An Individualized Approach: Autoimmunity, Allergies, & Biochemical Pathways

CHRIS D. MELETIS, ND 

Autoimmune diseases afflict a considerable portion of the population, with recent numbers indicating that 15.9% of the US population, or 41 million people, suffer from an autoimmune condition.¹ Although autoimmune diseases are more common among women, the number of men with this type of condition is increasing, according to a study conducted by scientists at the National Institutes of Health.¹ At the same time, the incidence of food allergies and intolerances is increasing, impacting gut health and playing a role in autoimmunity by impairing intestinal permeability, otherwise known as leaky gut.² 

Quite often, when autoimmune patients arrive at our clinical practices, they have been affected by numerous disease triggers and may often have more than 1 condition that must be addressed. We need to move away from the idea of 1 cause for 1 disease. Our patients present to our clinics with similar and overlapping symptoms that we strive to identify so that we can fit them into ICD-10 coding. Yet, each individual cannot be simplistically lumped into a single category because a patient suffering from an autoimmune disease arrived at his or her condition due to different experiences than those of the autoimmune patient sitting next to them in the waiting room.   

In keeping with the need for individualized approaches in treating autoimmune patients, I have found that resolving certain lesser-known triggers of autoimmune disease yields excellent results. It is important to pinpoint the autoimmune trigger for each patient if there is any hope of resolving symptoms. In this article, I’ll discuss some of the most important autoimmune triggers and offer suggestions for eliminating those causes or at least reducing the burden. 

Mitochondria’s Role in Autoimmunity 

Mitochondrial abnormalities have been observed in a number of autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).^3,4 RA is characterized by self-reactive immune cells, leading to inflamed and painful joints. In RA, alterations in mitochondrial DNA may elicit changes in cellular functions that point immune cells toward an inflammatory phenotype.^4,5 Further evidence of the role of mitochondrial dysfunction in autoimmune diseases is the presence of a deficiency of mitochondrial respiratory chain complex I in Hashimoto’s thyroiditis.⁶ Mitochondrial complexes I and IV may also be altered in RA.⁵  

The inability of the body to effectively eliminate damaged mitochondria plays an important role in impaired autoimmunity.³ Supporting mitochondrial health is therefore critical in autoimmune patients. Coenzyme Q10 (CoQ10) is a mitochondrial rejuvenator that can be helpful in promoting autoimmune health by supporting mitochondrial function. For example, in a randomized, double-blind study of 54 RA patients given either 100 mg/day CoQ10 or a placebo for 2 months, CoQ10 supplementation led to reductions in serum matrix metalloproteinase-3 (MMP-3), an enzyme that degrades collagen.⁷ Furthermore, CoQ10 improved clinical outcomes, such as pain, swollen and tender joints, and reduced disease severity. CoQ10 has also had beneficial effects in other autoimmune diseases, such as antiphospholipid syndrome,⁸ psoriasis (together with vitamin E and selenium),⁹ and diabetes.¹⁰ 

Nitric Oxide Homeostasis 

Supporting beneficial nitric oxide (NO) pathways is an important part of an autoimmune protocol. This is where the saying, “Don’t throw the baby out with the bath water” is appropriate. We all need healthy levels of NO in order to not only survive, but also thrive. NO is essential for circulation, heart health, and systemic wellness. However, patients with many autoimmune diseases have high levels of inducible NO synthase (iNOS).¹¹ Ironically, however, these patients may have reduced endothelial NO bioavailability.¹¹ This is thought to occur due to overexpression of iNOS, which can in some circumstances be an undesirable NO pathway. Nitric oxide synthases are enzymes that catalyze the generation of NO from L-arginine. Overexpression of the iNOS pathway can lead to the uncoupling of what would normally be a more beneficial NO pathway: endothelial nitric oxide synthase (eNOS).^11,12 When eNOS is uncoupled, it generates the superoxide anion instead of NO.^11,12 The superoxide anion can also react with existing NO to produce a harmful free radical known as peroxynitrite.^11,12 This reduces the bioavailability of endothelial NO, resulting in endothelial dysfunction.^11,12 This diminished endothelial NO bioavailability is thought to explain why in rodent models of RA, plasma nitrite concentrations are reduced.¹²  

Additionally, RA patients have relatively high circulating levels of methylated arginine asymmetric dimethylarginine (ADMA), which significantly suppresses the activity of eNOS.¹³ By lowering levels of eNOS, ADMA is thought to be involved in the increased endothelial dysfunction, vascular inflammation, and atherosclerosis observed in RA patients.¹³  

