Researchers recently discovered a major facet of vitamin D. It is its modulating action on the immune system. However, its contribution to health is not new. The cold season was once associated with the spoonful of cod liver oil. A very tasty remedy! It was long before the use of antibiotics that this vitamin D-rich preventive potion against winter infections was circulating in our families, but also in the sanatoriums of the time to treat tuberculosis and drug use.

Vitamin D deficiency

Over the past decades, several studies have shown that vitamin D deficiency is a risk factor for various diseases, including osteoporosis and seasonal depression. Since then, epidemiological studies have shown strong associations between seasonal variations in vitamin D levels and the incidence of various infectious diseases, including respiratory infections and influenza. Indeed, in people with documented vitamin D deficiency, the immune response is believed to be weakened or abnormal, making them automatically more likely to fall victim to seasonal outbreaks and to develop an increased degree of severe respiratory symptoms.

Quick overview of the immune system

The main role of the immune system is to maintain the integrity of the body. It works to eliminate substances perceived as foreign, also called “antigens” (microorganisms, abnormal cells, debris) while ensuring the tolerance of the different structures that belong to us.

The immune system is made up of two types of defenses: innate and adaptive. Representing the first line of defense against antigens, innate immunity is made up of natural barriers (skin, mucous membranes and microbiota, tissue secretions such as saliva, sweat, sebum, hydrochloric acid from the stomach), inflammatory mechanisms (fevers , cytokines), production of antimicrobial substances and cleaning functions (phagocytosis). This response remains the same regardless of what type of antigen is left outside the body’s cells. Whereas adaptive immunity acts in the background. It is when the antigen enters cells that adaptive immunity will give a specific response to that antigen by creating antibodies (special proteins that neutralize antigens). Once the antibody is created, it stays in our body’s memory. This is called immunization. This is the basic principle aimed at by vaccinations.

Roles and characteristics of vitamin D

Vitamin D can be inactive or active (also called calcitriol). Recently, we discovered that the kidneys are not the only activating organs, but that immune cells are also important players. Directly at the site of infection, these cells are said to enhance their actions by changing vitamin D precursors to their biologically active form. When activated, calcitriol binds to its receptor (also found in these same immune cells) and triggers a cascade of events stemming from both innate and adaptive immunity, including increased antimicrobial secretions, the production of antiviral proteins, the activation of eliminator cells, the creation and release of antibodies, the modulation of the inflammatory response (neither too much nor less) and the repair of damaged tissues. These actions show us the importance of vitamin D for providing energetic immune defense.

Here are some useful functions related to vitamin D:

  • Reduction of pulmonary permeability to invaders;
  • Downward modulation of harmful inflammatory factors could cause narrowing of the bronchioles;
  • Muscle strengthening (including the intercostal muscles used during respiratory infections);
  • Improvement of the maximum volume of exhaled air (lung capacity);
  • Induction of the death of infected cells (apoptosis);
  • Synthesis of free radicals aimed towards destabilizing the intruder.

In the presence of a virus

During a viral infection, it is not the pathogen that determines the clinical severity or risk of mortality associated with diseases (e.g., influenza, Covid-19), but the exuberance of the immune response of the organism. SARS-CoV-2 produces a strong dysfunction of the immune system which creates an intense inflammatory response and the development of a potentially fatal condition; CRS (cytokine release syndrome). Deregulation of protective responses of the immune system as well as induction of ineffective activities in different types of immune cells can lead to acute respiratory distress syndrome (ARDS), mainly in the elderly.

An optimal level of vitamin D allows a marked improvement of the defense mechanisms, the reduction of the severity of the infection, the reduction of the convalescence and the promotion of the quality of life. These benefits then lead several researchers to consider the use of vitamin D as a strategic adjuvant to other therapies currently used. During the first wave of COVID-19, an inverse correlation between blood levels of vitamin D and the severity of the disease was found to be significant in more than 20 countries.

Epidemiological data shows that, compared to younger or healthier people, older or chronically ill people have a higher risk of death after being infected with SARS-CoV-2. In fact, these people present with a chronic weakening of the immune response induced by qualitative/quantitative dysfunctions of the various stakeholders resulting from both innate immunity and adaptive immunity. This results in an imbalance in favor of pro-inflammatory cytokines (IL-1α, IL-2, IL-6, IL-8, IL-12, IFN-γ) compared to anti-inflammatory drugs (IL-1 Ra, IL-4, IL-10, TGF-β), which constantly weakens their immune condition. This phenomenon is amplified on contact with SARS-CoV2 and can lead to a cytokine storm. The latter takes place both in the blood and in the lungs of infected people. The cytokine storm is the most severe form of the cytokine release syndrome mentioned above. The stronger the storm, the more alarming the disease as well as the lung damage.

Therefore, the regulation of the exaggerated inflammatory response observed during SARS-CoV-2 infection represents a key element in the strategy to counter the virus and prevent its potentially fatal effects. However, a vitamin D deficiency is associated with higher levels of pro-inflammatory cytokines, suggesting that an adequate status of this vitamin could help to limit their synthesis and therefore lessen the seriousness of the viral infection. Vitamin D also has a repairing action on the pulmonary alveolar tissues (with the contribution of vitamin A). Since about 20% of people with COVID-19 develop interstitial pneumonia with severe lesions, adding vitamin D to the conventional therapeutic arsenal appears to be beneficial to date.

