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Sîrbe, C.;  Rednic, S.;  Grama, A.;  Pop, T.L. Effects of Vitamin D on the Immune System. Encyclopedia. Available online: https://encyclopedia.pub/entry/27067 (accessed on 08 July 2025).
Sîrbe C,  Rednic S,  Grama A,  Pop TL. Effects of Vitamin D on the Immune System. Encyclopedia. Available at: https://encyclopedia.pub/entry/27067. Accessed July 08, 2025.
Sîrbe, Claudia, Simona Rednic, Alina Grama, Tudor Lucian Pop. "Effects of Vitamin D on the Immune System" Encyclopedia, https://encyclopedia.pub/entry/27067 (accessed July 08, 2025).
Sîrbe, C.,  Rednic, S.,  Grama, A., & Pop, T.L. (2022, September 09). Effects of Vitamin D on the Immune System. In Encyclopedia. https://encyclopedia.pub/entry/27067
Sîrbe, Claudia, et al. "Effects of Vitamin D on the Immune System." Encyclopedia. Web. 09 September, 2022.
Effects of Vitamin D on the Immune System
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This entry is adapted from the peer-reviewed paper 10.3390/ijms23179784

Vitamin D intervenes in calcium and phosphate metabolism and bone homeostasis. Experimental studies have shown that 1,25-dihydroxyvitamin D (calcitriol) generates immunologic activities on the innate and adaptive immune system and endothelial membrane stability. Low levels of serum 25-hydroxyvitamin D (25(OH)D) are associated with an increased risk of developing immune-related diseases such as psoriasis, type 1 diabetes, multiple sclerosis, and autoimmune diseases.

vitamin D immune function immunomodulation

1. Introduction

The role of vitamin D in health was first defined by its deficiency that results in rickets in children and osteomalacia in adults [1]. Vitamin D was first described in the early 1600s [2], and despite its name, it is a prohormone because humans do not obtain it only from their diet. Vitamin D is produced after exposure to ultraviolet B radiation (wavelength 290–315 nm) and can also be obtained from diet and supplements [3].
Vitamin D (calciferol) has two forms D2 (ergocalciferol) and D3 (cholecalciferol) [4]. After exposure to ultraviolet B radiation, cholecalciferol is produced in the skin from the precursor protein 7-dehydrocholesterol. The main supply of vitamin D derives from the skin; the diet only contributes in a small amount. The proteins involved in the transport of vitamin D are albumin and lipoproteins, most of vitamin D being transported in an inactive form by D-binding protein (DBP) to the liver. DBP also has an immunomodulatory role and intervenes in bone development [1][3][4][5]. In the liver, vitamin D is converted to 25-hydroxyvitamin D (25(OH)D), an intermediate inactive form in the presence of 25-hydroxylase encoded by the CYP2R1 allele [6]. The 25(OH)D is then transported by DBP to the kidney and converted to the active form, also called calcitriol, in the presence of 1α-hydroxylase encoded by the CYP27B1 allele [6]. This enzyme can be found in various cell types (i.e., skin, bone cells, immune cells, placenta), but the highest concentration is expressed in the proximal tubule in the kidney [1][3][4][5]. In the kidney, hydroxylation is controlled by parathyroid hormone (PTH), calcium and phosphate levels [7]. After passing through the cell membrane, 1,25-hydroxyvitamin D forms the 1,25-hydroxyvitamin D—vitamin D receptor (VDR) complex that modulates gene expression in the nucleus [7]. The outcome of this interaction is calcium homeostasis which inflects intestinal calcium absorption. In the case of low 1,25-hydroxyvitamin D levels, calcium will be absorbed from the bone in favor of the intestine [8]. Breakdown of both 25(OH)D and 1,25-hydroxyvitamin D is performed by the same 24-hydroxylation enzyme (CYP24A1) [1][3][4][5].
