Immunologic Effects of Vitamin D on Human Health and Disease

Abstract

Vitamin D is responsible for regulation of calcium and phosphate metabolism and maintaining a healthy mineralized skeleton. It is also known as an immunomodulatory hormone. Experimental studies have shown that 1,25-dihydroxyvitamin D, the active form of vitamin D, exerts immunologic activities on multiple components of the innate and adaptive immune system as well as endothelial membrane stability. Association between low levels of serum 25-hydroxyvitamin D and increased risk of developing several immune-related diseases and disorders, including psoriasis, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, tuberculosis, sepsis, respiratory infection, and COVID-19, has been observed. Accordingly, a number of clinical trials aiming to determine the efficacy of administration of vitamin D and its metabolites for treatment of these diseases have been conducted with variable outcomes. Interestingly, recent evidence suggests that some individuals might benefit from vitamin D more or less than others as high inter-individual difference in broad gene expression in human peripheral blood mononuclear cells in response to vitamin D supplementation has been observed. Although it is still debatable what level of serum 25-hydroxyvitamin D is optimal, it is advisable to increase vitamin D intake and have sensible sunlight exposure to maintain serum 25-hydroxyvitamin D at least 30 ng/mL (75 nmol/L), and preferably at 40-60 ng/mL (100-150 nmol/L) to achieve the optimal overall health benefits of vitamin D.

Keywords: 1,25-dihydroxyvitamin D; 25-hydroxyvitamin D; autoimmune disorders; endothelial membrane stability; immune function; immunomodulation; infectious diseases; inflammation; lymphocytes; macrophages; monocytes; multiple sclerosis; type 1 diabetes; vitamin D.

Figure 1

Summary of causes of vitamin D deficiency and diseases and disorders associated with vitamin D deficiency. Abbreviations: HARRT: highly active antiretroviral therapy; IBD: inflammatory bowel diseases; MS: multiple sclerosis; PsA: psoriatic arthritis; T1DM: type 1 diabetes mellitus; T2DM: type 2 diabetes mellitus; RA: rheumatoid arthritis. Reproduced with permission from Holick MF, copyright 2020. ‘*’ denotes diseases that are direct consequences of vitamin D deficiency.

Figure 2

Schematic representation of paracrine and intracrine function of vitamin D and its metabolites and actions of 1,25-dihydroxyvitamin D on the innate and adaptive immune systems. Abbreviation: 1,25(OH)₂D: 1,25-dihydroxyvitamin D; 25(OH)D: 25-hydroxyvitamin D, IFN-Ƴ: interferon- Ƴ; IL: interleukin; MHC: membrane histocompatibility complex, T_H1: T helper 1; T_H2: T helper 2; T_H17: T helper 17; Treg: regulatory T cell, TNF-α: Tumor necrosis factor- α; TLR2: toll-like receptor 2; TLR4: toll-like receptor 4. Reproduced with permission from Holick MF, copyright 2020.

Figure 3

Biochemical measurements of a 52-year-old multiple sclerosis female who received 40,000 international units per day of vitamin D3 for 5 years. Abbreviation: 1,25(OH)2D: 1,25-dihydroxyvitamin D; 25(OH)D: 25-hydroxyvitamin D; PTH: parathyroid hormone. Note: Red solid line represents serum 25-hydroxyvitamin D levels. Blue solid line represents serum total calcium levels. Green solid line represents serum 1,25-dihydroxyvitamin D levels (15–80 pg/mL). Black dotted line represents serum intact parathyroid hormone levels (18–72 pg/mL). Red highlight represents normal range for serum 25-hydroxytamin D (30–100 ng/mL/75–250 nmol/L). Green highlight represents normal range for serum 1,25-dihydroxyvitamin D (15–80 pg/mL). Blue dashed line represents normal range for serum total calcium (8.5–10.5 mg/dL). Black dashed line represents normal range for serum intact parathyroid hormone (18–72 pg/mL). Reproduced with permission from Holick MF, copyright 2020.

Figure 4

Biochemical measurements of a 32-year-old multiple sclerosis male who received 54,000 international units per day of vitamin D₃ for 4 months. Abbreviation: 1,25(OH)₂D: 1,25-dihydroxyvitamin D; 25(OH)D: 25-hydroxyvitamin D; PTH: parathyroid hormone. Note: Red solid line represents serum 25-hydroxyvitamin D levels. Blue solid line represents serum total calcium levels. Red highlight represents normal range for serum 25-hydroxytamin D (30–100 ng/mL/75–250 nmol/L). Blue dashed line represents normal range for serum total calcium (8.5–10.5 mg/dL). Normal range for serum intact parathyroid hormone is 10–72 pg/mL. Normal range for serum 1,25-dihydroxyvitamin D is 15–80 pg/mL. Reproduced with permission from Holick MF, copyright 2020.

Figure 5

Heatmaps of vitamin D responsive genes whose expression response variation in 6 vitamin D-deficient subjects taking 10,000 international units per day of vitamin D₃ for 6 months showing that 3 subjects had a robust response in gene expression compared to the other 3 subjects who had minimum to modest responses even though these subjects raised their blood levels of 25(OH)D in the same range of ~60–90 ng/mL (150–225 nmol/L). Abbreviation: 0m: 0 month; 6m: 6 months; 25(OH)D: 25-hydroxyvitamin D; PTH: parathyroid hormone. Reproduced with permission from Holick MF, copyright 2019.