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Conventional allopathic medicine can no longer ignore that the body and mind are inextricably intertwined. Research reveals the mosaic of autoimmune diseases linked to stress and natural solutions to restore immune homeostasis
The Evolutionary Origins of Stress
You are gripped by a strangle-hold of fear, a relentless foreboding feeling that catapults you into the spiraling black hole of fight-or-flight. Glucose is released from the liver as a quick energy source, and blood flow is diverted from your digestive system to your extremities in anticipation of an energy-demanding escape. Increased respiratory depth and bronchiolar dilatation occurs in tandem with enhanced cardiac output and blood pressure to improve oxygenation and energy delivery to the musculature. Reproduction and immunity are put on hold in favor of more primordial impulses to evade danger and elude predators. Stress hormones such as catecholamines, glucocorticoids, growth hormone and prolactin flood your system in order to mobilize energy reserves (1).
Cognitive processes inherent to your frontal lobe, that brain region governing executive functions such as learning, memory, problem-solving, and decision-making, are forestalled in favor of instinctual reflexes activated in pursuit of survival, which belong to the domain of your evolutionarily ancient reptilian brain. The mass activation of the sympathetic nervous system results in stimulation of the reticular activation system, a brain area responsible for heightened alertness and sensory amplification (2). Responsible for orchestrating and integrating the response to stress is the paraventricular nucleus of the hypothalamus, the ancient core of the brain that has its roots in the last common ancestors of vertebrates, flies and worms (3).
Whether you are fleeing from a lion, defending yourself against a burglar, or seething in traffic, your visceral reaction is the same. Sympathetic tone, the part of the autonomic nervous system devoted to emergency preparedness, predominates over parasympathetic, the arm that conserves energy and promotes repair and replenishment, as an adaptive response to stress. Contemporary living in the modern post-industrial age is accompanied by perpetual stress, thrusting our bodies into a perpetual low-grade state of emergency, which has real implications for human health. Fear, irrespective of the threat, absconds with logic in favor of instinct and suppresses quintessential physiological systems in the interest of self-preservation. Psychological perception translates directly into concrete physiological consequence.
Stress-induced disorders were once branded psychosomatic. A Freudian concept called hysteria, now relegated to the domain of conversion disorder, these disease labels imply that it is all in your head, questioning the legitimacy of your symptomatology, the compass of your innate intuition, and the veracity of the truths you expose raw, and lay bear at the feet of your practitioner. Even if the primary "complaint," another antiquated term with connotations of malingering, is psychiatric in nature, the notion of a divorce between mind and body, that long-disproven dualism which has been so foundational to allopathic medicine, has been debunked and discredited by the domain of psychoneuroimmunology.
There is an intimate connection between body and mind, such that what we call mental illness is subject to the same biochemical mechanisms and pathophysiological processes at play in the body. That formerly construed impenetrable blood brain barrier and the concept of the immunologically privileged brain are being challenged by the latest research. Your thoughts affect your physiology and your physiology affects your mental state, which is why stress is so central to the immune dysregulations behind the etiology of autoimmune disorders. Therefore, it is nothing short of a disgrace that nearly half of patients with autoimmune disorders, who are predominately female, are accused of hypochondriasis before receiving an accurate diagnosis (4).
The Biochemical Mechanisms Linking Stress to Autoimmune Disease
The concept of stress, first elucidated by Hans Selye, was initially defined as a non-specific response of the body to any demand placed upon it (5). Selye ushered in the idea of general adaptation syndrome, a stress-induced disease that results from abnormalities in the hypothalamus-pituitary-adrenal (HPA) system and sympathetic-adrenal system, neuroendocrine axes which coordinate the long- and short-term responses of the body and brain to environmental stress (5).
Due to the evolutionary mismatch between the environment to which our bodies have habituated and the modern day living circumstances, our stress responses have been deranged and many people find themselves embroiled in a feed-forward cycle of fight-or-flight, where sympathetic nervous system activity predominates over the feed-and-breed parasympathetic system that engenders anti-inflammatory effects. For instance, even occupational stress has been illustrated to up-regulate the adrenosympathetic system (6).
Perpetual stress can result in dysfunctional patterns of secretion of the stress hormone cortisol, a glucocorticoid hormone which should be high in the morning for induction of the awakening response and low at bed time to facilitate restorative sleep. After a period of cortisol becoming chronically elevated, the HPA axis that originates in the brain can become down-regulated or cortisol resistance can occur secondary to decreased cortisol receptor sensitivity. In the latter scenario, in a manner analogous to what occurs in insulin resistance, the cortisol receptor begins to ignore the signal conveyed by cortisol hormone, and the lock-and-key mechanism that occurs upon cortisol binding to its receptor fails to create a downstream cascade of signal transduction.
