By Debby Hamilton, MD, MPH
Introduction
The prevalence of autoimmune disease continues to rise around the world. Estimates range from 32 to 50 million people in the US live with more than 80 types of autoimmune disease.1 This prevalence means more people live with autoimmune disease than cancer and cardiovascular disease combined. As rates of autoimmune disease rise, it becomes increasingly important to understand the causative factors and the immune mechanisms underlying this change.
Over this time, our internal and external environment has continued to change. Our microbiome consists of many different commensal organisms that are critical for our immune system and overall health. With the changes in our food and environment, there has been a slow erosion of our microbiome contributing to the rise in autoimmune disease with the loss of immune tolerance. Toxins from pollution in our air to chemicals in our food have contributed to the accelerated loss of our microbiome from our lungs to our sinuses to our digestive tract.
Fortunately, the understanding of the intricacies of our immune system continues to advance. The past few years have given rise to added information about the T helper cells and their relationship to the development of autoimmunity. Specifically researching the role of elevated Th17 as one of the primary factors in autoimmunity development has changed our understanding. This elevation coincides with a loss of immune tolerance and an increase risk of infections, both contributing to a cycle of autoimmunity and inflammation.
Traditional Th1/Th2 Paradigm
In 1986, Mossman and Coffman identified two primary T helper cells and labeled them Th1 and Th2.2 Specific cytokines would trigger the development of either Th1 or Th2 from naïve T cells. Th1 was induced by IFN-Y and Il-2 where Th2 was induced by Il-4. These two T helper cells once induced into their role stayed stable in those roles.
These two types of T helper cells also consistently played a different role in the immune system. Th1 cells were important in the fight against intracellular pathogens such as viruses. The development and maintenance of autoimmunity also seemed to arise from an increase in Th1 cells compared to Th2 cells. On the other hand, Th2 cells helped the body fight extracellular organisms including many of the classic bacterial infections such as strep and staph. An excess of Th2 also led to allergies and asthma.
The goal with the Th1 and Th2 paradigm was to have a balance of the two cells to prevent both autoimmune and allergic diseases from developing. They were also thought to be antagonistic so if one of the T helper subsets was elevated, the other was low. Autoimmune diseases were labeled as Th1 dominant conditions in general and allergies as Th2 dominant. With this concept, a patient could have either autoimmune disease or allergic disease alone where we know that many of our chronic patients have both. In theory, autoimmune patients with an elevated Th1 would be able to fight many chronic infections, including viruses, Borrelia, and Mycoplasma better than people with a normal Th1 immune response. As we learn more about our chronic autoimmune patients, we realize that many of these patients cannot fight these chronic infections, which counteracts the thinking behind the Th1/Th2 paradigm.
Discovery of Th17 Cells
In 2003, another T helper cell was identified and labeled Th17.3 Both Th1 and Th17 share half of the same receptor leading to the difficulty in separating the two cells. The Th17 cells were also induced from naïve CD4 T cells by specific cytokines. Many of these cytokines are known as pro-inflammatory cytokines, including Il-23, Il-6, and Il-1. It appeared that a combination of cytokines was needed to induce Th17; and unlike Th1 and Th2, the role of Th17 could be either induced as pathogenic or protective. This induction was also fluid so the T helper 17 cell could change function depending on the environment.
Th17 cells play a critical role in first line innate immunity. These cells are induced along mucosal barriers when exposed to an antigen. Originally discovered in the lining of the digestive tract, they appear to be present along all hollow organs such as the sinuses, lungs, vagina, and bladder.4 An antigen from the environment triggers the CD4 naïve T cells to be induced to form the Th17 cells. Release of specific cytokines such as TGFB, IL-6, and IL-23 promote Th17 development. If triggered by inflammatory cytokines, an elevation in Th17 cells was seen with the release of pro-inflammatory cytokines such as Il-17. Elevated Th17 cells once identified were found in various autoimmune diseases leading to a change in the Th1/Th2 paradigm.
Balance Between Th17 and Treg Cells
When there is dysbiosis along a mucosal lining such as the digestive tract, for example, this will trigger an increase in pathologic Th17 cells and a decrease in Treg cells.5-7 This Th17/Treg cell imbalance leads to barrier disruption or “leaky gut.” For integrative practitioners, the concept of a digestive barrier disruption is well known. Upon discovering the induction of Th17 in other organs, the idea of other leaky mucosal barriers is common. Th17 cells appear to be able to induce “leaky” lungs, sinuses, and blood brain barrier also. All these breaks in immune barriers trigger an inflammatory response in the body that can become systemic.
T regulatory or Treg cells are immunosuppressive in opposition to Th1, Th2, and Th17, which promote an immune response. Multiple mechanisms are involved in Treg cell immunosuppression including inhibitory cytokines, metabolic disruption of T-cells, cytolysis, and regulation of dendritic cells.8 Development of Treg cells requires the transcription factor FOXP3 and the combination of IL-2 and TGFB. The major immunomodulating cytokines Treg cells release are TGFB and IL-10. TGFB is a critical cytokine for maintaining immune tolerance. The mechanism for developing immune tolerance is interfering with differentiation and survival of immune cells.9 With a break in the mucosal barrier from infection or other antigen, Th17 cells are induced with a concomitant decrease in Treg cells resulting in a loss of immune tolerance.
Development of T Helper Cells from CD4 Stem Cells
CD4 stem cells can be induced into any of the T helper subsets.3 Depending on what is triggering the immune system, different cytokines are released to increase the white blood cell response in the body. The cytokines then induce a subset of T helper cells. More than one T helper cell can be formed showing the complexity of our immune system. Transcription factors also influence the development of T helper subsets. Each of the four T helper cells have two specific transcription factors. Genetic mutations in specific transcription factors will decrease the production of the specific Thelper cell subset showing the importance of the role of this component. In a comparable manner to other transcription factors such as NFKB, some transcription factors such as Stat3 can increase inflammation in the body.
