Vitamin D, VDRs, Mast Cell Activation and Oxidative Stress
Hello, I am Julie Donaldson and I am a clinical nutritionist with functional health care training. I specialize in restoring balance in complex, chronic and acute health conditions. I welcome you to peruse other articles that may be of interest to you in your health investigation!
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There is powerful information emerging in the research world about vitamin D, VDRs (Vitamin D Receptors) and mast cell activation. With ever-increasing numbers of people facing high histamine and mast cell responses, it is critical to look at how either low vitamin D levels or low VDR function contributes to this vicious cycle. VDR also increases the proteins which regulate tight junctions in the GI tract - making dysbiosis and leaky gut another connection with vitamin D and as we already know, with mast cell activation and degranulation in the gut. The gut is one of the body’s “hollow spaces” - others are the lungs, sinuses, skin and urinary tract - all of which are susceptible to mast cell responses. We are also learning that pathogens in the body interfere with VDR function as well as effective autophagy of damaged mitochondria. As we’ve discussed here previously, autophagy and mitophagy are necessary for mitochondrial health and for the balance of oxidant and antioxidant activity. Here, we get one perpetual loop wherein a body that is inflamed by pathogens and ineffective VDR function also becomes burdened with excessive numbers of damaged mitochondria and ROS (Reactive Oxygen Species), causing oxidative stress. The latter loop back to make successful pathogen eradication and use of vitamin D nearly impossible. This creates chronic illness and inflammation, all of which can also ultimately lead to the development autoimmune disease.
The best vitamin D synthesis comes from sunlight on exposed skin
Is vitamin D really a vitamin?
Vitamin D is actually considered to be a “pro hormone” vs. a vitamin. This is because vitamin D has multiple actions in the body that are considered to be within the realm of endocrinology (glandular function). However, the endocrinology of vitamin D is not applicable in the hollow spaces of the body we are referencing here. Its application is directly linked with innate immune responses, and therefore more in the vitamin realm.
In the article linked above at “mast cell activation”, explanations of the Th1 and Th2 arms of the immune system are discussed. Anytime there is a foreign invader in the body, there are multiple cellular responses that trigger maturation of a naiive T cell into Th1 or Th2 cells. The appropriate response is towards Th1 which helps to attack and eradicate the invading pathogen. However, when D levels are low and/or VDR function is down regulated, inflammation in a hollow space results in Th2 dominance. Th2 dominance does not produce appropriate pathogen-killing and autophagy. On the other hand, it produces a lot of inflammatory cytokine production as well as the vulnerability towards autoimmune responses.
Most especially in the case of gut pathogens and inflammation, D levels are often affected by leaky gut and poor absorption. When vitamin D is taken internally as a supplement vs. synthesized naturally via the skin and sunlight, a person is dependent upon absorption in the gut. So, this is a particularly negative situation for controlling Th2 responses and promoting innate Th1 responses. Vitamin D deficiencies due to lack of sunlight/skin synthesis are on the rise in the U.S. and most other countries. As we hide from the sun due to indoor lifestyles, weather or fears of cancer, we radically alter what humans are designed to do on a daily basis.
As critical in this scenario of a healthy GI tract and vitamin D absorption is its role in calcium absorption in the gut. In order to preserve many chemical reactions dependent upon calcium, as well as bone health, calcium absorption in the gut must be high. It is shown in research that VDR activation to secure tight junctions and aid in calcium absorption is necessary.
How does vitamin D function in hollow space immunity?
We need white blood cells (WBCs) to fight pathogens in the body, inclusive of bacteria and viruses. In order to continue producing WBCs, we need autophagy of aged, damaged cells. In order to have autophagy, we need adequate D and VDRs. Vitamin D is a co-inducer of Interferon gamma, which is needed for successful autophagy. As these things occur, we have multiple Th1 responses which make up healthy innate immunity.
Vitamin D/VDR + interferon gamma = autophagy = white blood cell production = Th1 dominance
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Vitamin D/VDR + interferon gamma = autophagy = white blood cell production = Th1 dominance 〰️
Without this intended successful string, we get Th2 dominance, inclusive of mast cell activation caused by IL-4, a highly inflammatory immune cytokine. The research shows that vitamin D and VDR function contribute to mast cell stabilization. In this research it is shown that mast cells are spontaneously activated in a vitamin D-deficient environment.
GI inflammation and vitamin D
The connection between chronically ill/inflamed conditions, ROS and vitamin D
Another very important connection to make in this scenario is that of ROS in stressed immune conditions with failure to complete autophagy. As we have discussed previously, the proper balance between oxidative and antioxidant levels in the body is critical. Too much oxidative stress and the body carries excess free radicals which are disease-promoting. Too much antioxidant activity and the helpful ROS are knocked out. In order to control the buildup of excess ROS/free radicals, the body needs VDR activation. This activation also limits inflammasome assembly in response to failed autophagy. Are you seeing the loops occurring here?