Indeed, healthy levels of endothelial NO have been shown to protect the cardiovascular system of autoimmune patients. This group of patients often exhibits increased cardiovascular risk factors.¹⁴ For example, there is an increased prevalence of hypertension in patients with SLE, psoriasis, RA, systemic sclerosis, and periodontitis compared to controls.¹⁴ It is important to note, however, that some researchers have suggested that NO from iNOS could be beneficial for the control of multiple sclerosis (MS) and Th2-mediated allergic asthma by inducing S-nitrosylation of transcription factors, metabolic enzymes, apoptosis mediators, and cytoskeletal proteins.¹⁵ Consequently, iNOS is not always the villain. 

Another connection between impaired cardiovascular function and autoimmune disease is the increased prevalence of arterial dysfunction and increased cardiovascular disease risk in RA patients.¹⁶ Furthermore, dietary nitrates in the form of increased daily vegetable consumption are associated with better arterial function in RA patients compared to those who consumed fewer vegetables daily.¹⁶ This enhanced arterial health was thought to be due to the nitrate derived from vegetable consumption. Nitrate is converted to NO in the body. However, in clinical practice, optimally augmenting NO often takes more than merely increasing veggie intake; this is why supplementation is routinely pursued.  

Ultimately, it is not NO per se that is of concern to autoimmune patients, but rather misdirected NOS pathways. NO itself is not the enemy. In fact, it is critical to cardiovascular support in autoimmune disorders. This is why it is important to utilize nitric oxide test strips to evaluate NO levels in autoimmune patients, so we can test rather than guess their actual need for NO. We should be addressing the drivers of misdirected iNOS rather than hyperfocusing on avoiding substrates for NO such as beets, kale, watermelon, arugula, bok choy, spinach, cabbage, Swiss chard, etc. Unless these foods are immunologically problematic for patients (more on this later in the article), using them along with a nitrate-rich supplement that includes beetroot to increase endothelial NO levels can support the cardiovascular and overall health of autoimmune patients.^17-19  

Addressing Viral Causes  

Viral infections are suspected in the etiology of many autoimmune diseases. For example, encephalomyocarditis virus (EMCV) infection is linked to autoimmune diabetes,²⁰ and Epstein-Barr virus is linked to Graves’ disease, MS, and SLE.²¹ Immune support in autoimmune patients, in order to eliminate the viral trigger, can be effective in eliciting improvement. Additionally, balanced levels of NO can defend against viral and bacterial invaders.²² On the other hand, insufficient NO production can lead to serious and potentially fatal infections.²² 

In autoimmune diabetes, NO produced in pancreatic beta cells suppresses EMCV replication and the beta-cell lysis caused by EMCV.²⁰ NO therefore exhibits protective actions against EMCV infection in beta cells.²⁰ Consequently, maintaining NO homeostasis in the form of a nitrate-rich supplement may have beneficial effects in this arena. 

Hormonal Regulation in Autoimmunity 

Addressing hormonal imbalances is a good example of going after a potential trigger of autoimmune disorders. Autoimmune diseases are more prevalent in women, with 85% or more autoimmune patients being female.^1,23 This predisposition is likely due to their stronger immune response compared with men, as well as the influence of estrogen on autoimmune disorders.²⁴ In this population, alterations in hormones during menopause can impact inflammatory processes, which leads to increased vulnerability to autoimmune diseases among women undergoing peri- or postmenopause. At the age of 50, women’s neutrophil percentage declines while lymphocyte percentage increases, which leads to increased risk of lymphocyte-mediated autoimmune disease in the perimenopausal years.²⁵ Autoimmune diseases that develop in or near menopause usually have a more chronic disease course and fibrotic Th-mediated pathology.²⁶ Often, autoimmune diseases that develop during older age are associated with an age-related increase in autoantibodies.²⁶ Conversely, autoimmune diseases such as MS and RA improve during post-menopause.²⁶  

During menopause, alterations in sex hormones can change innate immune phenotypes via epigenetic remodeling.²⁴ Balancing hormones such as estrogen, progesterone, and dehydroepiandrosterone (DHEA) can be beneficial. DHEA levels fall progressively, at the rate of 2% per year.²⁷ Supplementation with DHEA is especially beneficial in autoimmune disorders like SLE.²⁷ A study of 41 female patients with SLE found that 20-30 mg/day DHEA improved mental well-being and sexuality scores.²⁸ However, it was also associated with a decrease in HDL-cholesterol.²⁸ Supporting healthy estrogen levels is also important, as estrogen upregulates NO production in immune cells.²²  

