Module 3: Acupuncture for the Treatment of Inflammation in Autoimmunity
Because autoimmune diseases can affect every organ system and tissue in the body, giving rise to innumerate clinical presentations both across and within diagnoses, the development of a clear and precise taxonomy remains an elusive goal of the medical and research communities. Despite variance being the rule and not the exception, several common features underlie autoimmune pathogenesis, the most prominent of them being inflammation.
Commonly perceived as an observable and transient characteristic – redness, swelling, a feeling of warmth to the touch – inflammation as it pertains to autoimmunity often extends beyond these outward features, occupying a veiled, pernicious role in the development and chronification of autoimmune disease.
Under normal physiological conditions, inflammation is a healthy and self-limiting response to an insult or injury. Woven into the immune system are checks and balances that promote the health-preserving functions of inflammation and prevent aberrant inflammatory activity. In the case of autoimmune disease, however, these checks and balances are altered or absent, allowing for untamed inflammatory processes to develop. This is detrimental to the host not only due to the overt inflammatory burden, but also because the unrestrained inflammation becomes pathologically self-perpetuating and reinforcing, continually encouraging a diseased state that grows increasingly resistant to self-regulation. This process contributes to the immune system’s loss of self-tolerance, which marks the fundamental shift from a state of health to a state of disease.
Immune System Basics
Since no discussion of the inflammatory milieu of autoimmunity would be complete without touching on the basic structure and function of the immune system, let’s take a moment to review. The two composite branches of the immune system are the innate and adaptive immune systems. Serving as the initial defense against invading pathogens, the innate immune system, comprised of epithelial barriers such as skin and the gut lining, phagocytic leukocytes, dendritic cells, toll like receptors (TLR’s), natural killer cells and circulating plasma proteins, is primed and ready to respond to infection by ingesting and chemically neutralizing invading microorganisms. Whereas innate immunity is non specific and expedient, adaptive immunity is complex, targeted, and slower to respond, as it lies dormant until called into action by the innate immune system. Once activated, adaptive immune responses have two forms: humoral responses, mediated by antibody-producing B lymphocytes (or more simply, B cells), and cellular responses, mediated by T lymphocytes (or T cells). Humoral responses involve the recognition of antigens by B cells; B cells differentiate into plasma cells that secrete antibodies which neutralize invading pathogens or tag them for destruction by other immune cells. Memory B cells, specially equipped to remember and recognize the provoking antigen, remain after the humoral response so that any potential re-exposure may be readily and swiftly dealt with. T cells also recognize antigens, but their scope is narrower than that of B cells, relegated to peptide fragments presented by Major Histocompatibility Complexes (MHC) on the surface of antigen presenting cells (APC’s). T cells are divided into two main subsets, CD8+ cytotoxic ‘killer’ T cells, which can directly kill infectious cells, and CD4+ ‘helper’ T cells, which assist B cells in producing antibodies and inducing macrophages to eliminate pathogens.7,8,18
Through a number of immune processes, lymphocytes are differentiated into various subcategories, some of which play anti-inflammatory roles, others which may be pro-inflammatory and some whose effects are dependent on the environment in which they operate. Lymphocytes secrete chemical messengers, broadly classified as cytokines, which promote communication with other bodily systems and tissues through chemical signaling. Under healthy physiologic conditions, the immune system is able to maintain balance between these pro and anti-inflammatory factors; autoimmune disease, however, is commonly characterized by an imbalanced cytokine profile that tips the scales towards a pro-inflammatory state.