When proper cortisol secretion is impaired, control over inflammatory responses is lost, and oral tolerance, or the ability to differentiate self from non-self, is jeopardized. Not only that, but excesses or deficiencies of cortisol and its upstream hormone, corticotropin-releasing hormone (CRH), can compromise integrity of the gastrointestinal mucosa, leading pathologic intestinal permeability to materialize (7). This breach in the architecture of the gut barrier, known as leaky gut syndrome, is a prerequisite for the development of autoimmune disease (8).
Stress has also been shown to produce alterations in the microbiota, those commensal microorganisms that inhabit our gut and promote nutrient assimilation, detoxification, regulation of intestinal barrier function, and educate the immune system as to what constitutes friend or foe. For example, habitual stress has been revealed to dramatically change the microbiota composition and metabolic signature, reducing levels of beneficial bugs such as Lactobacillus (9). As a result, it is unsurprising that, "Maladaptive neuroendocrine hyper- or hypoactive responses of the HPA or sympathetic nervous system (SNS) to stress, including glucocorticoid resistance, can function as risk factors for the initiation and progression of specific diseases, in particular viral infection and chronic, inflammatory autoimmune diseases" (10, p. 1010).
The ACE data: How Adverse Childhood Experiences Influence Autoimmune Risk
The ACE studies, which chronicle the connection between adverse childhood experiences and disease, are another line of evidence cementing the deeply interwoven fabric between stress and autoimmunity. Retrospective studies have illuminated that up to 80% of autoimmune patients report emotional stress as precipitating disease onset, and childhood traumatic stress has been shown to increase the likelihood of hospitalization with a diagnosed autoimmune condition decades into adulthood (5, 11). A vicious cycle ensues, since the diseases themselves also produce significant psychological distress due to pain, fatigue, mobility limitations, difficulties with activities of daily life, and loss of sense of self-efficacy (12, 13, 14, 15).
The quality of relationships and other social variables are prognostic factors in patients with rheumatoid arthritis (5), and inflammatory bowel disease (7), which illuminates the role of stress in the disease etiology. Likewise, stress has been found to be both a permissive and aggravating factor for juvenile idiopathic arthritis (JIA) (10). The onset or exacerbation of multiple sclerosis (MS) has similarly been shown to be preceded by critical life events, which is mirrored by animal models of experimental allergic encephalomyelitis (EAE), which demonstrate that both restraint stress or maternal deprivation influenced development of MS-like EAE (10, 16).
Psychological trauma has been correlated with increased utilization of health care services, onset of certain diseases, and premature death (17, 18). At a mechanistic level, patients with post traumatic stress disorder (PTSD) have been found to have lower cortisol, higher circulating T-cell lymphocytes, hyper-reactive immune responses on tests of delayed cutaneous hypersensitivity, lower levels of the anti-inflammatory anti-aging hormone dehydroepiandrosterone (DHEA), and higher levels of the antibody immunoglobulin-M (5). Hence, PTSD sufferers are at increased risk for autoimmune disease, as many of these biomarker trends confer increased risk for inflammatory disorders such as autoimmune and cardiovascular disease (17).
One retrospective cohort study of 15,357 adults found that upbringings that included adverse childhood experiences (ACEs) such as emotional, physical, or sexual abuse, parental divorce, mental illness, substance abuse, witnessing domestic violence, or having an incarcerated family member, were correlated with increasing rates of autoimmune disease diagnosis as an adult (19). The authors state, "First hospitalizations for any autoimmune disease increased with increasing number of ACEs" (19).
When compared to counterparts who had zero ACEs, people with two or more ACEs had a 70% increased risk for hospitalization with a Th1-mediated autoimmune disease such as inflammatory bowel disease (IBD), insulin-dependent diabetes mellitus, idiopathic myocarditis, and Wegener's granulomatosis (19). People with two or more ACEs were likewise at an 80% increased risk for hospitalization with Th2-mediated autoimmune diseases such as myasthenia gravis, rheumatoid arthritis, Sjogren's syndrome, scleroderma and systemic lupus erythematous. Shockingly, experiencing two or more ACEs increased risk of hospitalization with rheumatoid diseases, a subset of Th2 autoimmune conditions, by 100% (19).
Biochemical Evidence for the Trauma-Autoimmune Connection
The study of the role of stress in autoimmune disease has been legitimized by novel disciplines such as neuroendocrine immunology and psychoneuroimmunology, which aim to understand the role of stress in disease pathogenesis (20). According to researchers, "Stress-triggered neuroendocrine hormones lead to immune dysregulation, which ultimately results in autoimmune disease, by altering or amplifying cytokine production" (5). Pro-inflammatory cytokines are cellular messengers implicated in the pathophysiology of autoimmune disease, which recruit immune cells and can augment autoantibody production, tagging self-tissue for destruction.
In addition, neuropeptides such as corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), neuropeptide Y (NPY), endogenous opioids, and pituitary hormones such as prolactin and growth hormone (GH) are released during exposure to stressors and affect cell-mediated and humoral (antibody-mediated) immune responses (10). According to researchers, data from human and animal studies indicate that lymphoid or immune cells express beta-adrenoceptors and alpha-adrenoreceptors, meaning that their activity changes in response to adrenaline, the fast-acting hormone also known as norepinephrine released from the adrenal medulla during episodic stress (10).