The Endocannabinoid System as a Key Player 

Animal studies have shown that cannabidiol (CBD) may support the immune response in autoimmune conditions. CBD works through the endocannabinoid system, an endogenous pathway that involves endocannabinoids and their receptors. In a rodent study, CBD reduced autoimmune hepatitis.²⁹ In other research, it suppressed the development of type-1 autoimmune diabetes in mice.³⁰ In a study of 11- to 14-week-old female mice that were either in a latent diabetes stage or had the beginning symptoms of the disease, CBD inhibited the manifestations of the disease.³⁰ Only 32% of the mice in the CBD group developed diabetes, as compared with 86% and 100% of the control group and untreated animals, respectively. In a mouse model of autoimmune myocarditis, researchers administered CBD to mice and observed significant improvement in the animals.³¹ 

In vitro, CBD increases the activity of myeloid-derived suppressor cells (MDSCs), one of the primary regulatory cells of the immune system that migrate to sites of inflammation.²⁹ These cells can interfere with T-cell functions. By activating MDSCs, CBD can suppress inflammation and autoimmune hepatitis.²⁹ Another way in which CBD may support autoimmune health is by enhancing the activity of regulatory T cells (Tregs),³² which are often impaired in people with autoimmune disorders.³³ 

Role of Food Allergies/Intolerances & Leaky Gut  

Food Allergies/Intolerances 

Globally, the incidence of allergic reactions is increasing, with some countries experiencing a food allergy prevalence of 10%.³⁴ Until recently, food allergies were traditionally thought of as a pediatric problem, since food allergies often begin in early childhood and spontaneously resolve in adulthood. However, even the elderly are now increasingly suffering from food allergies, and diagnosis is often challenging due to comorbidities.³⁵ This vulnerability to food allergies in the elderly is due to physiological alterations in aging, impaired gut barrier function, age-related alterations to the gut microbiota, a switch from adaptive immunity towards a T helper type 2 (Th2) response, and impaired function of innate immune cells.³⁵ During aging, immune system function is progressively altered, resulting in elevated inflammation due to the dominance of type-1 cytokines.³⁵ On the other hand, serum immunoglobulin E (IgE) concentrations and the generation of Th2 cytokines are also observed to be increased in the elderly, indicating that a type-2 cytokine profile still operates effectively in older adults.³⁵ Other explanations for increased susceptibility to food allergies in the elderly include impaired dendritic cells in the gut, alterations in secretory IgA, and weakened Treg function.³⁵     

While the greatest attention in the past was paid to IgE-mediated food reactions, scientists are now recognizing that non-IgE-mediated food intolerances also play an important role in what is known as the Allergic March,³⁴ the course of atopic manifestations and clinical symptoms that last for years or decades. Gastrointestinal (GI) symptoms and atopic dermatitis are often initial symptoms in non-IgE-mediated food reactions, with asthma and allergic rhinitis subsequently developing as comorbidities.³⁴ However, often symptoms are delayed and/or subtle and not obviously related to the food consumed. 

Leaky Gut 

Impaired GI permeability (leaky gut) creates a vicious cycle in both IgE- and non-IgE-mediated food reactions. Leaky gut can predispose to the development of food allergies and intolerances and can exacerbate preexisting sensitivities. Leaky gut can also contribute to the development of autoimmune disorders.² This is not surprising, as nearly 70% of the immune system is located in the gut in the form of gut-associated lymphoid tissue (GALT).³⁶ Many autoimmune diseases are thought to require a triad of factors for their development, including leaky gut³⁷: 1) a genetic predisposition of the immune system to generate an abnormal reaction to an environmental antigen; 2) the presence of the environmental antigen to activate the abnormal immune response; and 3) a leaky gut to allow the antigen exposure to, and interaction with, the mucosal immune system of the gut. 