Cytokine profiles can be categorized into several major classes that have relevance to autoimmunity. Th1 dominant profiles are generally pro-inflammatory, and involve the secretion of pro-inflammatory cytokines IL-1, IL-6, TNF-α and IFN-γ, among others. By contrast, Th2 dominant profiles are largely anti-inflammatory, and are responsible for the secretion of anti-inflammatory cytokines IL-4, IL-10, IL-5 and IL-13, among others. Related to the Th1 cytokine signature is the Th17 state, also pro-inflammatory, and responsible for the secretion of IL-17 and IL-22. Type 1 Macrophages are also pro-inflammatory and involved with Th1 and Th17 cytokine signatures. The Th2 cytokine signature is associated with regulatory T cells, ‘Tregs,’ which suppress immune responses through anti-inflammatory effects; Tregs secrete IL-35, IL-10 and TGF-β. Type 2 Macrophages are related to Th2 and Treg cytokine profiles and are also anti-inflammatory. 7,8,18
While a healthy immune system maintains relative balance between Th1 and Th2 states, autoimmune diseases typically feature dominance of one over the other. Organ-specific autoimmune diseases such as Type I Diabetes (T1DM) or Hashimoto’s Thyroiditis are mediated by Th1/Th17 processes, whereas systemic autoimmune diseases such as Lupus (SLE) or Scleroderma (Ssc), are mediated by Th2/Treg processes.7 To that end, it is important to remember that what may superficially seem healthful and beneficial – anti-inflammatory Th2/Treg cells – actually could be harmful and pathologic in a given context, as in the case of systemic AD’s delineated by Th2 dominance.7,8,18,19
Loss of Self Tolerance
The defining shift towards autoimmune processes and eventual development of autoimmune disease is the immune system’s loss of self-tolerance. The immune system misrecognizes its own constituents and mounts an attack as it would in response to foreign invaders. Under healthy conditions, B cells produce antibodies in response to foreign proteins, essentially tagging them for removal by other immune cells. In the case of autoimmunity, the immune system’s misrecognition of self-proteins as foreign triggers the production of ‘autoantibodies’ – antibodies that target the self-protein perceived as foreign. While it is not atypical for a healthy person to have some autoantibodies in the blood stream, they appear in pathologic concentrations and can inflict significant tissue damage to autoimmune disease sufferers. To that end, the presence of autoantibodies is considered a hallmark feature of autoimmunity.20,21
The misrecognition of self molecules can be caused by defects in a number of immunoregulatory functions, including: reduced deletion of self-reactive CD4+ T cells, increased activation of CD4+ T cells, impaired function of CD4+ Treg cells or CD8+ suppressor T cells, aberrant signaling leading to increased pro-inflammatory cytokines, structural similarity between self and foreign antigens, and expression of new epitopes (the part of the antigen that binds to and is recognized by antibodies) on self-molecules modified by xenobiotics.7 Tolerance is mediated centrally by primary lymphoid organs such as the thymus and peripherally by secondary lymphoid organs and inflamed tissue; whereas any failure of central processing to maintain tolerance to self-molecules is typically compensated for by peripheral checks and balances, triggering events such as infections and overstimulation of antigen presenting cells may break peripheral tolerance, ultimately contributing to the development of autoantibodies and onset of autoimmune disease.7,20,22 A great many factors participate in regulating and preserving immune tolerance; autoimmunity implies failure of tolerance mechanisms at multiple levels, and as we will see below, once immune tolerance is broken, the cascade of inflammatory actions that follows forms a pro-inflammatory bias that favors the continuation of a diseased state.7
A Vicious Cycle
For autoimmune disease to develop, the inflammatory process progresses into a self-sustaining feedback loop that favors its continuation and renders its interruption or reversal increasingly difficult. Numerous factors take part in the chronification of inflammation, the most salient of which are described below.
Treg cells, which play a vital role in the immune system’s suppression of invading pathogens (or in the case of autoimmunity, ‘perceived’ pathogens), are known to reduced – in terms of both numbers and function – in many autoimmune diseases. Inflammatory cytokines, typically present in elevated levels in autoimmune disease, can compromise Treg function by rendering effector T cells resistant to Treg cell suppression, further impairing the immune system’s ability to self-regulate.7,18,19
T cells have demonstrated a capacity for plasticity, allowing one subtype to convert to another; this can have grave implications for autoimmune disease, as anti-inflammatory T cells can convert to pro-inflammatory T cells, augmenting the inflammatory burden. An inflammatory environment can encourage macrophage polarization to the inflammatory M1 macrophage subset, high levels of which are associated with many autoimmune diseases.8,18,19
To further add insult to injury, dendritic cells, which bridge the gap between the innate and adaptive immune systems by presenting antigens to the adaptive immune system to trigger a response, may also contribute to autoimmune disease pathogenesis through their own secretion of pro-inflammatory cytokines.19,22
The gut microbiota, which will be discussed in detail in subsequent sections, also factors into the maintenance of chronic inflammatory states, as the presence of certain microbes and their metabolites can disrupt immune tolerance.8
Genetic predisposition, conferred by a confluence of genetic polymorphisms, plays a critical role in autoimmunity. None of the above-mentioned triggers would be sufficient to provoke the development of autoimmune disease in a host without genetic susceptibility. Genes that confer disease susceptibility contribute to the self-perpetuating cycle of inflammation by engendering disease-promoting immune cells: they encode cytokines, cytokine receptors, transcription factors and apoptosis-inducing proteins, ultimately giving rise to pathogenic T cell populations that encourage the preservation of inflammatory states.18
Furthermore, interactions of genes with environmental agents such as cigarette smoke, UV light, silica, mercury, medication and viruses can induce shifts in gene behavior – epigenetic shifts – that exacerbate disease states. These provoking agents generate oxidative stress in the body, leading to reduced DNA methylation of CD4+ cells; this can have significant implications for autoimmune disease, as DNA methylation serves to silence genes that would otherwise yield cell behaviors that are inappropriate – i.e. maladaptive – for a given T cell.7,8
These processes comprise a small highlight reel of the many factors that contribute to and favor the maintenance of inflammatory states and serve to illustrate the complex and layered nature of autoimmune disease development.