It is necessary not only to have adequate vitamin D levels, but also VDR function. Pathogens interfere with VDR & thus create a scenario of high ROS burden. It is not possible to take enough vitamin D to correct this problem. One will only create a condition of excess vitamin D in storage and in circulation, something which can cause its own problems. VDR activation and removal of harmful ROS are mutual to one another - without one we don’t have the other.
Histamine and sneezing
The difference between histamine reactions and causes
There are two problems with histamine and mast cell responses. One is immune and the other is detoxification/clearance. First, let’s look at some common symptoms of high histamine and/or mast cell activation (notice how many of these symptoms are occurring within hollow spaces):
Hives
Diarrhea
Wheezing
Sneezing
Headaches
Nausea
Itching
Skin flushing
Mood swings
Joint aches/pains
Any of these symptoms can be associated with either high histamine (failure to clear) or with mast cell activation. What we have been discussing here are the connections between failed immune responses, autophagy and vitamin D/VDRs. However, we have also discussed the interplay of ROS and the need for balance in them to achieve autophagy and VDR performance.
The crossover with detoxification and the failure to clear histamine in the body (which increases with mast cell responses) is that toxins also contribute to imbalances in ROS. Additionally, a person with mutations in methylation genes (as well as epigenetic stresses which complicate them) will suffer from poor clearance of histamine. This requires approaches unique to the individual and separate from vitamin D/VDR up-regulation. In these cases, we must assess a combination of markers in the blood and consider the use of a variety of cofactors known to support methylation and stimulate histamine clearance. These may include B vitamins, zinc, magnesium, selenium, phosphatidyl choline, SAMe and DAO among others.
The connection of vitamin D with autoimmune conditions
While this is a huge topic in and of itself, it is important to include a brief discussion on this topic here. There are multiple associations of low vitamin D with autoimmune disease, including lupus, MS, diabetes, inflammatory bowel disease (IBD), rheumatoid arthritis and psoriasis. It is also associated with uterine fibroids.
Remember our conversation about the innate immune system, Th1 and Th2 balances. When this balance goes out towards Th2 dominance, Th17 and 23 cells begin to stem from Th2 cells. These particular T cells cause autoimmune responses in the body, attacking self-tissue. The lower the D, the worse the disease expression. As D levels and VDR activation rise, Th17 is down regulated, pushing T cells towards the regulatory Th1 dominance. This is what reduces flares. In this process, lymphatic memory cells will “clone out” when an antigen is presented, allowing health to continue vs. a flare-up to be incited.
The standard/conventional recommended level of 30 pg/mL of vitamin D in the blood is insufficient to create remission and reduction of flares. The research indicates a bare minimum of 50 pg/mL is required, with the functional health range preferring 60-65 pg/mL.
In the case of IBD, adequate vitamin D plus lactoferrin supplementation are essential pieces of a comprehensive plan for healing.
Other issues described earlier in the article involving VDRs, autophagy, pathogen burdens and oxidative stress all apply in this scenario as well.
Summations and solutions
Vitamin D is a key player in human innate immunity. In this realm, it helps keep the healthy balance tipped in favor of the Th1 arm of the system. It steers the body away from potentially inflammatory responses of the adaptive immune system when stimulated excessively.
We must consider both the levels of vitamin D (including both forms, active & stored) as well as VDR activation. One without the other is unsuccessful.
Autophagy is supported by vitamin D and VDR function. Its completion is necessary to reduce ROS and to allow a cascade of effective immune responses to occur in response to pathogens in the body.
Vitamin D and VDR function are involved in mast cell stabilization. Without adequate support, mast cells in hollow spaces will degranulate, releasing histamine and causing multiple negative symptoms in the body.
VDRs regulate the intestinal barrier functions, helping to produce tight junction proteins which create a solid barrier. Leaky gut caused by destructed tight junctions adds to pathogen vulnerability and stressed immunity. Pathogens interfere with VDR function…it is not possible to take enough vitamin D to alter this interference - the pathogens must be identified and eradicated successfully with steps taken to rebalance the Th1 and Th2 arms of the immune system.
Sunlight is the best way to synthesize vitamin D in the body. In addition and/or when sunlight is not accessible, adequate intake of vitamin D with K is required. Blood testing of both forms of vitamin D (25-hydroxy and 1,25-OH) are needed in order to evaluate both stored and active levels of D. Note that there is no “ideal” amount of vitamin D to supplement…this is individual and based upon the pattern represented in your storage and activation into the bloodstream. There can be a variety of causative factors in “low” vitamin D.
Butyrate is a VDR promoter, and antioxidant therapy is a huge supporter of the ROS/autophagy needs related to VDR function. (Please reference the linked article for information and cautions on antioxidant use.)
Spore biotics encourage the colonization of healthy bacteria in the gut that help lift interferon gamma, an important player in VDR activation.
Maintaining all of these critical balances is essential for the prevention of autoimmune disease.
Please contact me at Julie@truenaturehealthconsulting.com for individualized testing and nutritional support. All systems in the human body are best supported with personalized nutrition.