Vitamin D Resistance and Autoimmunity

Is vitamin D resistance a cause of autoimmune diseases? A group of German researchers, led by Dirk Lemke, argue that it is and that high-dose vitamin D3 therapy is an effective treatment. They have used a high-dose vitamin D protocol, developed by Prof. Dr. Cicero Coimbra in Sao Paolo, Brazil and available in Germany since 2016, to successfully treat multiple sclerosis patients. “Underlying the Coimbra protocol is the hypothesis of a non-hereditary, but acquired form of vitamin D resistance…,” which the researchers discuss in their 2021 article for Frontiers in Immunology. The concept of vitamin D resistance first arose in 1937 when Fuller Albright, MD, and colleagues wrote that, in rare cases, some children required very high doses to resolve rickets. Later, it was shown that this resistance was often caused by hereditary vitamin D receptor (VDR) defects, which also produced hypocalcemia, secondary hyperparathyroidism, and alopecia (in about half of the patients). Unlike hereditary resistance that is identified in childhood, acquired vitamin D resistance “could develop during aging based on an interaction between genetic susceptibility polymorphisms of the vitamin D system and an accumulation of environmental factors…,” say Lemke, et al.

The authors discuss factors that can contribute to acquired vitamin D resistance. The first is inhibited VDR expression. The vitamin D receptor binds to calcitriol, the most active form of vitamin D; this molecular complex then enters the cell nucleus where it activates or inhibits gene expression. VDR is found in early all cells, including most immune cells. Among its many effects, the VDR-calcitriol complex is known to inhibit B and T helper lymphocyte proliferation, thereby regulating antibody production and inflammatory cytokines—which are factors in autoimmune disease. Lemke and colleagues say, “…work of Booth et al who studied polymorphisms within the context of VDR binding to genes in human monocytes and dendritic cells, suggests that certain polymorphisms predispose to autoimmune diseases by perturbing VDR binding at autoimmune disease risk gene variants. In other words, SNPs of the VDR may predispose to acquired vitamin D resistance….”

So, what environmental factors could heighten the risk of autoimmune disease in genetically susceptible people? Elevated glucocorticoids (cortisol, cortisone) for long periods due to chronic stress or long-term cortisone treatment is one factor. When the body experiences stress and produces glucocorticoids, it shifts energy to the motor system (for fight or flight) and away from immune function. Pathogens are another factor. Lipopolysaccharides, sepsis-inducing bacterial toxins, inhibit VDR expression in THP-1 human monocytes. Live Borrelia burgdorferi caused a 60-fold downregulation of the VDR. Epstein-Barr virus also inhibits VDR mRNA and protein expression. Both chronic stress and infections have been correlated to autoimmune activity. In addition, environmental toxins, such as aluminum, can inhibit enzymes that convert the storage form of vitamin D into the active form that binds to VDR.

Lemke and colleagues use the parathyroid hormone (PTH) as a biomarker for acquired vitamin D resistance: “If 25(OH)D3 levels are high, PTH should be low and vice versa.” This inverse relationship tends to be “disturbed” in people with autoimmune disease. They suggest that the optimal 25(OH)D3 level of >40 ng/ml should accompany “a PTH value in the middle of the lower third of its laboratory-specific reference range”—since laboratory measures for PTH vary. The authors say, “…high PTH values are indicative for vitamin D resistance, assuming that dietary calcium and phosphate intake are adequate and a differential diagnosis of hyperparathyroidism has been ruled out.”

Vitamin D3 therapy under the Coimbra protocol for autoimmune disease treatment uses very high doses: 1000 IU/kg body weight for people with multiple sclerosis; 300-500 IU/kg body weight for people with rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, psoriasis, Crohn’s disease, and ulcerative colitis; 300 IU/kg body weight for systemic scleroderma, ankylosing spondylitis, and Hashimoto’s thyroiditis; and 150 IU/kg body weight for other autoimmune conditions. “Doses are successively adapted (almost always lowered) during follow-up according to a standardized procedure, which considers parathyroid hormone and calcium concentrations as well as the clinical condition of the patient,” Lemke and colleagues explain. Patients need to avoid milk products and drink at least 2.5 liters of fluid each day. The German authors have treated 41 patients with multiple sclerosis, who have reported significant improvement in their symptoms.

This protocol needs to be monitored by certified Coimbra practitioners to ensure that neither hypercalcemia nor kidney damage occur.

Lemke D, et al. Vitamin D Resistance as a possible Cause of Autoimmune Diseases: A Hypothesis Confirmed by a Therapeutic High-Dose Vitamin D Protocol. Frontiers in Immunology. April 2021;12:655739.

The Wim Hof Method for Decreasing Inflammation

At age 17, early one icy winter morning, Wim Hof jumped into a body of cold water at a local park in The Netherlands. He stayed in the water for just a minute or two, but the “connection within” that he experienced “felt great.” In his book The Wim Hof Method – Activate Your Full Human Potential (Sounds True, 2020), he writes:

The body’s default mode is survival. It does what it needs to do to keep its vital organs functioning, and that’s precisely what it does when it is confronted by an environmental stressor like the cold. The cold is a teacher. It’s merciless. You don’t picnic when you go into the cold. You don’t think about your mortgage or your kid’s braces or your divorce; you just survive. You reactivate the deepest part of your brain.

