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From the Townsend Letter
June 2019

New Understanding of Autoimmunity Development Through T Helper Cell Regulation, Part 1
by Debby Hamilton, MD, MPH
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Types of Autoimmune Diseases with Elevated Th17
The rate of autoimmune disease continues to increase around the world. Research on Th17 has helped explain some of this prevalence. While autoimmune diseases were originally thought to be primarily Th1 dominant, new research and understanding of Th17 and its cytokines has changed this view (see Table 1). Many of the common autoimmune diseases continue to find elevated Th17 and a dysregulated immune system including rheumatoid arthritis, multiple sclerosis, and Hashimoto's. Chronic inflammatory diseases such as asthma also have imbalanced T helper cells.

Table 1: Summary of Th Cells Development and Function .pdf

BDNF EssentialsIn integrative medicine, the concept of a broken mucosal barrier in the intestine is well known. Practitioners are taught to detect and treat the digestive tract and improve the microbiome. What is now being more recognized is that disruption of other mucosal barriers can also lead to autoimmune disease. The lungs and the sinuses appear to be common locations. Organs such as the bladder and vagina can also be an issue. The concept is that any hollow space in the body that is lined by epithelial cells forms a mucosal barrier. It is created to be the first line immune response to foreign antigens. The problem is when this first line immune barrier is broken, leading to loss of immune tolerance and development of inflammation.

Table 2: Diseases Associated with Elevated Th17 Levels .pdf

Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a common autoimmune disease that leads to systemic inflammation, destruction of the joints, and an increase in cardiovascular disease risk. Rheumatoid arthritis was traditionally seen as a Th1 dominant autoimmune disease. The discovery of Th17 has changed the understanding of the pathogenesis of the disease.
Although the disease is an autoimmune disorder of the joints, the disease does not appear to originate in the joints. Disruption of the mucosal barrier in the lungs and the digestive tract has both been linked to the development of RA.12,13 When the intestinal microbiome of patients with rheumatoid arthritis has been evaluated, it appears that it is different compared to control subjects. Patients with RA tend to have a decrease in Bifidobacterium and Bacteroides bacteria with an increase in the Prevotella species.13-15 This often creates intestinal hyperpermeability. The disruption of the mucosal barrier leads to loss of immune tolerance and induction of Th17 cells from naïve T cells through the inflammatory cytokines IL-6 and IL-23.16 These Th17 cells travel in the blood stream to the joints where they instigate the autoimmune process. IL-17 has been associated with an increase in inflammation, influx of immune cells, and both cartilage and bone erosion in RA.17
Air pollution has been found to be another causative factor in the development of RA.12 Diesel exhaust particles in air pollution when they are breathed into the lungs can cause the formation of Th17 cells through the activation of the aryl hydrocarbon receptor.12 It is well known that other toxins such as the organophosphate pesticides trigger this receptor resulting in the development of inflammation.18 The air pollution overall creates a pro inflammatory environment leading to high citrullination levels in the lungs, leading to the production of anti-citrullinated peptide antibodies.12 Smoking is a known risk factor for RA.19 As cigarette smoke contains multiple toxic chemicals, the mechanism appears to be the same with the development of inflammation, leading to the induction of elevated Th17 levels.

Multiple Sclerosis
Another common potentially debilitating autoimmune disease is multiple sclerosis (MS).
It is a neuroinflammatory disease characterized by recurrent demyelination leading to neuro-degeneration. The initial insult in MS is disruption of the blood brain barrier (BBB).20 This barrier is another example of a mucosal surface altered to allow for the increased development of Th17 cells. Why there is an altered blood brain barrier is not completely understood. The activated Th17 cells produce the cytokines IL-17 and IL-22, which disrupt tight junction proteins in the central nervous system endothelial cells that form the BBB.20,21 Once through the BBB, the Th17 cells produce multiple pro-inflammatory cytokines such as (IL)-17, IL-6, IL-21, IL-22, IL-23, and tumour necrosis factor (TNF)-α contributing to the neuroinflammation present in MS.21,22
In an equivalent manner as RA, IL-17 appears to play a destructive role. It is a potent inducer of neutrophil recruitment into the CNS.11 Neutrophils release toxic compounds that trigger recruitment of macrophages into the tissue and continue with immune system activation. Without removal by macrophages, they go through apoptosis releasing ATP and other compounds that cause tissue destruction. Elevated levels of IL-17 are found in MS plaques and the CSF of patients with MS, contributing to the neuroinflammation in the CNS.23 In addition to the MS lesions, white blood cells of patients with active MS have higher IL-17 levels.24 Severity of MS varies over a patient's lifetime with classic exacerbations and remissions. Higher levels of IL-17 are associated with worsening severity.23 Understanding of the proinflammatory role of Th17 releasing the destructive IL-17 leads to more options in terms of treatment targets including natural immune system modulators.

