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Vitamin D and Its Analogues in Immune System Regulation Patricio Artusa, John H. White
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Vitamin D and Its Analogues in Immune System Regulation Patricio Artusa, John H. White

Pharmacological Reviews Dec 2024 https://doi.org/10.1016/j.pharmr.2024.100032.
Patricio Artusa1, John H. White1’2’* department of Physiology, McGill University, Montreal Qc, H3G 1Y6, Canada department of Medicine, McGill University, Montreal Qc, H3G 1Y6, Canada

Vitamin D was discovered as the cure for nutritional rickets, a disease of bone growth arising from inadequate intestinal calcium absorption, and for much of the 20th century was studied for its critical role in calcium homeostasis. However, we now recognize that the vitamin D receptor (VDR) and vitamin D metabolic enzymes are expressed in numerous tissues unrelated to calcium homeostasis. Notably, vitamin D signaling can induce cellular differentiation and cell cycle arrest. Moreover, the VDR and the enzyme CYP27B1, which produces the hormonal form of vitamin D, 1,25- dihydroxyvitamin D (1,25D), are expressed throughout the immune system. In addition, CYP27B1 expression in immune cells is regulated by physiological inputs independent of those controlling its expression in calcium homeostatic tissues. These observations have driven the development of 1,25D-like secosteroidal analogues and non-secosteroidal analogues in an effort to separate the effects of vitamin D on cell differentiation and function from its calcemic activities. Notably, some of these analogues have had considerable success in the clinic in the treatment of inflammatory and immune-related disorders. In this review, we describe in detail the mechanisms of vitamin D signaling, and the physiological signals controlling 1,25D synthesis and catabolism, with a focus on the immune system. We also survey the effects of 1,25D and its analogues on regulation of immune system function and their implications for human immune-related disorders. Finally, we describe the potential of vitamin D analogues as anti-cancer therapeutics, in particular, their use as adjuncts to cancer immunotherapy.
Significance Statement
Vitamin D signaling is active in both the innate and adaptive arms of the immune system. Numerous vitamin D analogues, developed primarily to minimize the dose-limiting hypercalcemia of the active form of vitamin D, have been used widely in preclinical and clinical studies of immune system regulation. This review presents a description of the mechanisms of action of vitamin D signaling, an overview of analogue development, and an in-depth discussion of the immunoregulatory roles of vitamin D analogues.
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Detailed Table of Contents (PDF contains many charts and tables)

A Brief History of Vitamin D
Introduction to Vitamin D Metabolism and Signaling
Sources of Vitamin D
Serum 25D levels in populations worldwide
Vitamin D Metabolic Enzymes
Vitamin D Binding Protein
The Vitamin D Receptor
Development of Vitamin D Analogues
Secosteroidal Analogues
Non-secosteroidal analogues
Vitamin D Signaling in the immune system
Overview of immune system function
The VDR and vitamin D metabolic enzymes in the immune system
Signaling pathways controlling CYP27B1 expression in immune cells
Vitamin D signaling and immune system regulation
Vitamin D and its analogues in immune-related disorders
Vitamin D supplementation in bacterial infections
Vitamin D supplementation in viral infections
Inflammatory Bowel Diseases
Vitamin D and allergies
Vitamin D and autoimmunity
Vitamin D analogues in inflammatory disorders
Vitamin D analogues and their potential as adjuncts to cancer immunotherapy
Concluding statement

A Brief History of Vitamin D

Vitamin D was discovered as the cure for nutritional rickets, a disease of bone growth arising from inadequate dietary calcium uptake, and vitamin D status has long been linked to diet or sun exposure. Rickets was first described as a clinical phenomenon in the early 17th century, and became widespread in the rapidly industrializing, polluted cities of 18th and 19th century Europe (Discovery; Guy, 1923; Jones, 2022). The 2020’s represent significant anniversaries of advances in our understanding of vitamin D biology in several regards. In 1822, a Polish physician, who noticed that the condition was rare outside of polluted cities, concluded that sun exposure cured rickets. The antirachitic properties of cod liver oil were first noted by a French researcher in 1827 but did not initially gain widespread attention because of a lack of understanding at the time about micronutrients. Approximately 100 years later, Elmer McCollum (1922) showed that cod liver oil heated in the presence of oxygen to inactivate vitamin A retained its anti-rachitic activity, confirming the presence of a distinct active substance. In the same decade, multiple groups showed that UV irradiation of excised skin or food substances was effective at protecting against rickets (Discovery; Guy, 1923; Jones, 2022). The structure of vitamin D3 was determined in 1936.
While vitamin D was initially identified and characterized for its anti-rachitic properties, there are also longstanding links between vitamin D status or sun exposure and immunity. In ancient Greece, heliotherapy (sun therapy) was used as a treatment to alleviate the symptoms of phthisis (tuberculosis, TB), which is caused by an uncontrolled infection of the intracellular pathogen Mycobacterium tuberculosis (M.tb.) (Clancy et al., 2013). Use of cod liver oil as a treatment for chronic rheumatism dates from the 18th century. Vitamin D was subsequently used as a therapy for scrofula, a form of tuberculosis infecting the lymph nodes (Guy, 1923), and the idea of using sun exposure to treat TB was reborn in the 1800’s with the advent of the sanatorium movement in Europe, when disease incidence was at its peak (Grad, 2004; Martineau et al., 2007). In 1903, Niels Finsen received the Nobel Prize for Medicine for his work demonstrating that cutaneous UV exposure was an efficacious treatment for cutaneous TB (lupus vulgaris) (Grad, 2004; Martineau et al., 2007). Finally, in the 1980’s, the active form of vitamin D was shown to control M.tb. proliferation in macrophages infected in tissue culture (Rook et al., 1986).

Introduction to Vitamin D Metabolism and Signaling.

