In this issue, we discuss the strategies used to manage autoimmune disease in functional medicine, including dietary and lifestyle strategies and the use of key supplements targeting the major areas of immune dysfunction and autoimmune reactions as identified by the most current literature and described in part 6.
When you look at the dysregulation of the immune system that occurs in autoimmunity, we know there are several systems involved in the targeting of self-tissue for destruction. The goal of autoimmune management should be to dampen or decrease the immune attacks against self-tissue. In order to do this, we have to understand these various systems that become dysregulated and ultimately lead to autoimmunity and self-tissue destruction. In functional medicine, we attempt to modulate autoimmunity by regulating these various systems with the use of natural compounds that have been identified in the literature to have an impact on these mechanisms of immune dysfunction. In part 6 of this series, we identified several key mechanisms of immune dysfunction which have been shown to play a role in the development of autoimmune reactivity and autoimmunity. Let’s briefly review these mechanisms and their role in autoimmunity and then look at the evidence in the literature supporting the use of various natural compounds in regulating each of these mechanisms. This information is a bit technical, so for those that are not interested in the following technical information but are interested in learning about how dietary and lifestyle changes can improve autoimmune expression and the progression of autoimmune disease, please skip down to the final sections of this article, Lifestyle Strategies for Autoimmunity and Dietary Strategies for Autoimmunity.
For a more thorough review of these various mechanisms and how they are involved in autoimmunity, please refer to part 6 of this series.
- NF-kB activation and dampening
- Glutathione recycling system
- Barrier system integrity
- TH-1 and TH-2 polar shifts
- TH-3 or regulatory T-cell activation
- TH-17 activation and dampening
- Nitric oxide isomer expressions
In the last segment of this series, we learned that an increasing number of studies indicate that a protein complex known as NF-kB plays an important role in the development and progression of autoimmunity.  NF-kB controls the expression of genes encoding the proinflammatory mediators involved in autoimmune disease. NF-kB can become chronically elevated because of its own amplifying loop.  This means that elevations in NF-kB can perpetuate further elevations of NF-kB. NF-kB signaling needs to be downregulated in order to maintain tissue homeostasis.  If this does not occur, then immune dysregulation takes place that can eventually lead to autoimmunity. Recent data has shown that NF-kB is required for activation of immune cells against self-tissue, and its hyperactivity should be minimized, since it promotes autoimmunity. 
“NF-kB is a key signaling component in autoimmunity and an attractive target for autoimmune disease therapy” 
“Since NF-kB represents an important and very attractive therapeutic target for drugs to treat many inflammatory diseases, including arthritis, asthma and the autoimmune diseases, most attention has been paid in the last decade to the identification of compounds that selectively interfere with this pathway” 
Clinical Strategies to Dampen NF-kB Activation
Overall, it appears that the two most potent natural NF-kB minimizers that researchers have discovered are curcumin and resveratrol. Curcumin is the alkaloid derived from turmeric, a spice used in Indian cooking. Resveratrol is a compound found in the skin of red grapes, peanuts and some berries. In recent studies, both curcumin and resveratrol have shown to support healthy numbers of T-cell cytokines (inflammatory messengers). These results suggest the potential use of these select phytochemicals for supporting healthy immune responses. Here is what some recent literature is saying about these compounds:
“Curcumin, a dietary spice from turmeric, has outstanding anti-inflammation and neuroprotective effects. Herein, we review key features of curcumin involved in biology, pharmacology, and medicinal chemistry and discuss its potential relevance to pathophysiological progress of multiple sclerosis”
“Curcumin, a component of turmeric, has been shown to be non-toxic, to have antioxidant activity, and to inhibit such mediators of inflammation as NFkB, cyclooxygenase-2 (COX-2), lipooxygenase (LOX), and inducible nitric oxide synthase (iNOS)”
“In a larger, randomized, double-blind, multicenter trial involving patients with quiescent ulcerative colitis, administration of 1 g of curcumin twice daily resulted in both clinical improvement and a statistically significant decrease in the rate of relapse”
“In various chronic illnesses in which inflammation is known to play a major role, curcumin has been shown to exhibit therapeutic potential. These diseases include Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis, epilepsy, cerebral injury, CVDs, cancer, allergy, asthma, bronchitis, colitis, rheumatoid arthritis, renal ischemia, psoriasis, diabetes, obesity, depression, fatigue, and AIDS”
“…curcumin has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various malignant diseases, arthritis, allergies, Alzheimer’s disease, and other inflammatory illnesses. The underlying mechanisms of these effects are diverse and appear to involve the regulation of various molecular targets, including transcription factors (such as nuclear factor-kB)…”
Resveratrol has been shown in the literature to have powerful anti-inflammatory effects which involve multiple pathways including inhibiting NF-kB, inhibiting iNOS (inducible-nitric oxide synthase) expression and inhibiting inflammatory cytokines such as IL-6 in various inflammatory conditions, including multiple sclerosis , diabetic neuropathy , arthritis , autoimmune myocarditis , colitis , and exerts immunomodu-latory effects both in vitro and in vivo lymphocytic leukemia in lymphocytic leukemia. 
“These studies demonstrate that SRT501 (a pharmaceutical grade formulation of resveratrol) attenuates neuronal damage and neurological dysfunction in experimental autoimmune encephalomyelitis (the animal model of multiple sclerosis) by a mechanism involving SIRT1 activation”
“In summary, our results suggest that resveratrol suppresses apoptosis and inflammatory signaling through its actions on the NF-kB pathway in human chondrocytes”
“Resveratrol significantly ameliorated myocardial injury and preserved cardiac function in a rat model of autoimmune myocarditis” 
In addition, both curcumin and resveratrol have been shown to reduce the inflammatory mediators that contribute to the low-level, chronic inflammation found in obese individuals and have been linked to the onset of cardiovascular disorders, insulin resistance and type 2 diabetes mellitus.