There are alternative pathways of vitamin D activation different from 25(OH)D and 1,25-hydroxyvitamin D. This novel in vivo pathway of vitamin D metabolism initiated by P450sc includes: 20-hydroxyvitamin D3 [20(OH)D3], 22(OH)D3, 20,23(OH)2D3, 20,22(OH)2D3, 1,20(OH)2D3, 1,20,23(OH)3D3, and 17,20,23(OH)3D3. These novel metabolites are produced by the placenta, adrenal glands and, at low levels, by epidermal keratinocytes. The predominant human in vivo production of 20(OH)D3 is approximately 20 times more reduced than 25(OH)D. The role of cytochrome P450scc (CYP11A1) and CYP27B1 enzymes in vitamin D metabolism was demonstrated in studies using isolated mitochondria and purified enzymes [9][10]. In addition, CYP11A1-derived secosteroids produced in vivo in the skin, serum and adrenal gland manifest their biological activity as hormones [11]. In the placenta and adrenal glands, the main pathway comprised 20(OH)D3, 20,23(OH)2D3, 17,20,23(OH)3D3, and minor pathways included 25(OH)D and 1,25(OH)2D, and 22(OH)D3 and 20,22(OH)2D3. In epidermal keratinocytes, the predominant metabolites were 22(OH)D3 and 20,22(OH)2D3 [9].
Similarly, human placentas, rat and bovine adrenal glands, human epidermal keratinocytes, and colon cancer Caco-2 cells can produce alternative pathways of ergocalciferol. The novel hydroxy-derivatives include 20(OH)D2, 17,20(OH)2D2, 1,20(OH)2D2, 25(OH)D2 and 1,25(OH)2D2 with high CYP11A1 and CYP27B1 expression. These pathway products present tissue- and cell-type specificity with a higher production of 25(OH)D2 in placentas and Caco-2 cells, and 20(OH)D2 and 25(OH)D2 production in human keratinocytes [12].
CYP11A1 can convert vitamin D into the non-calcemic analog 20S-hydroxyvitamin D3 [20S(OH)D3]. This analog could be used as a potential treatment for rheumatoid arthritis (RA) and other autoimmune disorders by suppressing clinical signs of arthritis and repairing joint damage in a mouse model. 20S(OH)D3 can also decrease the number of CD4 and CD19 cells, reducing inflammatory cytokines. Arthritis can be attenuated by 20S(OH)D3 by reducing pro-inflammatory cytokines and antibodies against type II collagen [13].
Alternative nuclear receptors for CYP11A1-derived vitamin D-hydroxy-derivatives comprise the retinoid-related orphan receptors (ROR)α and γ [14], the arylhydrocarbon receptor (AhR) [15], and liver X receptors α and β [16][17]. Notably, CYP11A1 is expressed in the immune system, in human [18] and murine [19] T cells, in human CD4, CD8, B cells and monocytes [20]. CYP11A1 is involved in the local production of steroidogenesis in the skin and the specific vitamin D metabolism, lumisterol, and 7-dehydrocholesterol. CYP11A1 metabolites play a role in the protective barrier and skin immune functions. Malfunction of CYP11A1 can result in skin disorders [21]. CYP11A1 hydroxy-derivatives and lumisterol hydroxy-derivatives present photoprotective effects by stimulating intracellular free radical scavenging and DNA repair. As photoprotective agents in human keratinocytes, CYP11A1 hydroxy-derivatives are involved in p53-phosphorylation, in the antioxidant response regulated by NRF2, and induction of DNA repair [17].
Human epidermis and serum production of a photoproduct of pre-vitamin D, CYP11A1 and CYP27A1 hydroxylate tachysterol3 produce 20S-hydroxytachysterol3 [20S(OH)T3] and 25(OH)T3. These metabolites can inhibit the proliferation of epidermal keratinocytes and dermal fibroblasts similar to 1,25-dihydroxyvitamin D resulting in stimulation of the differentiation and anti-oxidative genes in keratinocytes. They attach to VDR, express CYP24A1, activate AhR, and bind to the ligan-binding domain (LBD) of LXR α and β, and the peroxisome proliferator-activated receptor γ (PPARγ). The biological function of tachysterol3 is demonstrated by endogenous production of 20S(OH)T3 and 25(OH)T3, which can interact with VDR, AhR, LXRs, and PPARγ [22].
VDR is associated with the nuclear receptor superfamily. Ligand-receptor dimerization is established with the retinoic X receptor (RXR). This complex attaches to the vitamin D responsive elements (VDREs), inducing gene expression by targeting promoter sequences of calcitriol, underlining its genomic function [23][24][25]. The non-genomic effect of vitamin D is highlighted by the connection of calcitriol to a membrane-bound to VDR and caveolin-1 [26].