Sources of Vitamin D.
Vitamin D (calciferol) is a secosteroid that is found in two principal forms, vitamin D3 and vitamin D2. Vitamin D3 can be produced in skin in the presence of adequate ultraviolet B (UVB) irradiation by photochemical cleavage and thermal rearrangement of the last intermediate in cholesterol biosynthesis, 7-dehydrocholesterol (Fig. 1). Because of its relationship to cholesterol biosynthesis, vitamin D3 is also known as cholecalciferol. It is distinguished from vitamin D2, or ergocalciferol, which is derived from the steroid ergosterol, and differs from vitamin D3 by a double bond and a methyl group in its sidechain (Fig. 1). Cholecalciferol is available from animal sources, whereas ergocalciferol is found in fungi and a limited number of plant species, notably alfalfa and lichen (Horst et al., 1984; Mau et al., 1998; Wang et al., 2001). Lichen also produces vitamin D3 and thus serves as a source of supplements for vegan diets (Mangels, 2014). While both D3 and D2 are active, vitamin D3 produces a more sustained rise in circulating vitamin D metabolite levels and greater than 2-fold more subcutaneous storage than vitamin D2 at identical doses (Armas et al., 2004; Heaney et al., 2011). While cod liver oil and fatty fish are relatively rich sources of vitamin D3, and sun-dried shiitake mushrooms contain high levels of vitamin D2, most western diets are vitamin D-poor. There are only limited amounts of vitamin D in meat, eggs and dairy products (Baeke et al., 2010), and many countries resort to dietary supplementation, notably of dairy products, which are also important sources of dietary calcium. Even with supplementation, sun exposure in many populations is the major source of vitamin D. However, solar UVB irradiation is absorbed by the ozone layer, and at sea level its intensity is insufficient for cutaneous vitamin D synthesis when the sun is below 45o. This period, known as vitamin D winter, can last several months at temperate latitudes, notably in populous regions of northern Europe (Tavera-Mendoza, 2007). Thus, in the absence of appropriate supplementation, circulating vitamin D metabolite levels vary seasonally (Hypponen and Power, 2007). Moreover, the amount of vitamin D3 produced in skin exposed to a given UVB dose is dependent on both skin color and age (Webb, 2006).

Serum 25D levels in populations worldwide.
Serum 25D levels are used as biomarkers of vitamin D status. In past, there was not universal agreement on 25D levels that constituted vitamin D sufficiency, although those of the U.S. Endocrine Society were widely used (Holick et al., 2011). Vitamin D sufficiency was defined as circulating 25D levels above 75 nM (30ng/mL), based in part on the inverse relationship between circulating 25D and levels of parathyroid hormone (PTH), which is released upon a drop in tightly controlled circulating calcium concentrations (Holick et al., 2011) (NB: Metabolite levels are measured in ng/mL in the US and nM elsewhere, with a conversion factor of 2.5-fold). Recently, however, a new Endocrine Society panel was convened to assess clinical trial evidence supporting establishment of 25D threshold levels associated with outcome-specific benefits (Demay et al., 2024). Notably, the panel did not endorse a 25D level of 30 ng/mL (75 nM) as a threshold for sufficiency, nor did it endorse specific 25D levels to define sufficiency, insufficiency, or deficiency. Therefore, we will describe specific vitamin D metabolite levels whenever possible to avoid the use of the term deficiency. These findings are significant for clinicians as vitamin D-poor diets and vitamin D winter combined with sun avoidance, and in some areas, conservative dress, can lead to low levels of circulating 25D in several populations worldwide (Arabi et al., 2010). A survey of >1,000 adolescents across Europe found that 80% had circulating vitamin D metabolite levels below 75 nmol/L, and that 15% were below 27.5 nmol/L (Gonzalez-Gross et al., 2012), findings consistent with estimates of poor dietary vitamin D intake in adolescents (Diethelm et al., 2014). They are also in agreement with the broader European population; an analysis of 55,844 Europeans of all age groups found that 40% had circulating 25D levels below 50 nmol/L (Cashman et al., 2016). Such observations are not limited to Europe, as low vitamin D is also common in the Middle East and India (Kamboj et al., 2018; Lips et al., 2019). A systematic review and metaanalysis, which included 21,676 participants from 23 African countries, found that 17.3% had serum 25D levels <30 nM and 34.2% had levels <50 nM. As expected, mean serum 25D levels were lower in northern countries and South Africa than in sub-Saharan Africa (Mogire et al., 2020). Other parameters in addition to latitude and diet can also control vitamin D status. The European study cited above found that poor vitamin D status (< 30 nmol/L) was more frequent in dark-skinned people, consistent with reduced cutaneous synthesis (Cashman et al., 2016). Finally, as vitamin D is fat- soluble, deficiency in circulating metabolite levels can be exacerbated by high body mass index (Rabufetti et al., 2019).