The ways in which acupuncture exerts anti-inflammatory effects on the body are numerous, complex and in many cases, inter-related. As there is an extensive integration between the nervous and immune systems as it relates to inflammatory processes, many of the pathways through which acupuncture influences inflammation involve both systems. Specifically, acupuncture has demonstrated the capacity to modulate both the innate and adaptive branches of the immune systems, downregulate pro-inflammatory cytokines and neurotrophins, exert local antihistamine effects, and activate central anti-inflammatory pathways via vagus nerve stimulation and HPA Axis modulation. Some of the anti-inflammatory actions of acupuncture are secondary to its interactions with the serotonergic and catecholamine systems, allowing for not only suppression of inflammation, but also changes in mood and behavior. The modulation of nociceptive systems by acupuncture via the NMDA, AMP/KA, and TRVP1 receptors implicate its role in affecting both analgesic and anti-inflammatory responses.23
While the effects of acupuncture on the HPA Axis will be discussed in greater detail in subsequent chapters, the following discussion will elucidate each of the above-mentioned mechanisms by which acupuncture regulates inflammatory responses. As the available acupuncture research pertaining to these anti-inflammatory mechanisms in the context of autoimmune disease may be sparse in some instances, research focused on acupuncture in the treatment of other chronic, inflammatory conditions may serve as a proxy for the discussion of autoimmune conditions. Though results drawn from non autoimmune study populations cannot be categorically extrapolated to an autoimmune population, facets of the inflammatory activity germane to both autoimmune and non autoimmune inflammatory conditions are sufficiently similar to warrant the inclusion of the latter in this discussion. Further, that the continually-evolving understanding of autoimmunity has led to recategorization of conditions once thought to be non autoimmune as autoimmune further fuels the inclusion of non autoimmune chronic inflammatory disease research within this analysis. Research findings derived from animal studies are also incorporated into the discussion, as they yield critically important insights that guide human research in the realm of autoimmunity. Lastly, for the sake of establishing a foundational understanding of acupuncture’s role in mediating inflammation, studies conducted on healthy populations will be discussed as a means of representing the anti-inflammatory potential of acupuncture in relation to isolated inflammatory markers.
Innate Immune System
While the adaptive immune system plays a critical role in the pathogenesis and pathoprogression of autoimmune disease, the importance of the innate immune system, the body’s first defense response, cannot be overlooked. NK cells have been shown to be reduced in number and/or function in a number of autoimmune conditions, including Multiple Sclerosis, Rheumatoid Arthritis, Juvenile Onset Arthritis, autoimmune thyroid disease, and Lupus, among others;24 given that their function is to eliminate abnormal cells through the release of chemokines and cytokines such as IFN-γ, a process that primes the adaptive immune system to take action, defects in their function can have significant consequences for immune system regulation.22,24
Administered to rats and mice once daily for three days, acupuncture enhanced natural killer cell activity, thought to be mediated by increases in IFN-γ and β endorphin.25 Acupuncture increased expression of an enzyme responsible for increasing NK cell activity, protein tyrosine kinase (PTK) and decreased mRNA expression an enzyme responsible for decreasing NK cell activity, protein tyrosine phosphotase-1 (SHP-1).25 Additionally, a study of single-dose acupuncture on healthy human subjects showed significant increases in CD16+ and CD56+ cells, which are associated with NK cell activity,26 while another study similarly indicated the NK cell activity-enhancing effects of acupuncture on mice subjected to restraint stress, as well as an alleviation of stress-induced hyperglycemia following seven days of once daily acupuncture treatments, hinting at the potential for acupuncture to induce integrated immunomodulatory and stress relieving effects via its modulation of the immune and nervous systems.27
Adaptive Immune System – Inflammatory Markers
We have established that autoimmune diseases present with imbalanced cytokine signatures, such that either Th1 or Th2 cytokines are dominant depending on the condition. We also know that the dominance of one cytokine subset perpetuates its proliferation and inhibits activity of the opposing subset.25 Interestingly, acupuncture has been shown to restore balance to cytokine profiles, such that it suppresses the expression and function of Th2 cytokines in Th2 dominant conditions and does the same for Th1 cytokines in Th1 dominant conditions.25 For example, in a study of Collagen Induced Arthritis, an animal model for the Th1 dominant condition Rheumatoid Arthritis, acupuncture significantly downregulated serum levels of Th1 cytokines IFN-γ, TNF-α and IL-6, ultimately preventing histological