After activation, vitamin D binds to calcium transporting proteins in the small intestine triggering calcium absorption [26][27]. Vitamin D stimulates osteoclasts leading to bone resorption and increased blood calcium [28]. In bone growth, vitamin D supports collagen matrices and osteoblasts mineralization [29]. Vitamin D induces the expression of osteocalcin, an important non-collagenous bone protein, and stimulates bone resorption RANKL (receptor activator of nuclear factor kappaB ligand), a TNF family member [3][30][31][32]. Vitamin D with parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) regulate calcium and phosphate homeostasis [33]. The negative feedback consists of vitamin D directly inhibiting PTH production, which decreases bone resorption and increases urinary calcium excretion. In this loop, osteocytes induce FGF23 production, increasing urinary phosphate excretion [30][33][34].
The clinically significant reserves of vitamin D are serum 25(OH)D levels (defined as the sum of ergocalciferol and 25(OH)D). In contrast, calcitriol has a short half-life (4–8 h) and depends on calcium homeostasis. An important debate is the proper standardization of tests [35]. Two different methodologies are used: competitive immunoassays (radio-immunoassays or binding-protein assays) and procedures that use high-performance liquid chromatography and liquid chromatography tandem-mass spectrometry. The latter methods are the gold standard procedures [28][36][37].
The Clinical Guidelines Subcommittee of The Endocrine Society defines the deficiency of 25(OH)D to be less than 20 ng/mL (50 nmol/L) [38], while the Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium defined it to be less than 12 ng/mL (30 nmol/L) [39]. The first society defined insufficiency at levels of 21–29 ng/mL (52 to 72 nmol/L) [38], while the latter at levels of 12–20 ng/mL (30–50 nmol/L) [39]. Vitamin D intoxication is described at values higher than 150 ng/mL (374 nmol/L) [3].
Beyond its classical role in calcium homeostasis, evidence arose from studies demonstrating antioxidant [40][41][42] and anti-fibrotic [43][44][45] functions, preventing inflammatory response [46] and intervening in immune-mediated injuries [3][8][47][48][49][50][51][52]. Treatment opportunities influence the prognosis and quality of life in patients with autoimmune diseases, and the immunomodulatory effects of vitamin D represent a potential supplementation therapy as vitamin D is deficient in patients suffering from autoimmune diseases [29].
Vitamin D has pleiotropic effects suggested by the expression of VDR in lymphocytes and dendritic cells. Many studies are based on vitamin D’s role in various diseases such as autoimmune disorders, cardiovascular diseases and tumors. In autoimmune and inflammatory diseases, vitamin D intervenes in the innate and adaptive immune systems [3][8][41][43][46][49][50][51][52]. Animal studies have demonstrated that administering vitamin D or its analogs can influence the occurrence and progression of many immune-related disorders [5][29]. This underlines that vitamin D can lead to changes in the incidence and severity of various diseases such as infectious diseases, psoriasis, rheumatoid arthritis, type 1 diabetes, and multiple sclerosis [53].

2. Vitamin D Effects on the Innate Immune System

Calcitriol is a pluripotent regulator of the innate immune system (Figure 1). The bacterial infection triggers the activation of toll-like receptors (TLRs) that regulates VDRs expression and 25(OH)D-1α-hydroxylase activity. TLRs are a class of non-catalytic transmembrane pathogen-recognition receptors (PRRs) that interact with specific pathogen-associated molecular patterns (PAMPs) [53]. Calcitriol stimulates antimicrobial activities of macrophages and monocytes through VDR-RXR signaling, which triggers the production of cathelicidins that attach to microbial membranes to eliminate the bacteria and fungi [3][5][27][29][50][54][55][56]. Cathelicidin directly influences various respiratory viruses by disrupting viral envelopes [55][57][58][59]. This is also important in granulomatous inflammation such as TB, lymphomas, and sarcoidosis [3][60][61][62].