Vitamin D Metabolic Enzymes.
Vitamin D derived from dietary sources, supplementation or cutaneous UVB exposure is not a biologically active molecule. It must undergo sequential hydroxylations, first at C25 on the end of the cholesterol sidechain and then at the 1a position (Fig. 1) to produce the active form, 1,25- dihydroxyvitamin D (1,25D). 25-hydroxylation occurs largely but not exclusively upon passage through the liver. The enzyme CYP2R1 is the major but not only vitamin D 25-hydroxylase (Shinkyo et al., 2004). Ablation of the mouse Cyp2r1 gene led to a greater than 50% reduction in circulating 25- hydroxyvitamin D (25D) levels (Zhu et al., 2013). Similarly, humans with CYP2R1 gene mutations are characterized by reduced serum 25D levels and symptoms of vitamin D deficiency (Al Mutair et al., 2012; Cheng et al., 2004). Residual 25-hydroxylase activity may be accounted for by several other enzymes, including CYP27A1 and CYP3A4 (Zhu and DeLuca, 2012). 25D metabolites are the major circulating forms of vitamin D, with the half-life of 25-hydroxyvitamin D3 being 2-3 weeks, whereas that of the D2 form is somewhat shorter (Jones et al., 2014). 25D is a substrate for the unique 25- hydroxyvitamin D 1a-hydroxylase, a mitochondrial enzyme encoded by the nuclear CYP27B1 gene. Cyp27b1 was first cloned from the rat by St-Arnaud et al in 1997 (St-Arnaud et al., 1997), followed by genes from other species, including human (Prosser and Jones, 2004). Loss of CYP27B1 expression in humans and mice leads to vitamin D-dependent rickets type 1A (Fu et al., 1997; Glorieux and St- Arnaud, 2024). Circulating hydroxylated forms of vitamin D were first identified over 50 years ago, and initial studies on 1a-hydroxylase activity suggested that CYP27B1 expression was largely restricted to kidney (Lawson et al., 1971). Subsequently, the central role of renal CYP27B1 in calcium homeostasis became clear; transcription of the CYP27B1 gene is under control of Ca++ and phosphate regulatory signals (Prosser and Jones, 2004). Notably, a drop in circulating Ca++ attenuates the break on PTH release from the parathyroids controlled by the calcium-sensing receptor, and the subsequent increase in PTH binding to its cognate receptor on proximal renal tubular epithelial cells induces expression of CYP27B1. 1,25D thus produced is released into the circulation, which, in addition to its pleiotropic roles, inhibits PTH production in a negative feedback loop. Moreover, renal CYP27B1 activity is inhibited by fibroblast growth factor 23 (FGF23), whose production from bone cells is stimulated by high phosphate levels but acts independently of PTH (Bikle, 2000; Saito et al., 2003). Collectively, the above leads to the classical model of vitamin D activation, featuring renal expression of CYP27B1 under control of calcium regulatory inputs and 1,25D acting largely as an endocrine hormone.
Catabolism of both 25D and 1,25D is initiated by the enzyme encoded by the CYP24A1 gene. Initially characterized for its capacity to hydroxylate 25D or 1,25D at the 24 position, we now know that CYP24A1 catalyzes a multi-step catabolic pathway that leads to elimination of much of the sidechain, culminating in the production of calcitroic acid (Fig. 1) (Jones et al., 2012). CYP24A1 expression is strongly induced in the presence of 1,25D, constituting a negative feedback loop (Prosser and Jones, 2004). The phenotype of Cyp24a1-null mice (St-Arnaud, 1999) underlines the importance of the enzyme in vitamin D metabolite catabolism and calcium homeostasis. Null mice are hypercalcemic, can exhibit renal calcification, and half of them die before weaning. Similarly, in humans, CYP24A1 mutations cause infantile idiopathic hypercalcemia (IIH) (Jones et al., 2012; Schlingmann et al., 2011). Increased incidence of IIH in the United Kingdom corresponded with increased vitamin D supplementation of infant formula and fortification of milk. Like the mouse knockout model, the initial cohort of IIH patients presented with nephrocalcinosis in addition to profound hypercalcemia and suppressed PTH levels. Even after elimination of vitamin D supplementation and implementation of a low-calcium diet, circulating Ca++ concentrations remain elevated and PTH suppressed in IIH patients (Schlingmann et al., 2011).
Vitamin D Binding Protein.
Group-specific component of serum (GC globulin) or vitamin D binding protein (DBP) is present in the circulation at micromolar concentrations. The transport of circulating lipophilic vitamin D metabolites by a binding globulin parallels that of steroid hormones, which are also bound by specific binding globulins. GC globulin was first identified in 1959 by electrophoresis of serum proteins (Hirschfeld, 1959). Several groups subsequently showed that it acts as a binding protein for serum metabolites of vitamin D. Other work revealed that DBP is also a scavenger of globular actin and binds fatty acids (Bouillon et al., 2024). It is genetically and structurally related to albumin and D-fetoprotein, and all family members share conserved 3-domain alpha-helical topologies, although the orientations of the individual domains vary widely between members. Vitamin D binding residues lie within the first domain of DBP (Swamy et al., 2002; Verboven et al., 2002), and differences in local folding likely explain the specificity of DBP for vitamin D metabolites (Bouillon et al., 2024). DBP is produced almost exclusively by the liver. Its serum concentrations do not vary with vitamin D status, and there is no evidence to date that 1,25D regulates the expression of its gene. It is noteworthy that the estimated turnover rate of DBP is several-fold faster than that of its principal ligand, 25D (Haddad et al., 1981), indicating that 25D must be recycled. It is also noteworthy that the affinity of the 25-hydroxy metabolite of vitamin D2 for human DBP is somewhat lower than that of its D3 counterpart (HADDAD et al., 1976), which may explain the longer circulating half-life of the D3 form (Jones et al., 2014).
The high affinity of vitamin D metabolites and other steroid hormones for their binding globulins has led to the free hormone hypothesis, wherein most circulating ligand is globulin-bound, with only a small fraction free to enter cells (Mendel, 1989). Under these conditions, bound fractions represent circulating reservoirs, and bound hormone can be released continuously, replacing free hormone taken up by cells. However, the kidney, parathyroid glands, and placenta express megalin and cubilin, which form an endocytic complex that allows for the uptake of DBP-bound vitamin D metabolites into cells. Loss of megalin/cubilin results in osteomalacia and poor survival, demonstrating the importance of vitamin D transport into key cells via uptake of DBP-bound metabolites for regulation of vitamin D and calcium homeostasis (Bikle, 2000; Nykjaer et al., 1999; Nykjaer et al., 2001). The central role of DBP in maintaining circulating vitamin D metabolite levels, and support for the free hormone hypothesis, is manifested in DBP-null mice (Safadi et al., 1999). Under vitamin D-replete conditions, null animals are normocalcemic in spite of having extremely low levels of circulating 25D and 1,25D. Remarkably, while 1,25D levels are below the limit of detection of many assays, tissue-resident concentrations appear normal (Zella et al., 2008). However, null mice develop vitamin D deficiency more rapidly than their wild-type counterparts when on a vitamin D deficient diet, but, intriguingly, are resistant to vitamin D toxicity (hypercalcemia) (Safadi et al., 1999).
To date, there have been two patients identified with undetectable circulating DBP. In one case (Henderson et al., 2019), a 58-year-old woman presented with largely normal bone metabolic markers, in spite of the extremely low concentration of serum 25D of 0.25nM. Her major clinical feature was debilitating ankylosing spondylitis, an inflammatory condition affecting the spine and joints, although the connection of the condition to DBP loss was not established. The patient carried two chromosome deletions: one of 139kb eliminating the entire GC gene, and another of 144kb deletion, which deleted part of the NPFFR2 (neuropeptide FF receptor 2) gene. The clinical significance of the latter deletion is not clear. In a second case of a 60-year-old male, bone markers and serum calcium and phosphate were normal, and, unlike the first patient, there was no sign of rheumatological disease. Aggressive vitamin D3 supplementation of the patient failed to restore normal 25D levels, and eventually a homozygous G>A substitution was identified, which led to exon 7 skipping and production of a truncated protein subject to nonsense-mediated decay (Banerjee et al., 2021). Taken together, phenotypes of these patients show that the effects of loss of DBP in humans largely phenocopy those seen in null mice.