In repeating the process, Hof became aware of his body’s habit of gasping—taking in a deep breath. Following his body’s lead, he took 25 deep breaths: “…it made my body tingle like crazy, like electricity….It was an amazing feeling, and over time, a routine gradually took shape. It was organic and progressive, and this physical experience of the cold and following my gut led me to a true personal discovery of my own consciousness, my own mind-body connection.” Cold water exposure (immersion or in a shower), deep breathing (30 deep breaths followed by breath retention), and a positive, committed mindset are the core of the Wim Hof method. Over the years, Hof has astounded the public and researchers alike as he broke world records for cold exposure. But more importantly, the physiological effects of his method, which include voluntary activation of the sympathetic nervous system, have expanded our understanding of the mind-body connection and offered new ways to address inflammation, pain, depression, and perhaps even aging.

Hof’s abilities are not unique to him. In 2013, Matthijs Kox and colleagues conducted a small randomized controlled trial. Healthy male volunteers (age 19-27) were taught the Hof method during a four-day intensive training involving cold exposure, breathing techniques, and third eye meditation. After practicing their own for another five to nine days, they underwent experimental endotoxemia (IV administration of 2 ng/kg Escherichia coli endotoxin) to incite inflammation and immune response (n=12). An untrained group (n=12) acted as the control. Despite less than two weeks of practice, the intervention group “exhibited profound increases in the release of epinephrine, which in turn led to increased production of anti-inflammatory mediators and subsequent dampening of the proinflammatory cytokine response elicited by intravenous administration of bacterial endotoxin.” In response to the endotoxin, the trained group had fewer flu-like symptoms, higher anti-inflammatory IL-10 levels, and lower pro-inflammatory TNF-α, IL-6, and IL-8 levels than the control group. A 2015 follow-up study found that a more optimistic outlook correlated to higher plasma epinephrine levels (Rho=0.76, p<.01) and IL-10 levels (Rho=0.60, p<.05), and having a greater expectation of the training’s benefit correlated to fewer flu-like systems (Rho=-0.71, p<.01): “The findings suggest a possible role of especially optimism as a predictor of the autonomic and immune response to inflammatory stress after a brief training program. If replicated, these findings may be used for predicting training responses and potentiate their effects by means of optimism-inducing interventions….”

Five years later, the Dutch researchers published a study on the participants’ plasma metabolome. They identified 224 metabolites in plasma that had been obtained from both the control group and the training group at six timepoints; 98 metabolites “were significantly altered following [endotoxin] administration.” At baseline, the trained subjects had higher lactate and pyruvate levels than the control group. These higher levels corresponded to higher IL-10 levels that occurred after endotoxin exposure. “In vitro validation experiments revealed that co-incubation with lactate and pyruvate enhances IL-10 production and attenuates the release of pro-inflammatory IL-1βand IL-6 by LPS-stimulated leukocytes.”

The Hof method reduces inflammation in young, healthy males but what about people with inflammatory disease? A 2019 randomized proof-of-concept trial enrolled 24 patients (18-55 years old) with “moderately active” axial spondyloarthritis (ASDAS >2.1 and hs-CRP ≥5 mg/L). This condition is characterized by chronic rheumatic inflammation of the spine and involves altered innate immune responses. It mainly affects young adults with few comorbidities. Only 60-70% of these patients respond to current treatment, and 30% of respondents show only a partial response.

The participants in this study were divided into an early intervention that started training at baseline and continued until week 8 and a late intervention group. The late intervention group received no training for eight weeks (acting as a control) before receiving training. Study visits were done at baseline, week 4 and week 8; and a final follow-up occurred sixteen weeks after the intervention period. The Hof training was an add-on, not a replacement for medication therapy that was stable for at least 6 weeks before screening and throughout the study. In addition to the Hof method, participants took part in strength and yoga balance exercises.

Safety assessment was the primary objective of this study. The authors reported no serious adverse events during the intervention period. The common cold, the most frequent adverse event, occurred in four participants during the intervention and two during the control period.

After eight weeks of training, the participants showed a significant decrease in erythrocyte sedimentation rate (ESR; p=0.04), indicating less inflammatory activity, and a decline in ASDAS-CRP (p=0.044), indicating a decline in disease activity. This study simply aimed to assess the method’s safety in people with this condition; the authors would like to see more research with larger sample size to evaluate it clinical efficacy.

The Wim Hof Method explains the basics of the method and contains exercises to regulate pain and to decrease heart rate during times of stress; information is also available at https://www.wimhofmethod.com/. People who follow the method report improved physical and mental health. For Hof, this method is not just a way to strengthen the body and improve health, it is a way to “harness the consciousness and to direct it back toward the light and rediscover the soul.” Wim Hof does not recommend his program for people with epilepsy, high blood pressure, coronary heart disease, or those with a history of serious health issues like heart failure or stroke. Also, migraine sufferers need to be cautious about taking ice baths. He urges participants, “Listen to your body and never force the practices.”

Buijze GA, et al. An add-on training program involving breathing exercises, cold exposure, and meditation attenuates inflammation and disease activity in axial spondyloarthritis – A proof of concept trial. PLOS ONE. December 2, 2019.

Kox M, et al. Voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans. PNAS. May 20, 2014.

Van Middendorp H, et al. The role of outcome expectancies for a training program consisting of meditation, breathing exercises, and cold exposure on the response to endotoxin administration: a proof-of-principle study. Clin Rheumatol. 2016;35:1081-1085.

Zwaag J, et al. Involvement of Lactate and Pyruvate in the Anti-Inflammatory Effects Exerted by Voluntary Activation of the Sympathetic Nervous System. Metabolites. 2020;10:148.