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From the Townsend Letter
July 2019

New Understanding of Autoimmunity Development Through T Helper Cell Regulation, Part 2
by Debby Hamilton, MD, MPH
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Part one also online

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Introduction
As autoimmune disease continues to rise, we need to learn how to bring the immune system back into balance. In Part 1 of "New Understanding of Autoimmunity Development through T Helper Cell Regulation," I discussed the new understanding of how elevated Th17 cells were involved in autoimmunity. Previously it was thought that elevated Th1 cells created autoimmunity; but with the identification of Th17 cells, researchers now believe Th17 cells appear to be the primary driver.

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When Th17 cells are activated by pathogens or toxins along a mucosal border, they trigger an inflammatory response, leading to the development of autoimmunity. Since they are antagonistic to Th1, the Th1 cells are driven to lower levels, which increases the risk of infections. These infections can then trigger more elevation of Th17, continuing and worsening the autoimmune cycle. With the elevation of Th17, there is a decrease in Treg cells causing a loss of immune tolerance. With the lowering of Th1, there is an increase in Th2 with a concomitant increase in allergies.

DesBioTreatment Goal: Immune Balance
With autoimmune disease, the goal is to return the immune system to balance. This entails decreasing Th17 and Th2 while increasing Th1 and Treg cells. A balanced immune system decreases autoimmune disease and its triggers along with decreasing allergies. In addition, immune tolerance will be restored, and the immune system will be strengthened in its ability to fight infections.
     
Autoimmune disease is a chronic inflammatory disease. Therefore, one of the goals in treating autoimmune disease is to decrease inflammation. Elevated Th17, activation of STAT3 (the transcription factor for Th17), and activation of NFkB all contribute to chronic inflammation. All three of these drive neutrophils into the tissue. Neutrophils are the first line of immune defense and are necessary to mount a needed immune response. Macrophages are called in next, and they are responsible for removing neutrophils from the tissue after they complete their function in fighting infections. If there are too many neutrophils and they are not removed, they self-destruct, causing release of ATP and other damaging molecules that lead to tissue destruction. Chronic inflammation and tissue damage arise from a continual activation of neutrophils.

Transfer Factors
Transfer factors are one tool to help with immune imbalance. They are small proteins with RNA that are made by activated T helper cells. Transfer factors by other mammals appear to be molecularly similar to human transfer factors. Antibodies are like transfer factors in that they are proteins but released by B cells as immune markers instead of by T cells.
     
Transfer factors are part of cell mediated immunity which is considered a Th1 response needed to fight viruses and other intercellular infections.1,2 Research has found efficacy of transfer factors for fighting many of the herpes viruses and HIV.3,4 When a patient has a low Th1, supplementing with transfer factors is a good option to support this system. By increasing Th1, this helps balance and decrease elevated Th17 levels. Transfer factors then help the body fight infections better, without tilting the body towards elevated Th17 response and autoimmunity.
     
The cell mediated immune response starts with an infection that invades the body. A phagocyte engulfs the infected body cell and then forms an antigen on its surface and releases cytokines to notify the Th1 CD4 cells to mount a cell mediated response. These Th1 CD4 cells release transfer factors and Th1 cytokines, which stimulate an increase in new T helper CD4 cells, new cytotoxic T CD8 cells, natural killer cells and macrophages. The transfer factors bind to an antigen on an infected body cell. The CD8 killer T cells target the cell tagged with the transfer factor to destroy it. Natural killer cells are also cytotoxic by releasing proteins called perforin that form holes in the cell membrane where granzymes enter to destroy the virus inside the cell. NK cells are activated in response to interferons or macrophage-derived cytokines. They serve to contain viral infections while the adaptive immune response is generating antigen-specific cytotoxic T cells that can clear the infection.
     
LivOnTransfer factors are derived from leukocytes (dialyzable leukocyte extract: DLE), bovine colostrum, or egg yolk. General transfer factors increase the number of T helper CD4 cells, T cytotoxic CD8 cells, macrophages, and natural killer cells so the immune system is ready to fight infections. Targeted transfer factors can be made in a manner to promote passive immunity. Chickens or cows are infected with attenuated specific antigens. Once the animals produce an immune response, the transfer factors are collected. These targeted transfer factors when used as a supplement give the person passive immunity to that antigen. Research has shown this can be an effective way to support the immune system. Children with cancer and no immunity to varicella were randomized to receive a targeted transfer factor to varicella or placebo.5 After 12 to 30 months, only one out of 16 children developed varicella in the transfer factor group versus 13 out of 15 children in the placebo group developed varicella.5 Research has not repeated studies like this one even though the results were significant for strengthening immunity.