“Curcumin and resveratrol are able to inhibit TNFalpha-activated NF-kappaB signaling in adipocytes and as a result significantly reduce cytokine expression. These data suggest that curcumin and resveratrol may provide a novel and safe approach to reduce or inhibit the chronic inflammatory properties of adipose tissue.”
In part 6, we learned that glutathione (GSH) appears to be an important antioxidant that helps support regulatory TH-3 cells of the immune system (important immune-regulating cells), protect the intestinal barrier and quench oxidative compounds before they are activated by the NF-kB receptor. Recall that glutathione production occurs in all cells but primarily in hepatocytes (the cells of the liver) which is used in some phase II detox pathways, such as glutathione conjugation. Glutathione is also an important part of phase I detoxification. Some medications (such as acetaminophen or Tylenol™) block the production of glutathione by the liver. This is why glutathione precursors (such as N-acetyl-cysteine or NAC) is used to decrease liver toxicity in acetaminophen overdose.  Many studies suggest that intracellular GSH levels in antigen-presenting cells such as macrophages, influence the TH1/TH2 cytokine response patterns which are associated with immune dysregulation and autoimmunity.
“Accumulation of evidence suggests that intracellular GSH levels in antigen-presenting cells such as macrophages, influence the TH1/TH2 cytokine response pattern. The observations reported herein show that pro-GSH molecules represent new therapeutic agents to support immune modulation”
Low GSH levels have been associated with many autoimmune and inflammatory diseases, including rheumatoid arthritis, systemic lupus erythematosus, Crohn’s disease, multiple sclerosis, psoriasis, and contact dermatitis. 
Another study suggested that the severity of some autoimmune diseases, such as systemic lupus erythematosus (SLE), correlate with levels of glutathione in the blood, namely, the lower the glutathione levels, the more severe the autoimmune disease.
“A significant correlation between plasma glutathione and SLE severity exists that may aid evaluation of the disease severity and usefulness of the management of SLE”
In general, high oxidant burdens are a common feature in many immune dysfunctions and GSH plays a major role in quenching these oxidant species, and hence protecting the cell from damage. Therefore, any decrease in GSH may influence the immune system through perpetuating reactive species signaling events and increasing ROS-related damage. 
Age-related decline in cellular function is thought to result from increasing oxidative damage. Oxidative stress depletes intracellular GSH, so increasing production of glutathione may protect against mitochondrial and cellular damage. 
Glutathione helps support regulatory T cells, and differentiation of T-cells into their specific types by reducing damage from oxidative stress. This system is absolutely critical for overall modulation of autoimmunity.
“These data indicate that glutathione peroxidase-dependent control of intracellular reactive oxygen species accumulation is important not only for regulation of TH-cell proliferation, but also for modulation of differentiation into TH1, TH2 and TH17 cells.”
Summary of the Role of Glutathione in Autoimmune Modulation
- Modulates TH-1 and TH-2 polarization which dampens AI tissue destruction
- Activates TH-3 regulatory T-cells which dampens AI tissue destruction
- Dampens TH-17 activity which dampens AI tissue destruction
- Enhances tissue and intestinal regeneration which enhances AI recovery
- Protects cell mitochondria which enhances AI recovery
If you look at the literature, there are several natural compounds that have been shown to help raise intracellular glutathione and support the glutathione recycling system:
- Alpha lipoic acid
- Centella asiatica
- Silybum marianum
- Broccoli extract
N-acetyl-cysteine is a metabolite of the sulfur-containing amino acid, cysteine. It plays a role in the sulfation cycle, acting as a sulfur donor in phase II detoxification and as a methyl donor in the conversion of homocysteine to methionine. N-acetyl cysteine is rapidly metabolized to intracellular glutathione. It is used for acetaminophen overdose and as a nephroprotective agent for radiocontrast. [27-33]
Alpha lipoic acid is an antioxidant that is made by the body and is found in every cell, where it helps turn glucose into energy. Unlike other antioxidants, which work only in water (such as vitamin C) or fatty tissues (such as vitamin E), alpha lipoic acid is both fat- and water-soluble. This means it can work throughout the body. Alpha lipoic acid also plays an important role in the synergism of antioxidants. It directly recycles and extends the metabolic life spans of vitamin C, glutathione, and coenzyme Q10, and it indirectly renews vitamin E, all of which are necessary for glutathione recycling. [34-43]
L-glutamine is important for the generation of glutathione stores since glutamate is unable to be transported into cells. Glutamine is efficiently transported into the cell, converted to glutamate, and readily available for glutathione synthesis. Research has demonstrated that glutamine is important for the generation of glutathione. [44-57]
Selenium is a trace element nutrient that serves as the essential cofactor for the enzyme glutathione peroxidase. Selenium-deficient humans and animals are known to be deficient in glutathione peroxidase activity in their cells and plasma. [58-69]
Cordyceps (used in Chinese medicine for thousands of years) has been shown to activate glutathione peroxidase synthesis in the body (the enzymes that increase glutathione) and raise glutathione levels within minutes. Research has demonstrated cordyceps helps protect cells by engaging the glutathione enzyme cycle. [70-73]
Research has clearly demonstrated that oral intake of gotu kola very rapidly and dramatically increases the activity and amount of glutathione peroxidase and quantity of glutathione. [74-84]
Administration of Silybum marianum has shown to significantly increase glutathione, increase superoxide dismutase activity, and have positive influence in the ratios of reduced and oxidized glutathione. [85-101]
Broccoli has a high content of glucosinolates, which are metabolized into isothiocyanates and sulforaphane . These compounds exhibit chemoprotective activity through a mechanism involving inhibition of cytochrome P450 and induction of GST and other enzymes [103,104].