Figure 1. Immunomodulatory actions of active vitamin D (1,25-dihydroxyvitamin D3; 1,25-(OH)2D3) include effects on the innate and adaptative immune systems. 1,25-(OH)2D3 exerts its effect via direct binding on both VDR on the dendritic cell (DC) and the T lymphocytes. Calcitriol intervenes in APC differentiation and function by promoting APC to become more tolerogenic and decreasing the expression of major histocompatibility complex (MHC) class II and other similar molecules on the cell surface. Vitamin D may also reduce T helper (Th) cell differentiation and proliferation and induce a more tolerogenic immune response than a pro-inflammatory status with induction of T helper-2 (Th 2)-lymphocytes and regulatory T lymphocytes (Tregs), with downregulation of the pro-inflammatory T helper-1 (Th 1) lymphocytes, T helper-17 (Th 17) lymphocytes, and T helper-9 (Th 9) lymphocytes. Other abbreviations: IL: interleukin; Ig M: immunoglobulin M; Ig G: immunoglobulin G; IFN-γ: interferon-γ; TNF-α: tumor necrosis factor-α; toll-like receptors (TLRs), GATA-3: GATA binding protein-3; FoxP3: forkhead box P3, CTLA-4: cytotoxic T lymphocyte-associated protein-4.
Many studies reported that low vitamin D levels are associated with an increased risk of infections and autoimmune diseases due to molecular mimicry [63][64]. Vitamin D can influence dendritic cell activity, inhibiting monocyte differentiation into dendritic cells and reducing IL-12 production [7][65][66][67]. 1,25-dihydroxivitamin D regulates NK cell activity, degranulation process, cytokine secretion, and TLR4 expression. This could demonstrate the benefit of vitamin D supplementation in patients with cancer [68]. Vitamin D regulates the intracellular TLRs differently, down-regulating TLR9, whereas TLR3 is unaffected. The decreased expression of TLR9 results in less IL-6 secreted. This highlights the association between vitamin D deficiency and the risk of developing autoimmune diseases [69].
Calcitriol intervenes in antigen-presenting cells (APC) differentiation and function by promoting APC to become more tolerogenic and decreasing the expression of major histocompatibility complex (MHC) class II and other similar molecules on the cell surface [70][71][72]. The data regarding whether calcitriol induces or inhibits NK cell function is uncertain [68][73][74].
In 1986 Rook and colleagues demonstrated that calcitriol inhibits the growth of Mycobacterium tuberculosis [75]. Liu P.T. and colleagues reported that TLR activation of human macrophages intervenes in killing intracellular Mycobacterium tuberculosis by stimulating the expression of VDR and vitamin D-1–hydroxylase genes. The authors also highlighted the role of TLRs and vitamin D in modulating innate immune responses. This link contributes to the differences found among human populations in synthesizing vitamin D and responding to microbial infection [54]. Other studies showed that calcitriol generates the expression of antimicrobial genes and the interaction between VDREs and containing promoter sequences of the cathelicidin antimicrobial peptide (camp) and defensin β2 (defB2) genes. Ligand binding results in VDR heterodimerization with DNA binding and retinoid X receptors to related VDREs composed of direct duplicates of consensus PuG(G/T)TCA motifs. This underlies the importance of new therapeutic strategies using calcitriol analogs in treating opportunistic infections [53][76][77]. Calcitriol and its analogs have the potential to induce the expression of camp gene in bronchial epithelial cells [78], keratinocytes [79], and myeloid cell lines [80]. 25(OH)D can also induce promoter sequences of the cathelicidin, underlining the antimicrobial function in cells that express 1α-hydroxylase encoded by the CYP27B1 allele [79]. CYP27B1 allele is expressed on various types of cells, and its function depends on the stimulation of each specific cell. Enhanced sensitivity to calcitriol is achieved through PAMPs, activating innate immune responses mediated via TLRs [53][81].
Activated human macrophages after being treated with mycobacterial 19 kDa lipoprotein, a TLR2 that interacts with specific PAMPs, demonstrated increased gene expression of both CYP27B1 and VDR, inducing promoter sequences of the cathelicidin through 25(OH)D and further bacterial killing [46][64][82][83]. A similar result regarding the innate immune response to infection was revealed by inducing cathelicidin expression in monocytes exposed to M. tuberculosis mediated through calcitriol. Calcitriol was able to induce bacterial killing through other factors such as nitric oxide synthase [84]. The expression of cathelicidin-small interfering RNA can enhance the pathway by which calcitriol interacts with the innate immune system. This underlies that cathelicidin is needed for calcitriol antimicrobial activity against M. tuberculosis [54].