Not only that, but primary lymphoid organs such as the thymus and bone marrow, where lymphocytes mature, as well as secondary lymphoid organs such as the spleen and appendix, are innervated (supplied) by sympathetic noradrenergic nerve fibers, meaning that immune tissue is directly responsive to messaging from our stress-governing sympathetic nervous system (10). Another connection between stress and autoimmune disease is that functional capacity and cytokine production of immunocompetent cells as well as numbers of circulating white blood cell populations can be altered by epinephrine and norepinephrine, which are released during moments of fight-or-flight (10).
The link between stress and autoimmune disease is further crystallized by substance P (SP), a sensory peptide released from afferent nociceptors which convey information from peripheral tissues to the central nervous system. When liberated from these nociceptive pain receptors, substance P promotes inflammation to protect cells from irritants and pathogens (10). Not only do substance P-producing nerves innervate immune organs, but immune cells subpopulations express receptors for substance P, such that substance P binding to its receptors in the immune system enhances pro-inflammatory cytokine production (10).
Other signaling molecules released from peripheral sensory nerve fibers when triggered by stress, such as calcitonin gene related peptide (CGRP), adrenomedullin, neurokinins A and B, vasoactive intestinal peptide (VIP), neuropeptide (NPY), gastrin releasing peptide (GRP), nitric oxide (NO), glutamate, and eotaxin, regulate different aspects of immune cell function such as differentiation, activation, homing, chemotaxis, and vascular responses (21). Neuropeptides, chemokines, and glutamate, levels of which are altered during stress responses, can also cause polarization of the immune system toward Th1, Th2, Th17, or Treg populations (21). Dominance of any of the first three branches can occur with autoimmune disease (22).
Moreover, it is speculated that an acute phase response, which is part of the innate immune system or the first-line defense, can be induced by repeated episodes of acute or chronic psychological stress and has the potential to culminate in chronic inflammatory processes such as insulin resistance, metabolic syndrome, diabetes, atherosclerosis, and cardiovascular disease (20, 23). C-reactive protein (CRP) and interleukin-6 (IL-6), acute phase reactants synthesized during this process, are intimately involved in the development of this stress-induced inflammatory process (23).
Thus, activation of the stress response is closely intertwined with the sympathetic nervous system (SNS), immune system, and HPA axis (15). Cumulatively, these findings crystallize a direct connection between the perceptions of the mind and the visceral responses of the body, and provide evidentiary support for the notion that mindset matters.
Adaptogens for Stress Resilience
Therefore, to mitigate stress and arrest autoimmune mechanisms, any treatment protocol should include personalized mindfulness techniques and resources for transforming maladaptive coping mechanisms into constructive stress management tools--strategies for arming ourselves against toxic thoughts in the same way we safeguard ourselves against exposure to pollution, vaccinations, chemical cleaning agents, and irradiated, genetically modified, and pesticide-laden food.
Another natural approach to buffer stress-induced pathophysiological changes are adaptogens such as Rhodiola rosea, Schisandra chinensis, and Withania somnifera (ashwagandha). The history of research into botanical agents known as adaptogens began during the Second World War, with an order issued from the People's Commissions Council of the Union of Soviet Socialist Republics (24). The Russians decreed an order to investigate nature's pharmacopeia for tonic substances which could enhance the fitness of its soldiers and militia and later its cosmonauts (25). Formalized was a definition that conceptualized adaptogens as substances which stimulate the immune and endocrine systems, engendering a nonspecific resistance and improving the ability of the body to cope with and counteract stress.
When confronted with stress, biological response modifiers such as adaptogens can optimize physiology and "convey the organism from its normal steady state to a heightened level of dynamic equilibrium" (26). As benign substances, adaptogenic herbs do not perturb normal biological functions but rather normalize pathological processes and enable organisms to avoid stressor-induced damage (25). When used in concert with meditation, social support, and an evolutionarily appropriate diet and lifestyle, we can use adaptogens catered to our unique cortisol profiles and symptomatic presentations in order to course-correct our physiology and better contend with the barrage of never-ending stress.
We may not have control over the hand we are dealt or the backdrop against which our lives are set, but we can oversee the scripts we employ and the characters we include. We can choose to frame adversity in terms of a learning experience and an opportunity for personal growth. To use illness as an impetus to cultivate an intuitive understanding of our bodies, to re-claim our bodily autonomy, to arm ourselves with the tools nature has provisioned. To surrender rather than resist and to find transformative transcendence and enlightenment in the midst of misery and heartache.
Rather than dismissing, demeaning, and disparaging patients by branding their health conditions psychosomatic, implying that symptoms are figments of their imagination or patting their proverbial hands with a referral to psychiatry, it is time to collectively elevate the medical profession and recognize the intricate interconnectedness between body and psychology, and the enormous leverage we have over our health destinies by harnessing the healing power of our minds.
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