In part 6, we learned when the intestinal mucosa of the digestive tract is inflamed, the tight junctions of the intestinal mucosa are compromised and they become widened and permeable to large, undigested compounds, toxins and bacteria which can then enter the bloodstream. This condition is known as leaky gut. These large undigested proteins that are absorbed are reacted against by the underlying intestinal immune system and promote exaggerated immune responsiveness (inflammation) which leads to further destruction of the intestinal barrier. This creates a vicious cycle of further intestinal inflammation and greater loss of intestinal integrity. As the intestinal tract becomes inflamed from diet, lifestyle, medications, and infections, it promotes further intestinal inflammation and further intestinal permeability. Most importantly, the immune dysregulation from increased permeability has been shown to perpetuate immune overzealousness and loss of ability to regulate self and non-self tolerance, leading to autoimmunity.
“A more attentive analysis of the anatomic and functional arrangement of the GI tract however suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to nonself-antigens. When the finely-tuned trafficking of macromolecules is dysregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune disorders can occur.”
“There is growing evidence that increased intestinal permeability plays a pathogenic role in various autoimmune diseases. Therefore, we hypothesize that loss of intestinal barrier function is necessary to develop autoimmunity.”
Clinical Strategies to Support the Barrier System
L-glutamine is the preferred fuel source for the cells of the small intestine and has been shown in numerous studies to support the regeneration and repair of the intestinal lining. It has also been shown to increase the number of cells in the small intestine, the number of villi on those cells, as well as the height of the villi. Glutamine-reduced permeability of the lining may accompany “leaky gut” patterns that promote intestinal inflammation and the development of delayed food intolerances. [107-128]
Deglycyrrhizinated licorice is a popular and substantially studied natural compound that provides flavonoids that help heal the gastric and intestinal lining. Many different mechanisms have been shown with regard to its restorative properties including stimulation and differentiation of glandulars cells, protective mucous formation, protective mucous secretion, increased intestinal blood flow, and growth and regeneration of intestinal lining cells. [129-147]
N-acetyl glucosamine is a monosaccharide derivative of glucose that is used to support the intestinal glycoprotein cover of the mucosa called mucin. It is also a precursor substrate for the repair of the intestinal mucosal cells and provides support of mucosa membrane irritation. [148-151]
Aloe leaf extract contains natural phytochemicals and powerful antioxidant properties that reduce intestinal inflammation, soothe the intestines, aid in intestinal wound healing, and have an anti-ulcer effect. It also appears to have antifungal properties, supports cholinergic intestinal motility, and reduces intestinal pain and discomfort. [152-161]
Spanish moss is also known as Tillandsia and it has historically been used for intestinal irritation and allergies. Research on the plant has identified rich sources of flavonoids and other phytochemicals that provide antimicrobial activity and free radical scavenging properties. [162-167]
Marshmallow extract has high content of mucilage that can soothe and help heal compromised intestinal barrier tissue. It is also rich in antioxidants that can support healing of tissue. It also has properties that inhibit hyaluronidase, which is the enzyme involved in the production of hyaluronic acid that is involved with intestinal tissue destruction. [168-171]
Methylsulfonylmethane (MSM) is a rich source of natural sulfur which helps as a substrate for antioxidant defense systems as well as support substrates for hepatic phase II sulfation pathways. It has antifungal and anti-inflammatory properties that help support the compromised liver-gut axis. [172-176]
Gamma oryzanol is a mixture of plant sterols and ferulic acid esters from rice. It has demonstrated to be a powerful antioxidant. Numerous papers have demonstrated its effectiveness in gastrointestinal complaints, ulcers, irritable bowel syndrome and non-specific gastrointestinal conditions. It has also been shown to modulate and support the enteric nervous system in its ability to activate intestinal motility and secrete digestive enzymes. [177-184]
Slippery elm bark is very high in natural mucilage and helpful in soothing the inflamed intestinal cells. It reduces contact of inflammatory proteins with the intestinal mucosa, thereby enhancing recovery from intestinal barrier compromise and inflammation. [185-188]
The chief constituents of German chamomile have been shown to enhance wound-healing time, modulate prostaglandins and nitric oxide activity to provide gastric and intestinal protection. [189-196]
Marigold flower extract constituents include saponins, carotenoids, flavonoids, mucilage, bitter principle, phytosterols, polysaccharides, and resin. It has been used historically for varied gastrointestinal complaints. It provides substrates for digestive enzyme production, helps during inflammation and provides antibacterial activity. [197-204]
When a person loses their ability to recycle glutathione and glutathione levels become depleted, they are at risk for intestinal lining inflammation which then leads to leaky gut. The glutathione recycling system is one of the main systems that prevents leaky gut onset. Glutathione is suggested to play an important role in gut barrier function and prevention of intestinal inflammation. [205-210]
“Regarding intestinal permeability, zinc carnosine caused an approximate threefold increase in gut integrity and repair”
“VDR (vitamin D receptor) plays a critical role in mucosal barrier homeostasis by preserving the integrity of junction complexes and the healing capacity of the colonic epithelium. Therefore, vitamin D deficiency may compromise the mucosal barrier, leading to increased susceptibility to mucosal damage and increased risk of IBD (inflammatory bowel disease).” 
“1,25(OH)2D3 (vitamin D) may play a protective role in mucosal barrier homeostasis by maintaining the integrity of junction complexes and in healing capacity of the colon epithelium. 1,25(OH)2D3 may represent an attractive and novel therapeutic agent for the adjuvant therapy of IBD (inflammatory bowel disease).”