The Vitamin D Receptor.

1,25D as a free hormone can enter cells, where it binds to the vitamin D receptor (VDR), a member of the nuclear receptor family of ligand-regulated transcription factors. There are 48 genes encoding nuclear receptors in the human genome (Robinson-Rechavi et al., 2003). The first cDNAs encoding nuclear receptors were cloned in the mid-late 1980’s and their domain structures analyzed. That encoding the human VDR was cloned in 1988 (Baker et al., 1988). Typical of other classes of transcription factors, nuclear receptors are composed of a minimum of two structural and functional domains. There is a highly conserved site-specific DNA binding domain composed of two zinc finger motifs. Notably, the first VDR genes cloned from patients with hypocalcemic vitamin D-resistant rickets contained point mutations in sequences encoding the DNA binding domain (Hughes et al., 1988). C- terminal to the DNA binding domain lies a less conserved-terminal □-helical ligand-binding domain, which in most receptors serves as a ligand-regulated transcriptional regulatory domain (Mangelsdorf et al., 1995; Robinson-Rechavi et al., 2003; Weikum et al., 2018). Receptors also contain N-terminal domains that can contribute to transcriptional regulation. However, these are highly variable in sequence and length, and that of the VDR is essentially non-existent.
As cDNAs for steroid receptors predominated among the earliest cloned nuclear receptors, subsequent studies on their modes of action became paradigms for receptor action. Steroid receptors function as homodimers and bind in a hormone-dependent manner to cognate DNA sequences in the form of palindromes of hexanucleotide repeats. The universality of this paradigm was shaken by the observation that several nuclear receptors, in addition to recognizing response elements in the form of direct repeats with variable spacing, functioned as heterodimers with common retinoid X receptor (RXR) heterodimeric partners (Leid et al., 1992; Victor et al., 1991). The VDR is a member of this class of receptors, and VDR/RXRs recognize vitamin D response elements (VDREs) in the form of direct repeats of hexameric PuG/TTCA motifs separated by 3bp (so-called DR3 motifs) (Umesono et al., 1991) (Fig. 2). Dimerization of most nuclear receptors is essential to create a “footprint” large enough for stable DNA binding. However, even this characteristic is not universal; a subset of receptors possess extended DNA binding domains and can bind stably to DNA as monomers.
Human nuclear receptors have been divided into a series of 6 subgroups. The VDR (NR1I1) is in subgroup 1, which also includes receptors for all-trans retinoic acid (RARs), thyroid hormone (TRs), as well as receptors controlling lipid metabolism, liver X receptors (LXRs) and peroxisomal proliferator activated receptors (PPARs), among others. Unfortunately, reviews that provide high altitude views of nuclear receptor action tend to lump these receptors to together functionally. However, in some respects, function of VDR/RXRs is distinct from other members of group 1. For example, RXRs heterodimerized with RARs, TRs or LXRs bind DNA constitutively and, in the absence of cognate ligands, recruit transcriptional corepressor complexes, thus inhibiting transcription of adjacent genes. Subsequent hormone binding leads to eviction of corepressor complexes and recruitment of coactivators (Hu et al., 2003; Nagy et al., 1999; Perissi et al., 2004). Evidence for such a mechanism of regulation by VDR/RXRs is limited, largely because, unlike the receptors cited above, the association of VDR/RXRs with chromatin is strongly 1,25D-dependent (Jones and Pike, 2020; Meyer et al., 2012) (Fig. 2). Like other receptors, VDR agonist binding (and to some degree DNA binding) controls the movement of C-terminal helix 12 of the ligand binding domain. This generates a conformation optimal for recruitment of coactivator complexes required for transactivation (Zhang et al., 2011; Zheng et al., 2017). Competitive VDR antagonists prevent the movement of helix 12, thus blocking coactivator recruitment (Belorusova et al., 2020). Finally, unlike VDR/RXRs, LXR/RXRs and PPAR/RXRs function as so-called permissive heterodimers, where transcriptional activation can occur through specific ligand binding to either of the heterodimeric partners or to both (Pérez et al., 2012). In contrast, in VDR/RXR heterodimers, the VDR is the unique signaling partner.
Analyses of gene expression profiling studies (either by microarrays or RNAseq experiments) have shown that effects of 1,25D on transcription lead to transactivation or transrepression in roughly equal measure, and that expression profiles are highly cell specific (Dimitrov et al., 2021). It is often assumed that VDR-regulated gene transcription occurs essentially through its interaction with VDREs. However, the reality is considerably more complex. ChIP-seq (chromatin immunoprecipitation followed by high- throughput DNA sequencing) studies have provided valuable information about the genome-wide distribution of the VDR (and RXRs) (Heikkinen et al., 2011; John et al., 2014; Meyer et al., 2014; Meyer et al., 2012; Ramagopalan et al., 2010), notably confirming that 1,25D-induced binding occurs predominantly at DR3-type VDREs. However, some peaks are associated with DNA motifs bound by other types of transcription factors. Importantly, combining ChIP-seq studies with gene expression profiles revealed that VDREs are not enriched in peaks adjacent to downregulated genes. These and other data reveal that transrepression occurs through heterogeneous and cell-specific mechanisms (White et al., 2024). A good example is inhibition by 1,25D of genes whose transcription is driven by cMYC. In the presence of 1,25D, expression of the MYC gene is inhibited by ~50% via downregulation of D-catenin, a coactivator of the TCF/LEF transcription factor family that drives MYC gene expression. In addition, the 1,25D-bound VDR also induces turnover of MYC protein by recruitment of proteasomal subunits to DNA-bound cMYC (Salehi-Tabar et al., 2019; Salehi-Tabar et al., 2012). Combined, these mechanisms can lead to repression of cMYC-driven transcription and essentially complete loss of cMYC protein. Neither requires direct, sequence-specific DNA binding by the VDR. Other mechanisms of transcriptional regulation by the VDR in immune cells will be presented below.