Hashimoto's Thyroiditis
Hashimoto's thyroiditis is a chronic autoimmune disease of the thyroid gland that has been increasing in prevalence. Even in children, many integrative pediatric providers are testing for and finding thyroid autoantibodies in our patients. With most autoimmune diseases, there appears to be an environmental and genetic combination of causes. Researchers have been looking at the gut microbiome and finding differences between patients with Hashimoto's and controls, with the Hashimoto's group having microbiome dysbiosis.24 One study found significant differences in 27 distinct species between the two groups. The Hashimoto's group had decreased Bacteroides, like patients with rheumatoid arthritis, but also low levels of Prevotella which was elevated in RA patients.26 In a comparable manner to other autoimmune diseases, elevated Th17 cells were found in both the blood and the thyroid of patients afflicted with this disorder.27 Higher levels of Th17 cells correlated with increased severity of the disease and increased risk of ophthalmopathy.27
Researched NutritionalsWith an abnormal microbiome contributing to autoimmune disease, it naturally follows that having one autoimmune disease predisposes to other autoimmune diseases. This is true with Hashimoto's disease. Patients with this disorder often develop other autoimmune diseases such alopecia, vitiligo, type 1 diabetes, and celiac disease.28 Interesting that a common association with RA is not seen. They are both seen to develop from an abnormal GI microbiome, but different abnormalities lead to similar elevations in Th17 but different clinical manifestations.

PANS (formerly called PANDAS)
PANS (Pediatric Acute-onset Neuropsychiatric Syndrome), which was formerly labeled PANDAS (Pediatric Acute-onset Neuropsychiatric Disorders Associated with Streptococcus), is a neurologic autoimmune disorder increasingly seen in children. The incidence appears to be increasing, but recognition in the mainstream medical community is still low. Classic PANS is seen in children with no history of behavior or developmental issues. The clinical symptoms arise abruptly with acute behavioral symptoms including rage, separation anxiety, OCD, and tics among others.
The neurologic autoimmune issue called PANDAS was first identified from Streptococcus pyrogenes.29 The mechanism appeared to be an increase in pathogenic Th17 from multiple Group A strep infections.30 The activated Th17 was made in the nasal associated lymph tissue (NALT) and then migrated into the olfactory bulb where it caused inflammation and damage to the blood brain barrier.30 Once inside the brain it triggered neuroinflammation, including an increase in IgG cross reacting antibodies.30 Group A strep is a common pediatric infection so there appears to be a genetic susceptibility toward an autoimmune response in certain children. Multiple infections appear to be a key factor also since an initial priming of the immune system was needed.31

Autism spectrum disorders (ASD) are increasingly being recognized as having significant immune dysregulation. This immune dysregulation includes autoimmunity, immune deficiencies, inflammation, allergies, and increased risk of infections.32 Autoantibodies to the central nervous system play a role in the development and maintenance of ASD.33 Because of these multiple immune system issues, the ratios and levels of the T helper cells have been investigated. Abnormal ratios of Th1/Th2/Th17 and T reg cells have been found.33 An increase in Th17 cells with increased serum levels of the proinflammatory cytokines IL-17 and Il-6 are seen in children with autism.33,34
The question then becomes what is the origin of these differences? Each of the types of T helper cells have different transcription factors that induce the formation of these cells. Research has shown that children with ASD, compared to controls, have lower levels of Foxp3, which is a critical factor for Treg cell development.32 If Treg cell development is lower, this will lead to lower immune tolerance and increase risk for autoimmune disease. The transcription factors RORγt+, T-bet+, and GATA-3+ were all elevated compared to controls, which correlates with an increase in Th17, Th2, and Th1 cells.32 The question then becomes why the transcription factors are abnormal and is this the cause or the result of immune dysregulation?
Children exposed to maternal immune activation in utero have an increased risk of developing ASD. Maternal exposure to influenza and other infections such as rubella also increases the risk of ASD in childhood. One of the mechanisms appears to be inflammation associated with increased Th17 and IL-17 in the mothers when pregnant.35 Higher levels of IL-17 in pregnant women have been found to correlate with increased severity in ASD.35 Research has shown in animals that blocking IL-17A signaling prevented ASD like behavior in offspring exposed to maternal immune activation.35

As the number of autoimmune diseases continue to escalate, it is critical for us to understand the immune mechanism that leads to this imbalance. Only by understanding how these diseases develop can we try to reverse this trend. Learning about the delicate balance in the T helper subsets is a good first step. The next step is to learn the natural tools we have as practitioners to support our patients. Next month, I will discuss the use of transfer factors and natural anti-inflammatory compounds to help balance our immune system.

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References for Part 1 .pdf

Dr Debby HamiltonDr. Debby Hamilton, MD, MPH, is a pediatrician with experience in primary care, integrative medicine, research, speaking, and writing. Her education includes an undergraduate degree from Wesleyan University followed by a medical degree from Chicago Medical School, where she graduated with honors. She is board-certified in pediatrics, physician nutrition, and integrated/holistic medicine (AIHM), and has a Master of Science degree in Public Health (MPH). Dr. Hamilton founded Holistic Pediatric Consulting in Colorado in 2005. Her practice focused on treating children with chronic diseases such as autism and ADHD and preconception counseling based on her book, Preventing Autism and ADHD: Controlling Risk Factors Before, During & After Pregnancy. Her book led to her collaboration in the writing of The Healthy Child Guide through the Neurological Health Foundation. She has also contributed chapters for Child DecodedUnraveling Learning and Behavioral Disorders. In 2017, Dr. Hamilton joined Researched Nutritionals. Her focus is managing and expanding Researched Nutritional's clinical research on the efficacy of nutritional supplements, working on protocol development, and promoting the education of healthcare professionals.

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