Intestinal Permeability Dietary Restrictions
It is important to avoid certain types of food that tend to aggravate or worsen intestinal permeability when trying to repair the gut barrier and decrease autoimmune responses. These self-promoting vicious cycles become difficult to unwind unless aggressive dietary and nutritional strategies are employed. See Intestinal Permeability Dietary Restrictions at the end of this article for a complete list of these foods.
As we learned in part 6, the immune system has two major immune responses:
- T-helper-1 (TH-1) response, which is mediated by T-cells
- T-helper-2 (TH-2) response, which is mediated by B-cells
Both immune responses are important for protecting the body against foreign microbes and invaders. There is a constant interplay and subtle balance of these two immune responses and the regulation of these two responses is extremely important. This is carried out by the TH-3 regulatory system (described below), which acts in many ways like the conductor of a large complex orchestra. In healthy immune responses, there is always a balance in these two systems. In autoimmunity, there is a polar shift or dominance of either the TH-1 or TH-2 system and one side of the system becomes overactive or dominant. Many autoimmune diseases are classified in the immunology literature by their T-helper dominance.[215, 216] Let’s review the TH-3 regulatory system.
As discussed in part 6, TH-3 cells, or regulatory T-cells, are a subpopulation of T-cells that downregulate the immune system, maintain tolerance to self-antigens and minimize autoimmune disease. Regulatory T-cells are a component of the immune system that suppress immune responses from other cells. This is an important “self-check” mechanism inherent in the immune system to prevent excessive reactions. These cells are involved in shutting down the immune responses after they have successfully eliminated invading organisms and also in preventing autoimmune TH-1 and TH-2 polar shifts. [217, 218]
Two key nutrients have been shown over and over in the literature to support the regulatory T-cells and coordinate TH-1 and TH-2 balance: glutathione and vitamin D.
Glutathione (GSH) is one of the most critical immune-modulating substances that we know of. Like a conductor of an orchestra, glutathione regulates various aspects of immune balance. As previously discussed, studies show that GSH has a significant impact on the immune system’s ability to activate the appropriate T-helper cell response. [219-220] Because GSH is so important in the immune system’s activation of the appropriate T-helper response, altering its levels may have significant implications in TH1/TH2-related diseases. 
“Accumulation of evidence suggests that intracellular GSH (glutathione) levels in antigen-presenting cells such as macrophages, influence the TH1/TH2 cytokine response pattern. The observations reported herein show that pro-GSH molecules represent new therapeutic agents to support immune modulation.” 
“These data indicate that glutathione peroxidase-dependent control of intracellular reactive oxygen species accumulation is important not only for regulation of TH-cell proliferation, but also for modulation of differentiation into TH1, TH2 and TH17 cells.”
See the clinical strategies described above for strategies for increasing glutathione levels.
Numerous studies have been published establishing the critical immunoregulatory role that vitamin D plays in the prevention of immune dysfunction and the development of autoimmune disease. [224-231] Vitamin D appears to act on a number of different immune cells to promote various regulatory responses by the immune system. Vitamin D deficiency has been associated with many autoimmune disorders including multiple sclerosis, Type 1 diabetes, Crohn’s disease, rheumatoid arthritis as well as others. 
Studies have shown a significant relation between vitamin D deficiency and allergy and an important role of vitamin D in the pathogenesis and severity of allergic disease, and its capacity to control allergic disease. [233, 234] Vitamin D supplementation has been shown to reduce the occurrence of asthma in most related studies and may be useful in the prevention or adjunct treatment of chronic obstructive pulmonary disease. [235, 236]
Here are a few selections from the literature on the role vitamin D plays in immune health:
“Increasing evidence demonstrates a strong association between vitamin D signaling and many biological processes that regulate immune responses. The discovery of the vitamin D receptor in multiple immune cell lineages, such as monocytes, dendritic cells, and activated T cells credits vitamin D with a novel role in modulating immunological functions and its subsequent role in the development or prevention of autoimmune diseases.”
“It is apparent that vitamin D has significant effects on the immune system and as such may contribute to the pathogenesis of autoimmune disease. Low vitamin D status is reported in many inflammatory rheumatic conditions. In some this extends to an association with disease activity. Vitamin D acts on a number of cells involved in both innate and acquired immunity biasing the adaptive immune system away from Th17 and Th1, towards Th2 and T-regs (T3). Deficiency accordingly could encourage autoimmunity. Vitamin D deficiency may well be an important factor in autoimmune rheumatic disease, including initial disease development and worsening the disease once present.”
As discussed in part 6, T-helper 17 (TH-17) is a subset of T-helper cells producing IL-17. IL-17 is a potent proinflammatory cytokine that amplifies ongoing inflammation in epithelial and endothelial cells. [239-243] TH-17 is important for normal immunity, but it can also become excessively active, especially in those with autoimmunity. TH-17 activity is considered a key marker in the activation and severity of autoimmune flare-ups. TH-17 responses stimulate autoimmunity and TH-17 activation is like “adding fuel to the fire” of autoimmunity. The inhibition or attenuation of TH-17 cells is now considered a therapeutic strategy for the management of autoimmune disease in the literature:
“The absence of Th17 cells can lead to a decrease in proinflammatory cytokines. Thus, to achieve the end goal of a balanced immune response, CAM (Complementary and Alternative Medicine) practitioners may target components along the pathway leading from naïve T-cell differentiation to Th17, thereby lowering the levels of Th17 and IL-17.” 
Clinical Strategies to Dampen TH-17 Activation
There are two natural compounds which have shown to inhibit or minimize TH-17 activation in the literature: curcumin and resveratrol.
There is substantial evidence that curcumin minimizes the activity of TH-17. [8-12] A recent paper entitled, “Curcumin has bright prospects for the treatment of multiple sclerosis,” demonstrated that curcumin supports healthy anti-inflammatory and neurosupportive mechanisms. The researchers concluded that TH-17 cells are key immunological players for the pathophysiological process of multiple sclerosis and curcumin has outstanding effects in dampening this TH-17 system.