Development of Vitamin D Analogues.

Secosteroidal Analogues.
From the beginning, the vitamin D field has been the subject of intense analogue development, with likely over 1,000 secosteroidal and non-secosteroidal compounds generated to date (Jones and Pike, 2020; Maestro, 2024). The hydroxylated forms of vitamin D3, 25D and 1,25D, were discovered in the 1970’s and their chemical syntheses followed soon after. Perhaps the most straightforward of the vitamin D analogues is alfacalcidol, or 1a-hydroxyvitamin D (1aD3) (Fig. 3), which has been in use since 1981 (Kubodera, 2009). It is a pro-drug and substrate for 25-hydroxylases, which is converted to 1,25D upon passage through the liver (Kubodera, 2009). Weekly injections of 1aD are well tolerated, and in one clinical trial, were more efficacious than calcium plus vitamin D in correcting bone mineral density in osteoporotic patients (Nuti et al., 2006). Similarly, the 1a-analogue of vitamin D2, doxercalciferol, is used to treat secondary hyperparathyroidism (Brown, 2001). As described below, alfacalcidol has also demonstrated efficacy in the treatment of immune-related disorders.
In addition to its critical role in calcium homeostasis, it has been recognized since the early 1980’s that 1,25D can induce cellular differentiation and cell cycle arrest (Miyaura et al., 1981; Tsoukas et al., 1984). As a result, analogue development has been driven largely by a desire to separate the calcemic actions of 1,25D from its capacity to induce cell differentiation and growth arrest. Academic laboratories and the pharmaceutical industry have been at least partially successful in this regard, producing several analogues that present substantially reduced, if not absent, calcemic activity while retaining efficacy in inducing cell differentiation and antiproliferative activities. Hundreds of analogues have been produced and an in-depth treatment of their development is beyond the scope of this review. For more information on analogue structures and pharmacological properties, readers are referred to the comprehensive survey by Glenville Jones and J. Wesley Pike (Jones and Pike, 2020), and the review by (Maestro, 2024). However, a few relevant examples of representative analogues are presented here.
While a number of prodrug variants of vitamin D have been developed (Jones and Pike, 2020), the majority are analogues of the hormonal form 1,25D. Several of this latter group contain (multiple) sidechain modifications, which can substantially modify their pharmacological properties. Three excellent examples are Calcipotriol (MC903) (Calverley, 1987), 22-Oxacalcitriol (OCT, Maxacalcitol) (Murayama et al., 1986), and EB1089 (Seocalcitol) (Binderup et al., 1991a) (Fig. 3). Calcipotriol features a C22-23 double bond, a 24-OH group and a terminal cyclopropane ring, whereas in OCT an oxygen replaces the C22 carbon. The extended sidechain of EB1089 also contains conjugated double bonds, notably at the 24 position. Many such sidechain modifications do not substantially compromise the affinity for the VDR, and several compounds act as potent VDR agonists. Importantly, however, they generally substantially diminish affinity of compounds for DBP and alter analogue metabolic breakdown. CYP24A1 catalyzed catabolism of 1,25D is initiated by hydroxylation of the C24 carbon of the cholesterol sidechain, and EB1089 features a double bond at the 24 position. We performed comparative gene expression profiling studies of EB1089 and 1,25D in a human head and neck squamous carcinoma model and found, as expected, that there was extensive overlap between the two profiles. However, induction of expression by 1,25D of several target genes was more transient than that observed in the presence of EB1089, a difference that disappeared in the presence of a CYP450 inhibitor (Lin et al., 2002). This suggests that EB1089 is metabolically more stable in this model. Indeed, studies from Glenville Jones’ group have provided evidence that EB1089 is hydroxylated on the C26 carbon in a reaction that does not appear to be catalyzed by CYP24A1 (Shankar et al., 1997). In contrast, the same group showed that CYP24A1 is implicated in the catabolism of calcipotriol and OCT (Masuda et al., 1996; Masuda et al., 1994). Notably, calcipotriol breakdown led, among other products, to the formation of calcitroic acid, the end product of 1,25D catabolism (Masuda et al., 1994).
Several sidechain-modified compounds have been studied in an array of pre-clinical disease models and some have entered clinical trials. These compounds are generally less calcemic than the parent hormone 1,25D. For example, in our animal studies, 1,25D ata daily dose in mice of 0.25Dg/kg inhibited tumor growth but induced hypercalcemia in a head and neck squamous carcinoma model. In contrast, EB1089 at the same dose was a more efficacious anti-tumor agent and did not raise serum Ca++ concentrations (Prudencio et al., 2001). On the surface, it seems paradoxical that a compound that is resistant to CYP24A1-catalyzed catabolism is less calcemic than the parent hormone, given the devastating hypercalcemia described above in IIC patients deficient in CYP24A1 (Jones et al., 2012; Schlingmann et al., 2011). However, sidechain modifications usually substantially reduce the affinity of compounds for DBP, and EB1089, OCT and calcipotriol are no exception in this regard (Hansen and Máenpáá, 1997; Jones and Pike, 2020). In vitro, DBP in serum acts as a strong antagonist of 1,25D-induced gene expression in tissue culture experiments. Consistent with their reduced affinity for DBP, sidechain-modified analogues, some with substantially lower affinity for the VDR, behaved as highly potent VDR agonists in tissue culture experiments (Ferrara et al., 1994). In vivo, the reduced affinity of analogues for DBP has profound implications for their circulating half-lives as well as tissue distribution (Jones and Pike, 2020), and is consistent with the accelerated clearance of vitamin D metabolites observed in DBP null mice, which are resistant to hypercalcemia (Safadi et al., 1999).