joint degradation and reducing disease incidence.28 Furthermore, acupuncture reduced activated T and B cells in lymph nodes, and normalized CD4+/CD8+ ratios, illustrating broader immune system effects.28 Acupuncture’s ability to lower TNF-α and IL-6 was also demonstrated in a mouse model of hemorrhagic shock;29 together these two studies have important implications for autoimmunity, as both TNF-α and IL-6 have frequently been shown to be elevated in the organs of autoimmune disease patients.19 A study investigating the role of acupuncture in affecting T cell responses in mice with Experimental Autoimmune Encephalitis (EAE), a proxy for Multiple Sclerosis, acupuncture restored balance to skewed Th1/Th2 and Th17/Treg profiles, effectively reducing elevations in Th1 and Th17 cytokines IFN-γ and IL-17 and increasing Th2 cytokines IL-4 and TGF-β, as well as Tregs, relative to controls.30 Acupuncture reduced TNF-α-induced microglial activation in the brain stems and spinal cords in an animal model of ALS, ultimately attenuating neuroinflammation and preventing motor neuron loss.31 Activation of microglia has been implicated in a number of autoimmune diseases, including RA, MS, and Guillain-Barrée Syndrome,20 and while the concept of an autoimmune basis for ALS is currently contested, acupuncture’s demonstrated capacity for reducing neuroinflammation may have significant implications for neurological conditions clearly identified as autoimmune in nature, such as Multiple Sclerosis and Myasthenia Gravis. Acupuncture reduced TNF-α and IL-6 in a mouse model of hemorrhagic shock which prevented the development of gut barrier dysfunction.29 In an animal model of Ulcerative Colitis, acupuncture along with herb-partitioned moxibustion (an adjunctive therapy often administered during acupuncture treatments) reduced elevations in Th1 cytokines IL-12 and TNF-α.32 The reduction in IL-12 was significant because its function is to stimulate natural killer cells and T cells to secrete IFN-γ and TNF-α, which, together, are capable of impairing gut barrier function.32 The treatment also downregulated mRNA expression of Th1 cytokine IL-8 and intracellular adhesion molecule 1, helping to prevent further cell migration to inflamed tissues, effectively blunting the inflammatory response.32
Th2 dominant conditions, such as Lupus, Scleroderma, and Atopic Dermatitis, are characterized by increased IgE antibodies and Th2 cytokines IL-4, IL-10, and IL-6; as opposed to Th1 cytokines which are inflammatory, Th2 cytokines are generally anti-inflammatory, though unhealthy in excessive amounts, as in the case of Th2 dominant diseases. Acupuncture has been shown to be effective in suppressing IL-4 production in Th2 allergic conditions such as asthma and urticaria, leading to reductions in IgE antibodies and stabilizing the balance between Th2 and Th1.25,33,34 In a mouse model of experimental asthma, acupuncture ameliorated Th2 dominance by reducing IL-4, IL-10, Nitric Oxide (NO) and Leukotriene B4 (LTB4) and restoring levels of Th1 cytokines IL-1 and IFN-γ, ultimately reducing airway inflammation and disease severity.34 Lastly, acupuncture has also demonstrated anti-inflammatory effects in Th2 allergic conditions such as atopic eczema through reduction in histamine, thought to be attributable to its downregulation of TRPV1 receptor signaling, which mediates histamine responses.23
While muscle pain is not common to all autoimmune diseases, it does feature in many neuromuscular conditions of autoimmune origin and can have a profound effect on patients’ quality of life. A study investigating the role of acupuncture in inflammatory muscle pain found that once daily acupuncture for periods of 1, 5 and 13 days was sufficient to induce a phenotypic shift in macrophages from the pro-inflammatory M1 type to the anti-inflammatory M2 type, promoting the release of IL-10, ultimately yielding anti-inflammatory and analgesic effects.35 Interestingly, as low levels of IL-10 are associated with heightened nociception and increases in spontaneous pain behaviors, the increase in IL-10 seen in the acupuncture treatment groups was correlated with changed behavior profiles in the form of reduced escape and avoidance behaviors, suggesting that acupuncture may have a beneficial influence on some of the downstream maladaptive behaviors related to chronic pain.35
Vagus Nerve Stimulation
Acupuncture has been shown to exert anti-inflammatory effects through stimulation of the vagus nerve, which activates the cholinergic anti-inflammatory pathway.29,36,37,38,39 Numerous studies have indicated acupuncture’s effects on the vagus nerve as a mechanism for its anti-inflammatory influence. In mouse models of hemorrhagic shock, designed to test the effects of acupuncture on gut barrier integrity, organ function and both intestinal and systemic inflammation, acupuncture demonstrated efficacy in alleviating inflammation in the form of reduced TNF-α and IL-6 and preservation of the intestinal epithelial barrier via activation of enteric glial cells. Though hemorrhagic shock hardly parallels the pathology of autoimmunity, we will see in future chapters that intestinal permeability and the rampant inflammatory cascade that follows it are common denominators to both conditions.