“Th17 cells are considered as a key immunological player for the pathophysiological process of MS. Curcumin, a dietary spice from turmeric, has outstanding anti-inflammation and neuroprotective effects. Herein, we review key features of curcumin involved in biology, pharmacology, and medicinal chemistry and discuss its potential relevance to pathophysiological progress of MS”
Another study found that providing curcumin supplementation to Lewis rats significantly reduced the clinical severity of experimental autoimmune encephalomyelitis (EAE), and had a dramatic reduction in the number of inflammatory cells that infiltrated the spinal cord by dampening the TH-17 system.
“These findings indicated that curcumin amelioration EAE was, to a large extent, due to inhibiting differentiation and development of Th17 cells…and suggest it is useful in the treatment of MS and other Th17 cell-mediated inflammatory diseases.” 
Resveratrol appears to modulate immunological processes via multiple mechanisms. As we saw above, resveratrol has potent anti-inflammatory effects and has been shown to dampen inflammatory mediators including NF-kB, iNOS (inducible nitric oxide synthase) and various inflammatory cytokines. Several papers have also been published on the role of resveratrol and its ability to modulate TH-17 differentiation and activity as a potential complementary therapy for neuroautoimmune disease such as multiple sclerosis. [247-248] In fact, activation of NF-kB and other inflammatory cytokines has been associated with TH-17 activation and resulting neuroinflammatory processes and tissue destruction.
“Therefore, the modulation of NF-κB and associated cytokines such as IL-1β, IL6, IL-8 and TNF-α by using one or a combination of different herbal medicines may suppress Th17 and IL-17 production and inhibit neuroinflammation. CAM practitioners may thus consider NF-κB modulation for therapeutic intervention or maintenance of neuroimmune inflammatory disorders.”
“Thus, AHR regulates both T(reg) and T(H)17 cell differentiation in a ligand-specific fashion, constituting a unique target for therapeutic immunomodulation.” 
Resveratrol is a natural AHR antagonist. This is one of the mechanisms by which resveratrol is believed to decrease the activity of Th17 cells and has become an attractive therapeutic option for autoimmune disease.
“Resveratrol, a polyphenolic compound derived from grapes, suppressed swelling and bone erosion in the paws of mice with CIA (collagen-induced arthritis). This effect was associated with reduced serum levels of proinflammatory cytokines including IL-17 and reduced numbers of Th17 cells”
Therefore, it appears that both curcumin and resveratrol impact two major inflammatory pathways in our current understanding of autoimmune physiology: TH-17 activation and NF-kB activation.
As we previously learned, nitric oxide (NO) is an important messenger molecule involved in many physiological and pathological processes as well as a chemical-signalling molecule that is involved with communication in the nervous system, immune system and vascular system. It was proclaimed the “Molecule of the Year” in 1992. 
Nitic oxide plays both destructive and protective roles in autoimmunity, depending on which of the three enzymes, or synthases, is expressed. The three nitric oxide synthase (NOS) isomers (forms) are neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS). nNOS supports nervous tissue, including the brain, and neurological synapses involved in neuronal signaling and brain function. eNOS activity supports blood vessel health by producing dilation of blood vessels, dissolves endothelial plaques, and enhances blood flow. [253, 254] iNOS, however, has destructive effects on tissue. iNOS is activated by TH-17 and produces harmful free radical action and initiates tissue destruction.  How these isomers are manipulated or modulated will determine how much destruction of tissue or ability to recover from autoimmune flare-ups a person has.
“We conclude that NO (nitric oxide) plays a critical immunoregulatory role and NO modulation may prevent the onset of autoimmune reactions”
Research has shown that IL-17 and the TH-17 system activates iNOS and initiates tissue destruction in autoimmunity:
“Interleukin-17 is a proinflammatory cytokine involved in autoimmune disorders. The proinflammatory action of IL-17 depends considerably on its ability to trigger the expression of inducible nitric oxide (iNOS). We propose IL-17 and NO modulation could be relevant forms of therapy for autoimmune disorders” 
“Together, these data indicate that antioxidant modulation of nitric oxide might be a feasible therapeutic tool to interfere with development of autoimmune diabetes” 
The following compounds have been shown in the literature to modulate nitric oxide isomers:
- Adenosine 5’-triphosphate
- Huperzine A
- Alpha-ketogluteric acid
- Xanthinol niacinate
ATP (Adenosine 5’-triphosphate) is the fuel source for all biochemical reactions. ATP can be found inside the cell (intracellular) or outside the cell (extracellular). Research has also clearly demonstrated that supplementation with ATP also increases extracellular and intracellular levels of ATP. [262-264] Extracellular ATP has been found to activate eNOS and nNOS. [265-268] More importantly, ATP does not activate iNOS activity and has even demonstrated suppressive iNOS activity. [269-271]
Huperzine A is powerful compound for ideal nitric oxide isomer expression because it enhances acetylcholine activity necessary for eNOS and nNOS and it has powerful iNOS inhibiting properties. [272-273] Huperzine is a potent natural acetylcholine esterase inhibitor, leading to increased acetylcholine activity that is necessary for ideal eNOS and nNOS activity.  Not only does Huperzine A inhibit iNOS activity directly, but it also suppresses the same cytokines released during exercise that stimulate iNOS. [275-278]
Vinpocetine is classified as a selective cyclic GMP phosphodiesterase (PDE) balancer and modulates vascular tone and Nitric Oxide release in system circulation. [279-282] The net effect of PDE inhibitors, such as vinpocetine, is to increase eNOS activity, leading to healthy vasodilation and blood delivery to peripheral tissues, such as muscles and brain, important for peak athletic performance and recovery. In addition to vinpocetine’s properties of eNOS activation, the compound has powerful influences on the neurotransmitter acetylcholine. Acetylcholine activity is critical for ideal eNOS receptor site activity. [283-285]