The last few years have brought about a radical change in our perspective on how vitamin D influences health. The impact of vitamin D deficiency on the immune system (innate and adaptive) has become clearer. In such a situation, there appears to be an increased susceptibility to infections and a predisposition to toxic inflammatory outbreak. Several studies support the hypothesis that vitamin D sufficiency contributes to immunoregulatory functions and a balanced immune response, particularly in the context of respiratory infection of viral origin. In these times of pandemic, the state of current knowledge about vitamin D leads us to believe that its blood status is one of the factors that influence our fighting spirit against the disease.

 

 

References:

  • Adrian R Martineau,  David A Jolliffe,  Richard L Hooper et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017; 356: i6583. Published online 2017 Feb 15. doi: 1136/bmj.i6583
  • Alessandro Cuomo, Nicola Giordano et al. Depression and Vitamin D Deficiency: Causality, Assessment, and Clinical Practice Implications. Review Article – Neuropsychiatry (2017) Volume 7, Issue 5
  • Alexandra V. Yamshchikov, MD, Nirali S. Desai, MD et al. Vitamine D for treatment and prevention of infectious diseases: a systemic review of randomized controlled trials. Endocr Pract. 2009 Jul–Aug; 15(5): 438–449.doi: 4158/EP09101.ORR
  • Almerighi C, et al. 1Alpha,25-dihydroxyvitamin D3 inhibits CD40L-induced pro-inflammatory and immunomodulatory activity in human monocytes. Cytokine. 2009;45(3):190–7
  • Cannell JJ, Vieth R, Umhau JC, et al. Epidemic influenza and vitamin D. Epidemiol Infect. 2006;134:1129–1140
  • Cannell JJ, Vieth R, Willett W, Zasloff M, Hathcock JN, White JH, Tanumihardjo SA, Larson-Meyer DE, Bischoff-Ferrari HA, Lamberg-Allardt CJ, Lappe JM, Norman AW, Zittermann A, Whiting SJ, Grant WB, Hollis BW, Giovannucci E. Cod liver oil, vitamin A toxicity, frequent respiratory infections, and the vitamin D deficiency epidemic. Ann Otol Rhinol Laryngol 2008; 117: 864-870
  • Chan JF, Kok KH, Zhu Z, et al. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microbes Infect. 2020;9:221–236. doi: 10.1080/22221751.2020.1719902
  • Cheung CY, Poon LL, Lau AS, et al. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet. 2002;360:1831–1837
  • Christina T. Fiske, Amondrea Blackman et al. Increased vitamin D receptor expression from macrophages after stimulation with  tuberculosisamong persons who have recovered from extrapulmonary tuberculosis. BMC Infect Dis. 2019; 19: 366. Published online 2019 Apr 30. doi: 10.1186/s12879-019-3958-7
  • Cynthia Aranow, MD. Vitamin D and the Immune System. J Investig Med. 2011 Aug; 59(6): 881–886. doi: 231/JIM.0b013e31821b8755
  • D A Hughes and R Norton. Vitamin D and respiratory health. Clin Exp Immunol. 2009 Oct; 158(1): 20–25. doi: 1111/j.1365-2249.2009.04001.x
  • D’Ambrosio D, Cippitelli M, Cocciolo MG, et al. Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. J Clin Invest. 1998;101:252–262. doi: 10.1172/JCI1050
  • Dancer RC, Parekh D, Lax S, et al. Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS) 2015;70:617–624. doi: 10.1136/thoraxjnl-2014-206680
  • DeDiego ML, Nieto-Torres JL, Jimenez-Guardeno JM, et al. Coronavirus virulence genes with main focus on SARS-CoV envelope gene. Virus Res. 2014;194:124–137. doi: 10.1016/j.virusres.2014.07.024
  • Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. William B Grant, Henry Lahore et al. Nutrient. 2020 Apr 2;12(4):988
  • Exploring the Links Between Coronavirus and Vitamin D. Anahad O’Connor. New York times, june 10, 2020
  • Grant WB. Variations in vitamin D production could possibly explain the seasonality of childhood respiratory infections in Hawaii. Pediatr Infect Dis J. 2008;27:853
  • Ginde AA, Mansbach JM, Camargo CA. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med 2009; 169: 384-390. 32
  • Harant H, Andrew PJ, Reddy GS, Foglar E, Lindley IJ. 1alpha,25-dihydroxyvitamin D3 and a variety of its natural metabolites transcriptionally repress nuclear-factor-kappaB-mediated interleukin-8 gene expression. Eur J Biochem. 1997;250:63–71. doi: 10.1111/j.1432-1033.1997.00063.x
  • Harant H, Wolff B, Lindley IJ. 1Alpha,25-dihydroxyvitamin D3 decreases DNA binding of nuclear factor-kappaB in human fibroblasts. FEBS Lett. 1998;436:329–334. doi: 10.1016/s0014-5793(98)01153-3