Non-secosteroidal analogues.
While secosteroidal 1,25D analogues have had considerable success, including, as discussed below, in the clinic, their syntheses are relatively laborious. In an effort to generate synthetically more accessible compounds, non-secosteroidal 1,25D analogues have been identified from chemical libraries using high-throughput screens for VDR agonism based on reporter gene assays. Two of these, LG190178 and LY2108491 (Boehm et al., 1999; Ma et al., 2006) are shown in Fig. 3. There are remarkable parallels in the core structures of the two compounds, and the 25-hydroxy surrogates, which terminate with tert-butyl groups, are identical. While there is some sacrifice in affinity for the VDR in these compounds relative to 1,25D or other secosteroid analogues, they have the virtue of being relatively straightforward to synthesize (Demizu et al., 2011). Of the two, LY2108491 has been tested more thoroughly in vivo. Notably, it displayed a dose-responsive efficacy in a surrogate model of psoriasis in the absence of hypercalcemia, unlike 1,25D whose efficacy was paralleled by increasing serum calcium levels (Ma et al., 2006). As described below, secosteroidal and non-secosteroidal 1,25D analogues have been used extensively in pre-clinical and clinical studies of immunity and immune-related disorders.

Vitamin D Signaling in the immune system.

Overview of immune system function
The immune system consists of a complex network of distinct immune cell types working together with the aid of physical barriers and non-immune cells to protect the host from pathogens such as bacteria, viruses, parasites, and fungi, while providing surveillance of and protection from internal threats like malignancies (Chaplin, 2010). The cells of the immune system develop in the bone marrow from common progenitors and can be broadly classified into innate and adaptive arms (Rieger and Schroeder, 2012). As their names suggest, innate immune cells are first responders and provide a basal level of defense, whereas adaptive immune cells tailor their response to the specific type of pathogen encountered and generate long last memory. Physical barriers including the skin, mucous membranes, and endothelium represent the first line of defense, which have evolved their own innate immune mechanisms to contain the infection and stimulate the adaptive immune system (Chaplin, 2010). Physiologic barriers including pH, temperature, and chemical mediators work in tandem with physical barriers to destroy invading pathogens (Chaplin, 2010).
Pathogen recognition by innate immune cells and initiation of inflammatory responses relies on detection of microbial antigens by pattern recognition receptors (PRRs) such as toll-like receptors (TLRs) (Mogensen, 2009). For example, TLR4 and its co-receptor CD14 recognize lipopolysaccharide from gram-negative bacteria. Downstream signaling results in transcriptional changes and the production of pro-inflammatory cytokines. This stimulates effector responses to combat infection and antimicrobial peptide (AMP) production, which limits pathogen replication or directly kills them via membrane lysis (Mogensen, 2009). Broadly speaking, these effector functions include phagocytosis, degranulation, release of cytokines, growth factors, or enzymes, cytotoxic killing of infected cells, and antigen presentation to adaptive immune cells (Marshall et al., 2018). Phagocytes include monocytes, macrophages, dendritic cells (DCs), neutrophils, and mast cells. Phagocytosis of pathogens and damaged cells is aided by the complement system, a network of plasma proteins, which coat target cells or bacteria and trigger a proteolytic cascade that enhances their detection or induces directed lysis. Cell types such as neutrophils, eosinophils, natural killer cells, and cytotoxic T cells utilize degranulation to directly lyse target cells.
Specialized innate immune cells like DCs, termed professional antigen presenting cells (APCs), bridge the gap between the innate and adaptive immune system through their capacity to efficiently acquire and present pathogen-derived antigen to adaptive immune cells called lymphocytes, while providing additional signals that polarize lymphocyte differentiation and proliferation (Marshall et al., 2018). Antibody secreting lymphocytes (B lymphocytes) differentiate to generate high affinity antibodies. A subset of T lymphocytes (CD8+ cells) acquires cytotoxic effector functions, while the other major subset (CD4+ cells) acquires helper functions. These helper functions include the capacity to stimulate activation, proliferation, effector function, and recruitment of innate and adaptive immune cells, antibody production, and cytotoxic T lymphocyte activity (Marshall et al., 2018). Helper T cell subsets represent distinct differentiation states with limited plasticity between subsets and notably include highly pro-inflammatory T helper 1 (Th1) and Th17 cells, as well as Th2 cells, follicular helper T cells (Tfh), and regulatory T (Treg) cells (Zhu et al., 2010). Cell fate decisions during differentiation are guided by signals provided by APCs during activation. In this way, the innate and adaptive arms of the immune system coordinate to effectively eliminate pathogens.
Classically, an important distinction between the two arms is the acquisition by B and T cells of the adaptive immune system to form immunologic memory after the infection is cleared, allowing for rapid clearance upon reinfection with the same or similar pathogens (Marshall et al., 2018). However, recent work has described a form of memory in innate immune cells, called trained immunity. This results from epigenetic changes in innate immune cells and may explain how vaccines like the BCG vaccine, which was designed to provide protection from Mtb, provides broader immunity to a variety of pathogens (Covian et al., 2019). The expression of the VDR and key metabolic enzymes, and the important effects of their downstream signaling, have been characterized in numerous immune cell types and will be described in the following sections.