Alpha-GPC is a phospholipid metabolite that is isolated from lecithin. It is absorbed extremely well by the gastrointestinal tract and is used for the synthesis of acetylcholine. Oral intake of Alpha GPC has been shown to increase acetylcholine levels in the body. [286-287] Acetylcholine activity promotes nitric oxide synthase activity, and nitric oxide promotes acetylcholine activity that is responsible for eNOS vascular dilation and nNOS synaptic activity. [288-293]
Alpha-ketoglutaric acid (AKG) is a citric cycle intermediate and can be used to help produce nitric oxide via the urea cycle and metabolize harmful nitrogen out of the body. It is also an intermediate precursor for metabolites that are used by the mitochondria to produce energy. AKG supplementation has been shown to have positive modulating activity on nitric oxide and iNOS.  AKG supplementation has been shown to help modulate nitrogen balance and preserve protein synthesis after cell injury. [295-297]
Xanthinol niacinate has very powerful vascular-enhancing properties and the ability to improve peripheral hemodynamics.  It has demonstrated properties to increase eNOS by its nicotinate component activity on the acetylcholine receptors.  A human subject study comparing the effects of a placebo and xanthinol niacinate on exercise tolerance found that xainthinol niacinate significantly increased exercise tolerance at 1 hour and 1-9 hours respectively from ingesting the supplement.  Clinical research has found that xanthinol niacinate has antioxidant properties that may lead to decreased iNOS activities. Several research studies have found it improves microcirculation and aids in healing. [301-304]
Acetyl L-carnitine is composed of acetic acid and L-carnitine bound together and has very close structural similarity to acetylcholine. Research has shown that ALCAR mimics acetylcholine activity and has shown effectiveness in acetycholine mediated pathways. [305-308] Acetylcholine activity promotes nitric oxidesynthase activity, and nitric oxide promotes acetycholine activity that is responsible for eNOS vascular dilation and nNOS synaptic activity. [309-314]
Lifestyle Strategies for Autoimmunity
If individuals have autoimmunity or are at risk of autoimmunity, they must focus on the proper lifestyle and nutritional strategies to decrease the expression of this condition. Patients with autoimmunity must know they will have bad days. Bad days may be triggered by immune activation from various scenarios, such as stress, lack of sleep, blood glucose fluctuations, food sensitivities, etc. It is important for them to realize what mechanisms can promote their autoimmunity and what mechanisms can dampen their autoimmunity so that they can be empowered to improve their quality of life and slow down self-tissue destruction and the progression of the disease.
In addition to personal internal stressors, external stressors—such as their job, strict deadlines, unrealistic goals or any environment that places great demands on them—activates their TH-17 pathway, which promotes autoimmunity. The physiologic stress response that occurs from mental or physical stress increases pro-inflammatory cytokines such as IL-2, IL-4, IL-6 and IL-10 which activates the HPA axis and increases production of epinephrine and cortisol and activates the TH-17 pathways that then promote autoimmunity. [315-323] People with autoimmunity must take themselves out of a stressful environment even if it will effect their finances, relationships, commitments, etc. or they are at increased risk of progression of their autoimmune disease. Stress modification is a significant factor of autoimmunity expression, but completely overlooked by both alternative and conventional healthcare professionals today. They must create an environment that is protective and supportive for them so they can focus on their passions and increase opioid activity. This is necessary to break the vicious cycles of ill health they have established and help return them to better health
Recall that regulatory T-cells (TH-3 cells) are very important for regulation of proper immune responses. The release of natural opioids by the body activates TH-3 cells and promotes anti-inflammatory responses. [324-328] TH-3 cells are loaded with opioid receptors and as the body releases them, they activate the TH-3 cells that shift autoimmunity into suppression. The best example of opioid release is the feeling people get after they exercise. In order to get the best exercise, the exercise has to be challenging. Just walking on the treadmill passively is not going to get the best opioid response. They must make the exercise challenging enough to get their heart rate up and push themselves when they want to quit—this will create the opioid release. The key is to push themselves hard enough to get the best “exercise high” they can get after their workout, without creating an injury or overtraining. [329-333]
Being able to recover quickly after exercise is also very important and sets up the body chemistry to activate TH-3 without activating TH-17, which is critical for a healthy immune response. In addition to creating an “exercise high”, they want to create feelings that make them “high on life”. A positive mental attitude, love, appreciation for life, positive mental reflection, all increase opioids that make a person “high on life”. On the other hand, a negative attitude, violence, poor relationships, internal mental stress, all promote increased production of –pro-inflammatory cytokines which activate the TH-17 pathway and promote autoimmunity.
Summary of Lifestyle Modulation of Autoimmunity
Adverse Mechanisms which Promote Autoimmunity
- Excess stress
- Physical overtraining
- Lack of sleep
- Drops in blood glucose
- Poor social relationships
- Positive attitude
- Adequate exercise
- Adequate sleep
- Stable blood glucose
- Social/physical interaction
Dietary Strategies for Autoimmunity
Here are three common pathophysiologic stress responses that promote autoimmunity:
- Blood sugar fluctuations
- Gluten and cross-reactive foods
- Intestinal permeability
In addition to internal and external stressors, people with autoimmunity must decrease their physiologic stress response by optimizing their diet and eating patterns. Maintaining stable glucose levels and avoiding blood sugar spikes is important to minimize inflammatory responses. Autoimmune individuals must also avoid eating gluten or any foods that cross-react with gluten (discussed below). They must also try to improve their leaky gut/intestinal permeability condition by sticking with a low-carb/paleo diet and eating frequently throughout the day. Making the lifestyle and dietary changes as discussed below can lead to significant changes in their overall health and function. These changes will also dampen immune responses and potentially slow down the progression of the autoimmunity. Let’s discuss each of these in a bit more detail.