Macrophages stimulated with bacterial lipopolysaccharide converted calcitriol to a more polar calcitriol-like metabolite [85]. Vitamin-D-mediated pathway regarding bacterial killing consists of the expression of cathelicidin that is suppressed by specific pathogens. In this matter, macrophages infected with Shigella suppress the expression of cathelicidin and defensin β2 to bypass innate antibacterial immunity [86]. Local induction of calcitriol synthesis can increase cathelicidin expression in promoting the antibacterial function. This mechanism is controlled by feedback pathways limiting a potential exaggerated inflammatory response that could arise from the activation of the immune system. Both down-regulation of TLR2 and TLR4 on monocytes and up-regulation of CD14 were inhibited by VDR antagonist ZK 159222, underlining that calcitriol requires VDR transcription factor activation on immunity receptors [87]. The reduced expression of TLR might inhibit inflammatory T lymphocyte responses that could generate T-helper 1 (Th1) lymphocyte autoimmunity. Feedback regulation of vitamin D is controlled by CYP24A1, the enzyme that catalyzes the synthesis of less active vitamin D metabolites [88].
Vitamin D and its metabolites intervene in vascular permeability and endothelial function through various genomic and non-genomic pathways. 25(OH)D and calcitriol stabilized vascular endothelium via a non-genomic pathway [89][90]. Calcitriol up-regulates endothelial nitric oxide synthase (eNOS), causing increased endothelial production of nitric oxide [91][92]. The increase in eNOS activity via calcitriol activation of VDR through intracellular adenylyl cyclase/cyclic adenosine monophosphate (AC/cAMP) and inositol trisphosphate/diacylglycerol (IP3/DAG) pathways leads to increased intracellular calcium level. VDR also triggers eNOS activation through the phosphoinositide 3-kinase/protein kinase b (PI3K/Akt) pathway, resulting in phosphorylation of serine-1779 on eNOS [93]. In an animal model, calcitriol stimulates endothelial-cadherin-based cellular junctions, inhibits stress fiber formation, inhibits the endothelial intracellular gaps organization, and limits endothelial damage in chronic kidney disease. Vitamin D and its metabolites prevent vascular dysfunction and local and systemic inflammation with tissue injury [94].
Calcitriol stimulates the expression of CYP24A1 in macrophages with no concomitant increase in CYP24A1 activity as calcitriol stimulates the expression of a splice variant form (CYP24A1-SV) that encodes a truncated amino-terminal protein [95]. The cytoplasm inactive state of CYP24A1-SV can limit vitamin D metabolism by confining the conversion to metabolites. The autocrine mechanism for bacterial killing is enhanced through the metabolism of vitamin D with PRR responses that interact with specific PAMPs. This mechanism is involved in macrophage-mediated immune responses, but also keratinocytes can induce cathelicidin through TLR2-mediated recognition of PAMPs in relation to the autocrine synthesis of calcitriol [96]. Keratinocytes can produce calcitriol in the presence of the transforming growth factor β1 and stimulate the production of cathelicidin mediated through TLR2 with the expression of CYP27B1 [96]. Interaction between transforming growth factor β1 and vitamin-D-mediated cathelicidin production involves wound repair through innate immune activation [96].
Vitamin D intervenes in gut integrity and maintaining a balanced relationship between host and gut microbiota. Vitamin D signaling maintains the integrity of intestinal epithelial cells and limits the bacterial lipopolysaccharide damage to intestinal epithelium [97][98]. Multiple studies have shown that vitamin D stimulates the expression of proteins that recognize intracellular pathogens [99][100] and promotes the production of antimicrobial proteins by the intestinal epithelial cells, intraepithelial lymphocytes, and Paneth cells [101][102]. These inhibit intestinal bacterial translocation and maintain intestinal homeostasis, which is thought to contribute to developing many auto-inflammatory and metabolic disorders.

3. Vitamin D Effects on the Adaptive Immune System

Vitamin D and VDR can influence B and T lymphocytes [6][27] (Figure 1). Several studies have reported that Vitamin D may intervene in B-cell differentiation and proliferation, decreasing antibodies and auto-antibodies synthesis with B-cell apoptosis. Vitamin D may also reduce T helper (Th) cell differentiation and proliferation and induce a more tolerogenic immune response than a pro-inflammatory status [103][104]. Vitamin D inhibits the synthesis of various pro-inflammatory Th1, Th9 and Th22 cytokines and stimulates the synthesis of anti-inflammatory Th2 cytokines. These findings could demonstrate the beneficial effect of vitamin D in minimizing the risk of developing autoimmune diseases [104].