In a rat model of endotexia that gauged the effectiveness of acupuncture in attenuating inflammation and preserving organ function, activation of the cholinergic anti-inflammatory pathway via vagus nerve by acupuncture stimulation was once again established.37 In this study, acupuncture reduced levels of TNF-𝛼 and IL-8 in the intestines, lung, liver and blood, highlighting the capacity for acupuncture to exert anti-inflammatory effects both locally and distally.37
In all of the above studies, disruption of vagus nerve activity, whether through surgical or pharmacologic means, weakened or abolished the effects of acupuncture, firmly indicating that acupuncture influences the vagus nerve to mediate inflammation.129,36,37,38,39
The Nervous System
While the effects of acupuncture on the nervous system, namely through Hypothalamic-Pituitary-Adrenal axis modulation, are adequately profound and complex to warrant their own chapter, the intersection of the immune and nervous systems as they relate to acupuncture will be discussed here. The extensive interconnectedness of the immune and nervous systems has important implications for both inflammatory processes and the mechanisms by which acupuncture addresses them. We know that immune cells are able to produce neurotransmitters directly and also bear receptors for them, evidencing the ability of one system to influence the other.25,40 Specifically, lymphocytes, immune cells associated with sympathetic dominance – in other words, heightened stress – have been shown to bear cholinergic receptors, indicating a mechanism for obtaining nervous system homeostasis via parasympathetic activation, while granulocytes, associated with parasympathetic dominance, have been shown to bear adrenergic receptors, highlighting a mechanism to balance parasympathetic dominant states via sympathetic stimulation.41 In a study of healthy volunteers, individuals were grouped according to their leukocyte profiles, such that those with low granulocytes and high lymphocytes formed Group A, and those with low lymphocytes and high granulocytes formed Group B. Following a single acupuncture treatment, Group A experienced an increase in granulocytes while lymphocytes remained unchanged, while Group B showed an increase in lymphocytes and unchanged levels of granulocytes. Despite the fact that the same needling protocol was administered to each group, the effects of acupuncture varied based on the study subjects pre-existing imbalances, indicating a restorative effect of acupuncture on imbalanced nervous system profiles.41
One of the most frequently cited mechanisms to which acupuncture’s analgesic and anti-inflammatory effects are attributed is the release of β endorphin via stimulation of the hypothalamus.25 β endorphin, an opioid peptide, can bind to opioid receptors present on immune cells and influence the immunomodulatory activity of those cells,25 illustrating a mechanism by which the nervous system influences immune function.
Acupuncture has also demonstrated effects on the serotonergic and catecholamine systems of the nervous system that may have important implications as they pertain to inflammation. Pharmacological blockade of serotonin pathways has been shown to attenuate the response of acupuncture, and acupuncture has indicated the capacity to induce gene expression of serotonin receptors in the hypothalamus;25 taken together, these findings suggest a role for the serontonergic system in mediating acupuncture’s effects. As serotonin has recently garnered attention for its role in mediating inflammation, the interactions between acupuncture and the serotonergic system may yield benefits for patients beyond the commonly sought after objectives of mood regulation.42 That acupuncture has indicated the ability to increase levels of the epinephrine and norepinephrine may be of value in the context of inflammation,43 as both catecholamines have the capacity to suppress inflammation.40 Also, stimulation of the sciatic nerve by acupuncture has been shown to dampen inflammatory cytokine responses via dopamine-dependent modulation of the vagus nerve, further evidencing acupuncture’s role in mediating the cross talk between the nervous and immune systems to affect inflammation.43
The anti-inflammatory effects of acupuncture are achieved directly and indirectly and involve many pathways across multiple systems. Evidence supports the notion that acupuncture can not only alleviate inflammation in a general sense but can also adapt to an individual’s unique internal milieu to restore homeostasis.