The VDR and vitamin D metabolic enzymes in the immune system.
Studies over the last 40 years or so have provided evidence that CYP27B1 is expressed in several tissues with functions unrelated to calcium homeostasis (Bikle et al., 2018). The largest group of these are epithelial cells (Bikle et al., 2018). Notably, epidermal keratinocytes express higher levels of CYP27B1 than kidney cells and could in theory contribute to circulating levels of 1,25D (Bikle et al., 2018). However, much of 1,25D produced in the epidermis acts locally, suggesting that epidermal CYP27B1 expression is necessary to supply the local demand for 1,25D (Bikle and Christakos, 2020). There are several other extra-renal sites of CYP27B1 expression, including the liver, endocrine glands, thymus, brain, placenta, endothelia, bone. Importantly, CYP27B1 is expressed in several cell types of the innate and adaptive arms of the immune system including DCs, macrophages, monocytes, T cells and B cells (Bikle et al., 2018). Initial studies revealed VDR expression in peripheral blood mononuclear cells (PBMCs) isolated from healthy human donors (Bhalla et al., 1983; Provvedini et al., 1983). While VDR expression was high in monocyte-enriched fractions, no expression was observed in lymphocyte-enriched ones until activated with one of several mitogens. Subsequent studies have confirmed that the VDR is expressed in monocytes (Kreutz et al., 1993), macrophages (Kreutz et al., 1993), and DCs (Brennan et al., 1987). More recently, Vdr expression was detected in rarer cell types in the mouse, including natural killer cells and invariant natural killer T (iNKT) cells (Arora et al., 2022; Yu and Cantorna, 2008).
A sensitive approach to track Vdr expression utilizes mice carrying a floxed tdTomato reporter gene under the control of Cre recombinase linked to Vdr expression (Arora et al., 2022). This results in irreversible reporter gene expression in cells that express the Vdr. While traditional tools revealed little to no VDR expression in naïve lymphocyte populations, this approach found that 78% and 60% of splenic B and T cells, respectively, were tdTomato+, including the majority of naïve CD4+ and CD8+ T cells. Correspondingly, the majority of bone marrow precursors and thymic T cell progenitors were tdTomato+. As these cells are antigen-inexperienced, the results demonstrate (Arora et al., 2022) that the Vdr is expressed during important developmental stages in both T cell and hematopoietic progenitors without the need for antigenic stimulation, as previous data has suggested (Arora et al.,
. Furthermore, distinct subsets of innate lymphoid cells (ILC1 and ILC3, but not ILC2) were tdTomato+. Indeed, we recently showed that both the Vdr and Cyp27b1 are expressed at low levels in developing murine thymocytes, as well as in thymic DCs, B cells, and epithelial cells at higher levels (Artusa et al., 2023).

Signaling pathways controlling CYP27B1 expression in immune cells.
It is important to note that CYP27B1 expression in immune cells is independent of calcium homeostatic inputs (Ismailova and White, 2022) (Table 1). (N.B. data shown in Table 1 is derived only from studies showing primary or direct cell-specific effects on VDR or CYP27B1 expression or direct effects of 1,25D signaling on immune cell phenotype). In innate immune cells, CYP27B1 is induced downstream of cytokine and PRR signaling, for example, in response to stimuli such as IFNy and LPS (Overbergh et al., 2000), and thus represents a primary response to pathogen detection (Fig. 4). Incubation of human macrophages with TLR2 ligands resulted in increased VDR and CYP27B1 expression (Liu et al., 2006). Further work demonstrated that NF-kB signaling following TLR2/1 stimulation induced the expression of IL-15 and IL-1 p, which respectively act to stimulate CYP27B1 expression and induce Th1 cell differentiation (Krutzik et al., 2008; Liu et al., 2009). TH1-derived IFNy then feeds back on macrophages, potently stimulating the vitamin D regulatory network through NF- kB. Mast cells and neutrophils are granulocytes that act as potent mediators of initial inflammatory cascades. While both express the VDR (Yip et al., 2014), neutrophils do not appear to express substantial levels of CYP27B1 (Szymczak and Pawliczak, 2016). DCs and T cells upregulate CYP27B1 when activated by bacterial cell components or signaling through the T cell receptor (TCR), respectively, and 1,25D signaling in these cell types induces a more tolerogenic T cell phenotype (Wei and Christakos, 2015). Intracrine 1,25D signaling in DCs controls their maturation and capacity to present antigen to T cells. Interestingly, DC differentiation is characterized by increased CYP27B1 expression but decreased expression of the VDR, suggesting that 1,25D production by mature DCs is utilized in a paracrine fashion (Hewison et al., 2003). Like T cells, B cells have low expression of the VDR and CYP27B1 in resting conditions but upregulate both in response to stimulation with mitogens (Adams et al., 2014; Provvedini et al., 1983). Evidence suggests that the role of autocrine or paracrine 1,25D signaling is not redundant with renal-derived 1,25D in the circulation (Lindner et al., 2017). Specifically, T cell but not B cell specific Cyp27b1-deficient mice mirrored the elevated IgE response of total Cyp27b1 KO mice in a model of ovalbumin sensitization, suggesting that loss of 1,25D production in T cells only is sufficient to drive the hyper-IgE response observed. The numerous signaling pathways controlling CYP27B1 expression in various immune cell types underline the importance of 1,25D signaling in immune system regulation.