Studies demonstrated that VDR expression in lymphocytes enhances vitamin D  as a pluripotent regulator of the innate immune system [105][106][107]. VDR expression is described in activated proliferating T lymphocytes [105] and B lymphocytes [108], implicating vitamin D as a modulator of the adaptive immune system. Inactive B lymphocytes do not present VDR; they upregulate VDR expression only when they are activated for proliferation through mitogens [109].
Initially, calcitriol suppression of immunoglobulin production was thought to be an indirect effect mediated via Th lymphocytes [110]. Further studies showed that calcitriol could directly influence B lymphocyte homeostasis [109]. In this concern, calcitriol can inhibit B cell differentiation into antibody-secreting plasma cells, inducing apoptosis, a process linked to DNA hypo-methylation [111][112]. This suggests the implication of vitamin D in B cell-related diseases such as systemic lupus erythematosus (SLE). Patients with SLE have significantly lower serum levels of calcitriol and 25(OH)D compared to controls [25][109].
As part of the adaptive immune system, Vitamin D intervenes in T lymphocyte proliferation and function [105]. Calcitriol targets Th lymphocytes by suppressing their proliferation and cytokine production, such as interleukin 2 (IL-2) [113]. The antigen-activated pluripotent Th0 lymphocytes generate various cytokines, including IL-2, IL-4, IL-10 and interferon γ (IFN-γ) [114]. Calcitriol directly inhibits [115] the expression of Th1 cytokines (IL-2, IFN-γ, tumor necrosis factor) [116] and stimulates Th2 (IL-3, IL-4, IL-5, IL-10) [115][116][117][118] or indirectly through APCs [72]. It also suppresses mature B cells to form plasma cells and class-switched memory B cells [109][119][120].
Calcitriol stimulates the expression of CTLA-4 and FoxP3, requiring the presence of IL-2 [121]. Calcitriol promotes Th1 cellular immunity more than Th2 humoral immunity. This is an essential key factor regarding the beneficial effects of vitamin D in autoimmune diseases [122]. Reports have shown that calcitriol stimulates the production of CD4+CD25+ Treg. Treg cells generate self-tolerance and contribute to preventing autoimmune disorders and graft-versus-host disease in transplantation [123].
Cytotoxic T lymphocytes (CTL), similar to Th cells, express both VDR and CYP27B1. Expression of VDR can appear in the presence of infection and mitogen stimulation, underlining a connection between the VDR signaling pathway and CTL activity [124][125]. Studies have reported that decreased CD4/CD8 ratio is associated with reduced levels of 25(OH)D [126]. Administration of 5000–10,000 IU of 25(OH)D increased CD4/CD8 ratio, suggesting immune suppression [127][128], but there is limited information about the direct effect of vitamin D on CTL. Induction and functions of CTL are influenced via direct activation of VDR and alteration in the expression of inflammatory cytokines through Th cells and APCs [103][125].
Calcitriol or its synthetic analogs can cause induction of Treg cells offering protection against autoimmune disorders and immune tolerance in organ transplantation [129][130]. Vitamin D targets for the adaptive immune system are the dendritic cells (DCs), especially a certain class of DCs known as myeloid DCs [131]. Calcitriol suppresses the maturation of DCs and the development of Th1 and promotes the induction of tolerogenic DCs and Treg [65][132]. A similar effect on DC could be obtained through CC-chemokine ligand (CCL) 22, which is a chemoattractant factor secreted by DCs that stimulates the synthesis of Treg. In myeloid DCs, calcitriol inhibits intracellular signaling nuclear factor κB [131].

4. Vitamin D Target Genes with Functions in the Immune System

Vitamin D target genes present a key role in the action of vitamin D in innate and adaptive immunity, and each function is demonstrated based on particular gene regulatory scenarios. A study described these genes by performing transcriptome-wide datasets based on peripheral blood mononuclear cells (PBMCs) and human monocytic cell line (THP-1), which were treated in vitro by calcitriol. These genes were described based on their VDR stimulation and their mRNA production. The following genes were identified here: ACVRL1, CAMP, CD14, CD93, CEBPB, FN1, MAPK13, NINJ1, LILRB4, LRRC25, SEMA6B, SRGN, THBD, THEMIS2 and TREM1. Vitamin D target genes were categorized based on their role in acute infection, infection in general and autoimmunity (Figure 2). These immune-related genes encoded proteins placed in the plasma membrane (ACVRL1, CD14, CD93, LILRB4, LRRC25, NINJ1, SEMA6B, THBD, TREM1) or are secreted (CAMP, FN1 and SRGN). In addition, the kinase MAPK13 is located in the cytoplasm, and the transcription factor CEBPB and the TLR scaffold protein THEMIS2 are placed in the nucleus [133].