The most common and significant biochemical stressor today is dysglycemia or poor glucose control from diet and lifestyle. Individuals with autoimmunity need to make sure their blood glucose levels are not going up and down all day like a roller coaster. Numerous studies have shown the effects of oxidative stress and upregulation of pro-inflammatory cytokines when glucose levels fluctuate. [334-338] Studies also show there is a decrease in oxidative stress and inflammation by blunting glucose fluctuations. 
When blood glucose is low from missing meals or eating meals that are not sufficient in fiber or protein, pro-inflammatory cytokine production (ie: IL-6) increases to raise blood glucose. [340-345] IL-6 not only activates the endocrine system (to produce more adrenal hormones to raise blood glucose) but recall it also stimulates the TH-17 pathways that activate autoimmunity, which we discussed above. 
If they get tired after meals, they are likely eating too much food for their body to handle, particularly excess carbohydrates with insufficient protein and/or are not getting enough exercise. This type of person is often overweight and will often show elevations of fasting blood glucose and triglycerides in their labwork. These are all signs of insulin resistance, as discussed in part 1 of this series. This is an issue of the body’s cells not responding to insulin the way they should. Recall that insulin is the hormone that allows the cells to uptake glucose and lower glucose levels in the blood.
If someone gets shaky, lightheaded or irritable when they go too long without eating, this is a sign of their blood glucose levels falling too low. Symptoms are often relieved after eating. If they feel better after they eat, they are either going too long without eating or are not getting enough fiber and protein to stabilize their blood sugar. These people will often show low to normal fasting blood glucose levels and tend to be thinner and often have low blood pressure. Either way, symptoms that improve or worsen after eating meals is not a good sign and indicates some type of blood glucose regulation issue that needs to be addressed to improve autoimmunity.
Signs of Blood Glucose Issues and Dietary Needs
- Fatigue between meals
- Eating relieves fatigue
- Crash in the afternoon
- Difficulty staying asleep
- Shaky, lightheaded or irritable between meals
- High-protein meals
- Avoid simple sugars
- Eat every 2-3 hours
- Fatigue after meals
- Sugar cravings after meals
- Need for coffee or stimulants after meals
- Avoid or limit carbohydrates
- Eat small meal portions
Avoiding food allergens and inflammatory foods is critical to minimizing the triggering of immune responses and tissue destruction in autoimmunity. By far, the most inflammatory food being consumed in the U.S. is gluten. Non-celiac gluten sensitivity has been linked with several types of disease, including autoimmune disease, as we discussed in part 4 of this series [347-353] but it is important to understand that gluten can make any autoimmune disease worse in individuals who are gluten-sensitive because of the inflammatory nature of gluten. [354-358]
As we saw in part 4 of this series, gluten sensitivity is extremely common, potentially affecting a much larger percentage of the population than we realize. We do not know exactly how common gluten reactions actually are (because conventional blood testing for this is not reliable since it is only testing for one fraction of wheat seen in celiac disease, as discussed in part 4) but we do know that approximately 30-40% of the normal population have the HLA-DQ2 or DQ8 genotype (the genotype associated with celiac disease)  and one estimate is that gluten sensitivity affects 29% of the normal population. 
We also know that gluten sensitivity presents as a wide variety of symptoms , and has been implicated in the development of intestinal permeability or leaky gut syndrome . As we learned in part 5, intestinal permeability is now being theorized to be one of the primary mechanisms in the pathogenesis (development of disease) of autoimmune disease. [363-366] So there is a clear connection between gluten sensitivity, leaky gut and the development and progression of autoimmune disease.
Once a patient is diagnosed as Celiac Disease (CD) or showing signs (or suspected of having) gluten sensitivity, he/she is instructed to adhere to a gluten-free diet (GFD). There are many resources that can help the patient with this seemingly difficult process. However, a significant percentage of these patients will continue to have gluten-like complaints even after being on a GFD for months.  Why is that?
“Gluten-Free” Products are Not Necessarily Gluten-Free
Most countries define “gluten-free” products based on the recommendation of the Food and Agricultural Organization of the United Nations and World Health Organization. This codex allows the inclusion of up to 0.3% protein from gluten containing grains in foods labeled “gluten-free.” In some gluten-sensitive individuals who are exposed to 0.3% gluten protein, the immune system can still recognize and react to the protein. [368-369]
Wheat/gliadin is commonly added to foods as a “hidden” ingredient in various types of food additives such as soy sauce, food starches, food emulsifiers, malt extract and dextrins. These are often referred to as “natural flavors”, “food starches” or “food stabilizers.” A complete understanding of ‘hidden wheat/gluten’ sources is necessary to have a better outcome with the GFD. Additionally, education of gluten-containing grains, such as rye, barley, Polish wheat and spelt, is also important.
Hidden sources of gluten:
- Soy sauce
- Salad dressings
- Food starches
- Food emulsifiers
- Food stabilizers
- Artificial food coloring
- Malt extract, flavor, syrup
Another major reason for gluten-related symptoms while on a GFD is because there exists antigenic similarity, or cross-reaction, among many grains, and other dietary proteins with gluten. In order to understand this concept of cross-reactivity, let’s review some basic concepts of immunology.
Immune responses to food occur when antibodies of the immune system recognize and bind to antigens (specific to that food) made of proteins which are composed of a sequence of amino acids. There are a number of foods that have been identified to have a similar amino acid sequence as gluten, including dairy. In fact, resarch indicates about 50% of patients with celiac disease have problems digesting dairy and may, therefore, contribute to persistent symptoms in patients who are on a GFD.  Gluten antibodies can bind to these non-gluten food antigens initiating inflammatory responses similar to those seen with gluten. This type of response is termed “cross-reactivity” and has been clearly-established in the literature. [371-378] This is a big problem for people who are gluten-sensitive because their immune systems “cross-react” to many types of food as if they were consuming gluten and cause major problems for these people, especially if they already have autoimmunity.