Transfer Factor Multi-ImmuneTM
To learn more about transfer factors' specific effects on the immune system, research was done on a supplement called Transfer Factor Multi-Immune™ (TFMI).6 This product is a multi-ingredient supplement that contains transfer factors, a small amount of colostrum along with immune-supporting mushrooms and herbs, zinc, and selenium. In vitro research was completed to investigate both immune response and immune modulation. Much confusion has existed about whether proline rich peptides are the same as transfer factors, so Transfer Factor Multi-Immune™ was compared to proline-rich peptides (PRP) with the additional immune support the same as the supplement. Colostrum with the herbal blend but no transfer factors was also compared. All were measured against a control.
     
The three products compared for the study:

  1. Transfer Factor Multi-Immune™ (Researched Nutritionals) plus colostrum/herbal blend
  2. Colostrum and Herbal blend portion (excludes transfer factor)
  3. Proline-rich Peptides (in place of transfer factor), colostrum and herbal blend

The study measured immune activation, cytokine response, and cytotoxic response. The research studied three different effects on the immune system:

  1. Immune activation: How the body begins an immune response by activating specific types of white blood cells
  2. Cytokine (inflammatory) response: Measurement of cytokine chemical messenger release from white blood cells
  3. Cytotoxic response: Measurement of cell destruction ability by natural killer cells

The study found a difference between the three supplements for immune activation and immune modulation. With this information, it appears that transfer factors and proline-rich peptides (PRP) are not the same entity, as the transfer factors demonstrated the most powerful response in all immune categories tested. For both natural killer cell activation and T and B cell lymphocyte activation, TFMI had a three- to four-fold improvement over the colostrum and PRP supplements. For an acute immune reaction, a strong immediate cytokine response is needed; TFMI was significantly stronger than the PRP and colostrum blends. Immune modulation is needed to prevent autoimmunity and allergies. This involves keeping a balance between Th17, Treg, Th1, and Th2 cells. TFMI showed a greater immune modulation than the other two products, including an elevation of the anti-inflammatory cytokine IL-10 needed for the development of Treg cells. Overall the research showed the efficacy of transfer factors' supporting a strong immune response along with immune modulation needed to balance the immune system.

Researched Nutritionals WinsNatural Anti-inflammatories
Autoimmune disease is a chronic inflammatory state. Therefore, decreasing inflammation is a critical part of treatment. Inflammation supports the development and the continuation of autoimmune pathology. There are several transcription factors that influence the development of inflammation and can be either pro- or anti-inflammatory. Activation of NFkB and STAT3 both lead to an increase in pro-inflammatory cytokines, inducing Th17. In contrast, activation of the transcription factor Nrf2 leads to an increase in cellular protective responses, including increasing many antioxidants in the body. When researching natural anti-inflammatories, finding herbs and nutrients that impact these pathways has been helpful. Increasing Treg cells to increase immune tolerance is another mechanism to decrease autoimmune disease. Several supplements have been discovered that impact autoimmunity through this mechanism. Below I will discuss some examples of some researched-backed natural compounds that improve immune balance. Other natural anti-inflammatories exist but were excluded due to insufficient research.

Curcumin
Curcumin is one of the active ingredients in turmeric. It is one of the most well known and researched natural anti-inflammatories. By targeting multiple cell signaling molecules, it has many actions in the body. Two of the resulting mechanisms of action from these molecules are active antioxidant and anti-inflammatory effects.7 It has been shown to benefit multiple inflammatory conditions including pain, metabolic syndrome, and chronic kidney disease.7 The primary mechanism of action that has been studied is curcumin's ability to block the activation of NFkB and therefore the release of the pro-inflammatory cytokine TNF-alpha. NFkB is then activated further by TNF-alpha, creating an escalating inflammatory cycle.8
     
For the autoimmune inflammation created by elevated Th17 and low Treg cells, curcumin also appears to play a role. Il-23 is one of the main cytokines that induces the formation of Th17 from naïve T cells. Curcumin plays a role in inhibiting the formation of Th17 by selectively inhibiting the production of Il-12 and Il-23 by dendritic cells.9 The transcription factor STAT3 that is related to the development of Th17 is silenced by curcumin.9 In addition to decreasing Th17 and therefore Il-17, curcumin also has a role in increasing Treg cells.10 Research has shown a modulation of the Th17/Treg balance away from autoimmune conditions such as SLE (lupus).10 Treg cells are the primary producer of the anti-inflammatory cytokine IL-10. Curcumin enhances IL-10, which may be one of its anti-inflammatory mechanisms.11
         
One of the main drawbacks of curcumin clinically is its poor bioavailability. Much of the curcumin is broken down in the intestine before it is absorbed systemically.12 Many companies have created better absorbed forms of curcumin that have been researched and found to achieve better curcuminoids in the blood stream.12,13 What is important when using curcumin is to dose it appropriately for the form being used for inflammation.

Page 1, 2

Part one also online

 

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