Figure 2. The proteins encoded by the 15 key genes are present at a certain location in the cell. The classification of the proteins is based on their transcriptome profile: orange—genes that encode proteins related to autoimmunity; purple—genes that encode proteins with a general function in infection; blue—proteins that are involved in acute response to infection.
CD14, TREM1, FN1, and CAMP are proteins involved in acute response to an infection via LPS/TLR4 signaling pathway [133]. The CD14 glycoprotein is mainly expressed in monocytes and macrophages and is located on the surface of the plasma membrane via glycosylphosphatidylinositol. CD 14 is a co-receptor for TLR 1-4, 6, 7 and 9 [134] and presents bacteria produced by LPS to TLR4 in inflammation [135]. Another vitamin D target gene located on monocytes and macrophages [136] is TREM1, associated with TLR4 signaling that generates inflammation in bacterial infection [137]. The extracellular matrix protein FN1 encoded by vitamin D, secreted by macrophages, epithelial cells and fibroblasts, is involved in inflammatory responses in LPS/TLR4 signaling, cell adhesion, and wound healing [138].
THBD, LILRB4, SEMA6B, LRRC25, MAPK13, and THEMIS2 genes encode proteins with a general function in infection [133]. THBD is secreted by monocytes, macrophages and endothelial cells [139] and reduces blood clots by turning thrombin pro-coagulative action to anti-coagulative. It also prevents pro-inflammatory responses of NF-kB signaling, binds to LPS and promotes LPS binding to CD14 and TLR4 [140]. The THBD gene is a vitamin D target in monocytes [141] and PBMCs [142]. LILRB4 is a receptor involved in the inhibition of APCs such as macrophages, monocytes, DCs and microglia, resulting in the production of TNF, bactericidal activity [143], and stimulation of Treg differentiation [144]. The LILRB4 gene is a vitamin D target gene in PBMCs [145]. One vitamin D target gene in bone is SEMA6B [146], belonging to the semaphorin protein family, which presents immune activity by controlling cell movements and cell-to-cell communication [147]. The LRRC25 protein acts on monocytes, granulocytes T cells, and DCs, inhibiting NF-kB signaling [148] and interferon [149]. It intervenes in response to viral infections by decreasing the production of inflammatory cytokines [150][151]. The kinase MAPK13 intervenes in LPS/TLR4 signaling and inflammatory responses along with MAPK11 [152]. It is a vitamin D target in skeletal muscle [153]. THEMIS2 is a TLR signal transduction modulatory protein that acts on macrophages, DCs, and B cells in TNF production induced by LPS [154] and T cell development [155].
CD93, NINJ1, CEBPB, ACVRL1, and SRGN genes encode proteins related to autoimmunity. CD93 glycoprotein acts on monocytes, endothelial cells, granulocytes, platelets and stem cells [156] and affects innate immunity in adhesion, phagocytosis and inflammation [157].    It functions as a DNA receptor for presenting to TLR9 and is involved in inflammatory responses in LPS/TLR4 signaling [158]. NINJ1 protein is expressed in myeloid and endothelial cells [159] and is described in the immune pathogenesis of multiple sclerosis [160] by promoting cell adhesion and leukocyte migration in inflammation of the endothelium. CEBPB gene is a vitamin D target in myeloid leukemia cells [161]. It proved to be involved in inflammation via Th17 in models of multiple sclerosis [162]. ACVRL1 is known to be a protein of the transforming growth factor-beta superfamily, which is associated with monocyte to macrophage differentiation [163], and with the signaling of the bone morphogenetic protein (BMP)9 and BMP10 [164]. SRGN is expressed by monocytes, macrophages, lymphocytes, mast cells, and endothelial cells [165]. It is involved in the secretion of inflammatory mediators via LPS [166].   
These 15 genes are considered the most important vitamin D targets in connection to immunity and biomarkers in diagnosing vitamin D deficiency related to immune diseases [133].

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Claudia Sîrbe
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