  • Hewison M, Freeman L, Hughes SV, Evans KN, Bland R, Eliopoulos AG, Kilby MD, Moss PA, Chakraverty R. Differential regulation of vitamin D receptor and its ligand in human monocyte-derived dendritic cells. J Immunol 2003; 170: 5382-5390
  • Hewison M. Antibacterial effects of vitamin D. Nat Rev Endocrinol2011;7:337-45. 10.1038/nrendo.2010.226
  • Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008;87:1080S–6S
  • Hsueh PR, Chen PJ, Hsiao CH, et al. Medicine SRGoNTUCo, National Taiwan University H Patient data, early SARS epidemic Taiwan. Emerg Infect Dis. 2004;10:489–493. doi: 10.3201/eid1003.030571
  • Khazim K, Azulay EE, Kristal B, Cohen I. Interleukin 1 gene polymorphism and susceptibility to disease. Immunol Rev. 2018;281:40–56. doi: 10.1111/imr.12620
  • Kobasa D, Takada A, Shinya K, et al. Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus. Nature. 2004;431:703–707
  • Laaksi I, Ruohola JP, Tuohimaa P, Auvinen A, Haataja R, Pihlajamäki H, Ylikomi T. An association of serum vitamin D concentrations < 40 nmol/L with acute respiratory tract infection in young Finnish men. Am J Clin Nutr 2007; 86: 714-717. 31
  • Martineau AR, Honecker FU, Wilkinson RJ, Griffiths CJ. Vitamin D in the treatment of pulmonary tuberculosis. J Steroid Biochem Mol Biol. 2007;103:793–798
  • Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, Esposito S, Ganmaa D, Ginde AA, Goodall EC, Grant CC, Griffiths CJ, Janssens W, Laaksi I, Manaseki-Holland S, Mauger D, Murdoch DR, Neale R, Rees JR, Simpson S Jr, Stelmach I, Kumar GT, Urashima M, Camargo CA Jr. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017; 356: i6583
  • More evidence on vitamin D deficiency and death rates from COVID-19. Sally Robertson, B.Sc.Jul 2 2020, News Medical Life Science, July 2, 2020
  • Paul Lips, Natasja M.van Schoor. The effect of vitamin D on bone and osteoporosis. Best Practice & Research Clinical Endocrinology & Metabolism, Volume 25, Issue 4, August 2011, Pages 585-591
  • Pfeifer M, Begerow B, Minne HW. Vitamin D and muscle function. Osteoporos Int. 2002;13:187–94. Et Hopkinson NS, Li KW, Kehoe A, et al. Vitamin D receptor genotypes influence quadriceps strength in chronic obstructive pulmonary disease. Am J Clin Nutr. 2008;87:385–90
  • Remmelts HH, van de Garde EM, Meijvis SC, et al. Addition of vitamin D status to prognostic scores improves the prediction of outcome in community-acquired pneumonia. Clin Infect Dis. 2012;55:1488–1494. doi: 10.1093/cid/cis751
  • Schwalfenberg, G.K. A review of the critical role of vitamin D in the functioning of the immune system and the clinical implications of vitamin D deficiency. Mol. Nutr. Food Res. 2011, 55, 96–108
  • Shen F, Hu Z, Goswami J, Gaffen SL. Identification of common transcriptional regulatory elements in interleukin-17 target genes. J Biol Chem. 2006;281:24138–24148. doi: 10.1074/jbc.M604597200
  • Sigmundsdottir H, Pan J, Debes GF, Alt C, Habtezion A, Soler D, Butcher EC. DCs metabolize sunlight-induced vitamin D3 to ‘program’ T cell attraction to the epidermal chemokine CCL27. Nat Immunol 2007; 8: 285-293. 25
  • Sirio Fiorino, Claudio Gallo, Maddalena Zippi et al. Cytokine storm in aged people with CoV-2: possible role of vitamins as therapy or preventive strategy. Aging Clin Exp Res. 2020 Aug 31 : 1–17. doi: 1007/s40520-020-01669-y
  • Venu Lagishetty, Nancy Q. Liu, and Martin Hewison Vitamin D metabolism and innate immunity. Mol Cell Endocrinol. 2011 Dec 5; 347(1-2): 97–105. Published online 2011 Jun 1. doi: 1016/j.mce.2011.04.015
  • Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. Adrian R Martineau,  David A Jolliffe,  Richard L Hooper et al. BMJ. 2017; 356: i6583. Published online 2017 Feb 15
  • Vitlic A, Lord JM, Phillips AC. Stress, ageing and their influence on functional, cellular and molecular aspects of the immune system. Age (Dordr) 2014;36:9631. doi: 10.1007/s11357-014-9631-6
  • Williams C. On the use and administration of cod-liver oil in pulmonary consumption. London Journal of Medicine. 1849;1:1–18
  • Zhu N, Zhang D, Wang W, et al. China Novel Coronavirus I, Research T (2020) a novel coronavirus from patients with pneumonia in China. N Engl J Med. 2019;382:727–733. doi: 10.1056/NEJMoa2001017