Mechanism of Development of Inflammation
Inflammation is a common term used in medicine, but many practitioners would have a difficult time explaining the precise details of the process. Everyone knows that chronic inflammation is damaging, but what is the exact mechanism of damage? It appears that one mechanism of inflammation development is through an ongoing innate immune system reaction. One of the first steps in innate immunity is the recruitment of neutrophils into the tissue. Neutrophils call in monocytes, which become macrophages to combat infection. Neutrophils are key for clearance of multiple pathogens, including Mycoplasma, B. pertussis, Candida, S. aureus, and Citrobacter.10 The macrophages are also supposed to remove old neutrophils from the tissue. If there are too many neutrophils or they are not removed in time, they release ATP and destructive molecules upon apoptosis that cause direct damage to the tissue. This in turn results in another influx of neutrophils causing a cycle for the development of chronic inflammation.
A neutrophil influx can be stimulated in multiple ways. One is the activation of NFKB transcription factor. This activation triggers the release of pro-inflammatory cytokines including IL-1B and TNF-alpha. If the cells in the tissue sense damage to the tissue, they will also release these two cytokines. Once IL-1B and TNF-alpha are released, they cause an influx of neutrophils into the tissue. Th17 cell elevation will also cause an increase in these pro-inflammatory cytokines leading to recruitment of neutrophils into the tissue.11 A prolonged elevation of Th17 will lead to excessive neutrophil recruitment causing inflammation. Activation of the STAT3 transcription factor involved in Th17 cell production can also lead to influx of neutrophils and inflammation.
Developing and Maintaining Autoimmunity
Ideally our immune system would be balanced between the Th subsets. The immune system would respond to threats, promote the T helper cells needed for the antigen and then have a resolution of the reaction. The problem with immune regulation for most patients is that the immune system and, concomitantly, inflammation is not turned off. The result is chronic inflammation and immune system imbalance. If there is elevation of Th17, there is often loss of immune tolerance and low levels of Treg cells. This leads to autoimmunity. In addition, Th17 and Th1 are antagonistic. With an ongoing elevated Th17, there is a decrease in Th1 cells. The Th1 cells are critical in fighting intracellular infections such as viruses. If there is an increase in infections, this will trigger an inflammatory response, which further triggers an increase in Th17, creating a cycle perpetuating autoimmunity. Since there is a balance between Th1 and Th2 cells, a decrease in Th1 results in an increase in Th2 cells resulting in more allergies. Increased Th2 and increased allergies is another source of inflammation continuing the cycle. In order to break this cycle, treatment needs to target lowering Th17 and Th2 while increasing and balancing with increased Treg cells and Th1 cells.
The problem with immune regulation for most patients is that the immune system and, concomitantly, inflammation is not turned off. The result is chronic inflammation and immune system imbalance.
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 graphic).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.
In 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.
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 neurodegeneration. 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
With 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
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
Summary
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.
Dr. 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 Decoded: Unraveling 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.
References for Part 1
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27. Vitales-Noyola M, et al. Pathogenic Th17 and Th22 cells are increased in patients with autoimmune thyroid disorders. Endocrine. 2017 Sep;57(3):409-417.
28. Radetti G, et al. Clinical aspects of Hashimoto’s thyroiditis. Endocr. Dev. 2014;26:158-70.
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35. Wong H, Hoeffer C. Maternal IL-17A in autism. Exp Neurol. 2017;299(Pt A):228–240.
Supporting References for Th17 Elevation Chart
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2. Anderson R. Smoking and air pollution as pro-inflammatory triggers for the development of Rheumatoid Arthritis. Nicotine Tob. Res. 2016 Jul;18(7):1556-65
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4. Basheer S. et al. Immune aberrations in children with Autism Spectrum Disorder: a case-control study from a tertiary care neuropsychiatric hospital in India. Psychoneuroendocrinology. 2018 aug;94:162-167.
5. Bernard NJ. Rheumatoid arthritis: Prevotella copri associated with new-onset untreated RA. Nature Reviews Rheumatology. 2014. 10(2).
6. Beurel E, Lowell JA. Th17 cells in depression. Brain Behav Immun. 2017;69:28–34. doi:10.1016/j.bbi.2017.08.001
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8. Cutforth T, DeMille MM, Agalliu I, Agalliu D. CNS autoimmune disease after Streptococcus pyogenes infections: animal models, cellular mechanisms and genetic factors. Future Neurol. 2016;11(1):63-76.
9. Dileepan T. et al. Group A streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells. J Clin Invest. 2016 Jan 4;126(1):303-317.
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11. Durelli, L, Conti, L, Clerico, M et al. T‐helper 17 cells expand in multiple sclerosis and are inhibited by interferon‐beta. Ann Neurol 2009; 65: 499– 509.
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13. Jadidi-Niaragh F. Et al. Th17 cell, the new player of neuroinflammatory process in multiple sclerosis. Scand J Immunol. 2011 Jul;74(1):1-13.
14. Jing W. et al. Passive smoking induces pediatric asthma by affecting the balance of Treg/Th17 cells. Pediatr Res. 2019 Jan 16th.
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21. Virilli C. et al. Gut microbiota and Hashimoto’s thyroiditis. Rev Endocr. Metab Disord. 2018 Dec. 2018 Dec;19(4):293-300
22. Vitales-Noyola M. et al. Pathogenic Th17 and Th22 cells are increased in patients with autoimmune thyroid disorders. Endocrine. 2017 Sep;57(3):409-417.
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