The association between leaky gut and autoimmune disorders involves the protein zonulin, which plays a role in intestinal permeability through the modulation of tight junctions between cells. Increased zonulin secretion from the lamina propria into the gut lumen leads to increased permeability of the gut barrier.² One example of the relationship between intestinal permeability and autoimmune disease is seen in type 1 diabetes. High zonulin levels were observed in prediabetic rats, which correlated with the generation of autoantibodies against pancreatic beta cells.³⁸ This preceded the development of type 1 diabetes by approximately 25 days. The prediabetic rats that did not develop diabetes had zonulin levels similar to that observed in diabetes-resistant controls. Administering a zonulin receptor antagonist to prediabetic rodents suppressed both the increase in intestinal permeability and the development of diabetes.³⁸ Commenting on that study, another group of researchers stated, “Removing the dietary stimulus or correcting the leaky gut can prevent the disease, despite retaining the abnormal genetics of this animal model.”²  

There is also evidence of the connection between autoimmunity and leaky gut in humans. Researchers have found increased intercellular spaces between enterocytes in duodenal biopsy specimens from patients with type 1 diabetes, as compared to specimens from healthy controls.³⁹ In a large cohort of patients with type 1 diabetes, their first-degree relatives, and controls, intestinal permeability was higher in diabetic patients and their relatives compared to controls, although type 1 diabetic patients had the highest intestinal permeability and zonulin levels.⁴⁰ In this same study, 7 of 10 prediabetic patients who had positive autoantibodies associated with type 1 diabetes but who had not progressed to clinical disease had high serum zonulin concentrations, and 3 of the subjects with high zonulin levels went on to develop diabetes 3.5 years after their zonulin levels were tested. Commenting on these studies, Teshima and colleagues stated, “Together, these findings suggest that in both the [prediabetes] rat model and human patients, an enteropathy in the small intestine, associated with increased paracellular permeability and perhaps driven by a zonulin-mediated pathway, precedes the clinical development of diabetes and may contribute to disease pathogenesis.”² 

Because wheat-gliadin peptides can enhance pathways that are dependent on zonulin,⁴¹ some scientists have suggested that wheat gluten is the environmental antigen that promotes type 1 diabetes in people who are genetically predisposed.⁴²  

This association between wheat gluten and type 1 diabetes, and the fact that food allergies and intolerances are associated with leaky gut,^43,44 indicates it is critical to identify food reactions when treating autoimmune patients. Our GI tract will process tons of food over the course of our lives. Even prior to our birth, we are essentially processing food being consumed by our mother. Due to epigenetics, we know that even food consumed by Grandma can affect future generations. The GI tract, when working optimally, is a glorified collander that filters good from bad. Yet, at the same time, when we eat, we are fueling the integrity of the GI tract, which determines how well this filter works. If we are consuming foods that are problematic (burdensome) to our GI tracts, we are burdening and triggering our immune systems. With each morsel of food we eat, we are either adding to or substracting from our ability to thrive vs survive. Testing for food allergies and intolerances and placing patients on an elimination diet is a beneficial way to address food-related autoimmune triggers while at the same time allowing patients to become empowered and motivated by taking charge of their health. Even supplements that seem healthy, such as turmeric, boswellia, and fish- and plant-based omega-3 fatty acids can in reality be harmful if a patient is intolerant to them. Likewise, vegetables that normally promote healthy nitric oxide levels may not be the best choice for patients who are sensitive to those foods. 

Conclusion 

Finally, it is important to begin measures to strengthen the gut barrier early in life by taking such actions as implementing probiotic supplementation to support the gut microbiota and knowing the individualistic food and environmental triggers for autoimmune disease in genetically predisposed individuals. We want to make certain we aren’t priming the next generation with a higher risk of conditions and disease states. For example, infants who consume a dust mite allergen in their mother’s breast milk may be more susceptible to IgE-mediated food allergies.⁴⁵ There is a lot of talk about diminishing fertility rates, yet fertility is more than just the outcome of a successful pregnancy; it is also the health of the child. Therefore, we as clinicians should be mindful of autoimmune health and allergic predisposition across all age groups, from the very young to the very old.      

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Chris D. Meletis, ND is an educator, international author, and lecturer. He has authored 18 books and more than 200 scientific articles in prominent journals and magazines. Dr Meletis served as Dean of Naturopathic Medicine and CMO for 7 years at NUNM. He was recently awarded the NUNM Hall of Fame award by OANP, as well as the 2003 Physician of the Year by the AANP. Dr Meletis spearheaded the creation of 16 free natural medicine healthcare clinics in Portland, OR. Dr Meletis serves as an educational consultant for Fairhaven Health, Berkeley Life, TruGen3, US BioTek, and TruNiagen. He has practiced in Beaverton, OR, since 1992.