Research has indicated that identifying these foods appears to be a valuable adjunct in the diagnosis and follow-up of diagnosed celiac disease, both in children and adults. Monitoring these antibodies may be particularly helpful in evaluating the response of patients on a gluten- and cross-reactive food-free diet.  The following is a list of foods which have been shown to cross-react with gluten.
Gluten Cross-Reactive Foods
Additionally, patients who are new to the GFD encounter new foods and/or over-consume old favorites to compensate for the lack of wheat in the diet. Gluten-free cookies, crackers, breads and cakes often contain copious amounts of rice, amaranth, sorghum and other substitutes. Some of these new-to-the-patient foods may illicit an adverse reaction. Other foods that are often introduced to the patient on the GFD are quinoa, buckwheat and hemp. Some patients may turn to the “ancient” grains (Polish wheat, spelt, barley, rye), not knowing that these contain gluten. Another problem patients often face on the GFD is the over-consumption of another starch to make up for the loss of wheat. They turn to potato, rice or corn as a substitute. This can lead to the development of a new sensitivity or the enhancement of old sensitivities. [380-386]
In part 4 of this series, we discussed the inappropriateness and unreliability of conventional lab testing (anti-gliadin and anti-tissue transglutaminase 2) for gluten sensitivity. This test was designed to detect celiac disease, not all the other types of responses now known to occur in gluten sensitivity. As a result, this test only tests for a limited number of antibody responses and we learned that there are many other types of reactions to gluten as well as other wheat fractions that are not detected in this test that can result in various illnesses.  Fortunately, there is a reliable comprehensive gluten sensitivity test available through Cyrex Labs which tests for IgA and IgG antibodies to twelve different reactions to wheat: Array 3x: Wheat/Gluten Proteome Reactivity and Autoimmunity test.
In addition to performing reliable testing for gluten sensitivity in individuals where gluten sensitivity is suspected, it is advised to check for immune responses to gluten cross-reactive foods in any individual shown to have gluten sensitivity when symptoms persist after initiation of a gluten-free diet (GFD). Cyrex Labs offers a comprehensive test which tests for immune responses to 24 different cross-reactive foods or foods that patients often develop sensitivity to after initiating a GFD, as discussed above: Array 4: Gluten-Associated Cross-Reactive Foods and Foods Sensitivity test. In my practice, I recommend this test for anyone who is known to have gluten sensitivity but continues to have gluten-related symptoms, even after initiating a GFD.
Intestinal Permeability Dietary Restrictions
Finally, as discussed above, it is important to avoid foods that tend to aggravate or worsen intestinal permeability when trying to repair the gut barrier and decrease autoimmune responses. Sugars and high glycemic foods can create more damage to the intestinal lining and increase permeability. Gluten (and other grains that cross-react with gluten), dairy and soy can also cause additional inflammation and lead to further damage to the epithelial lining of the GI tract. Lectins (found in grains, legumes, nightshade plants and dairy) have also been shown to damage this epithelial ling. It is important to implement an aggressive and complete dietary program to break the vicious cycle of leaky gut and minimize autoimmune reactions. Here is a list of foods shown to aggravate or worsen intestinal permeability as well as the foods that are generally safely tolerated in individuals with this condition.
- Sugars: including corn syrup, high fructose corn syrup, molasses, honey, chocolate candy, etc.
- High glycemic fruits: watermelon, mango, pineapple, raisins and canned fruit
- Grains: including gluten, wheat, oats, rice, barley, buckwheat, soy, corn, wheat germ, spelt, amaranth, kamut, millet, and quinoa, etc.
- Gluten-containing compounds: including processed salad dressings, ketchup, soy sauce, barbecue sauce, condiments, modified starches, etc.
- Dairy: including milk, whey, eggs, cheeses, creams, and mayonnaise, etc.
- Soy: including soy milk, soy sauce, soy protein, etc.
- Alcohol: including beer, wine, sake, cognac, liquors, etc.
- Lectins: including nuts, beans, soy, potatoes, tomato, eggplant, pepper, peanut oil, soy oil, etc.
- Processed foods
- Canned foods
- Most vegetables (except tomato, potatoes and mushrooms): including asparagus, spinach, lettuce, broccoli, beets, cauliflower, carrots, celery artichokes, garlic, onions, zucchini, squash, rhubarb, cucumbers, turnips, watercress, etc.
- Fermented foods: including sauerkraut, kimchi, pickled ginger, mixed pickle, coconut yogurt, kombucha tea, etc.
- Meats: including fish, chicken, beef, lamb, organ meats, etc.
- Low glycemic foods: apricot, plum apple, peach, pear, cherries, berries, etc.
- Coconut: including coconut oil, coconut bitter, coconut milk, etc.
- Herbal teas
- Olives and olive oil
Cyrex Labs offers a reliable intestinal barrier antigenic test which is currently the only commercial lab available that measures the immunological response against the proteins that compose the intestinal barrier and accepted markers of permeability, such as lipopolysaccharides (LPS). The profile includes actin/myosin network IgG, occludin/zonulin IgG, IgA, IgM and lipopolysaccharides (LPS) IgG, IgA, and IgM. Measurements of these antibodies can be used as reliable markers for intestinal permeability. This condition is extremely important to assess in individuals who have autoimmunity or autoimmunity is suspected, or patients that present with common signs or symptoms associated with intestinal permeability as described above and whom the development of autoimmunity is a concern.
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