, variants of which are known to be associated with impaired physiological and psychological stress responses; whereas cold stress exposure increased protein expression of ACTHR in the pituitary and adrenals, acupuncture-treated rats demonstrated decreased ACTHR protein expression,52 calling to attention a potential role for acupuncture in modulating genetic polymorphisms that confer susceptibility to ill health.

In summary, the evidence firmly suggests a role for acupuncture in alleviating impaired stress responses, and its demonstrated capacity for prolonged mitigation of stress responses before, during, and after the actual stressor is encountered indicates a wide and real life-relevant scope of clinical utility.

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