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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.
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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.
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