Vitamin D signaling and immune system regulation.
The roles of vitamin D signaling in immunity have been studied extensively, ranging from stimulation of antibacterial and antiviral responses to suppression of autoimmunity (Bouillon et al., 2019). One of the important breakthroughs in this regard was the discovery that vitamin D signaling induces the expression of genes encoding antimicrobial peptides (AMPs). Cathelicidins and defensins represent two major classes of AMPs. VDRE’s adjacent to the transcription start sites of human CAMP and HBD2/DEFB4 (P-defensin 2) genes have been characterized (Gombart et al., 2005; Wang et al., 2004), revealing that the genes encoding these AMPs are direct targets of the VDR. HBD2/DEFB4 induction is epithelial cell-specific, whereas CAMP expression was strongly induced in a wide array of cell types (Wang et al., 2004). This regulation appears to be human/primate-specific; e.g. 1,25D stimulated production of antimicrobial activity in cultured human, but not mouse, epithelial cells against Escherichia coli (E. coli), and the lung pathogen Pseudomonas aeruginosa (P. aeruginosa) (Dimitrov and White, 2016). In the clinic, circulating levels of CAMP were significantly increased in vitamin D- supplemented Crohn’s Disease (CD) patients versus those receiving placebo in a small placebocontrolled trial with 27 participants (Raftery et al., 2015).
Regulation of antimicrobial responses by 1,25D is multi-layered; in addition to inducing AMP production, 1,25D stimulates PRR expression and autophagy (Ismailova and White, 2022). Autophagy is a key process of immunity that ties the innate and adaptive immune systems together by enhancing antigen presentation and regulating cytokine production, in addition to its role in eliminating intracellular pathogens (Deretic, 2016). Vitamin D can activate autophagy in numerous cell types including keratinocytes, hepatocytes, and endothelial cells in response to cellular damage and oxidative stress (Bhutia, 2022). 1,25D induces autophagy in macrophages by enhancing branched chain amino acid (BCAA) catabolism (Dimitrov et al., 2021). BCAAs are essential amino acids that act as indicators of metabolic status in macrophages and activate signaling by the key metabolic kinase mammalian target of rapamycin (mTOR) (Dimitrov et al., 2021), a key inhibitor of autophagy. PRR expression is also regulated by 1,25D. Monocytic cells and keratinocytes treated with 1,25D strongly upregulated CD14 gene expression, the co-receptor of TLR4 (Oberg et al., 1993). 1,25D also induces the expression of genes encoding the PRR, NOD2/CARD15, whose gene is mutated in a subset of patients with CD, further supporting a role for vitamin D signaling in barrier immunity (Wang et al., 2010). Cytokines and chemokines, a type of cytokine which stimulates cell migration and recruitment to tissues, are critical messenger signals in the immune system. In macrophages, 1,25D stimulates the production of IL-ip and chemokines including CCL3, CCL4, CCL8, IL-8/CXCL8 (Verway et al., 2013). Co-culture of Mtb-infected macrophages with primary human airway epithelial cells revealed that 1,25D-dependent induction of IL-ip enhanced infected macrophage survival (Verway et al., 2013). Collectively, these data show that vitamin D signaling positively regulates the anti-microbial activity of first responders to infection, which include macrophages, neutrophils, and stromal cells.
Although 1,25D signaling stimulates antimicrobial immunity, it can also paradoxically function to dampen the immune response, particularly in the adaptive arm of the immune system. For example, 1,25D suppressed the production of pro-inflammatory cytokines IL-6, TNFa, and IFNy in Mtb-infected human peripheral blood mononuclear cells (PBMCs), in a dose-dependent manner (Khoo et al., 2011). Stimulation with lipopolysaccharide (LPS), a component of the outer cell wall of gram-negative bacteria and the ligand for TLR4, induced IL-6 and TNFa production in human and murine monocytes/macrophages. Notably, this induction was suppressed by 1,25D treatment (Zhang et al., 2012). In NK cells, 1,25D in combination with the synthetic glucocorticoid dexamethasone enhanced the expression the anti-inflammatory cytokine IL-10 and induced a regulatory phenotype (Deniz et al., 2008). Similarly, intracrine production of 1,25D by DCs induces a tolerogenic phenotype, characterized by IL-10 production, decreased IL-12 and IL-23 production, and decreased expression of MHC-II and co-stimulatory molecules including CD40, CD83, and CD86 (Adorini and Penna, 2009). This, in turn, has significant downstream effects on the phenotype of lymphocytes including reducing B cell proliferation and antibody production, as well as reduced differentiation of pro-inflammatory Th1 and Th17 T cell populations.
In addition to the cell extrinsic effects of 1,25D on T cell activation and differentiation, there are also intrinsic effects as well. As mentioned above, TCR triggering with co-stimulation results in upregulation of the VDR (Bishop et al., 2021). In human T cells, 1,25D signaling through the VDR results in enhanced expression of the VDRE containing gene PLCG1, which encodes PLC-y1, a central component of the TCR signaling cascade (von Essen et al., 2010). Therefore, 1,25D signaling in human cells contributes to T cell priming in a cell intrinsic manner. This may assist with the rapid activation of T cells when a threat is detected, however, 1,25D signaling through the VDR in T cells also attenuates IL2 transcription, which is fundamental to the differentiation and proliferation of both CD4+ and CD8+ T cells (Chen et al., 2014; Rigby et al., 1984). This may be essential to limit excessive proliferation of T cells after antigen exposure. Consistent with this, Vdr or Cyp27b1-deficient murine T cells have a hyperproliferative phenotype.
Regulation of T helper cell differentiation by vitamin D is well documented. CD4+ T cells derived from Vdr KO versus wildtype mice cultured in the presence of Th17 inducing cytokines (transforming growth factor beta (TGF-pi) and IL-6) with TCR stimulation resulted in double the amount of Th17 cells in KO cultures (Bruce et al., 2011). Conversely, treatment of wildtype T cells with 100nM 1,25D reduced the frequency of Th17 cells by half. 1,25D treatment also inhibits Th1 differentiation and IFNy production (Bruce et al., 2011). In addition, complement binding to CD46 on differentiated human Th1 cells induced VDR and CYP27B1 production and subsequent changes in gene expression leading to attenuation of their pro-inflammatory phenotype (Chauss et al., 2022). While the frequency of naturally occurring anti-inflammatory regulatory T cells (Tregs) in the circulation or in secondary lymphoid organs is unaltered in Vdr or Cyp27b1 KO versus wild-type mice (Artusa et al., 2024), in vitro polarization of Vdr KO Tregs using TGF-pi and TCR stimulation is significantly impaired relative to controls. Collectively, these results show that vitamin D signaling influences T cell differentiation at several levels, attenuating inflammatory T cell responses.
Recently, a randomized controlled trial of 25,871 participants, vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease (VITAL), examined the effect of daily intake of 2,000 IU of vitamin D, 1,000 mg of omega 3 fatty acids, or matched placebos, respectively, on autoimmune disease incidence within a 5 year period (Hahn et al., 2022). Participants included diverse but mostly non-Hispanic white (70%) ethnicities, made up of roughly 50% men and women over the age of 50 in the U.S. Vitamin D supplementation, with or without omega 3 fatty acid intake, reduced the incidence of all self-reported autoimmune diseases by 22% (hazard ratio 0.78, confidence interval 0.61-0.99, P=0.05). Intriguingly, the protective effects of vitamin D supplementation dissipated 2 years after the trial ended (Costenbader et al., 2024). Consistent with the results of the trial, low vitamin D status exacerbates disease severity and mortality in a variety of murine models of human autoimmune diseases. In a chemical injury model of gut colitis, which is dominated by pathogenic Th1 and Th17 responses (Froicu and Cantorna, 2007), Vdr-deficient mice exhibited increased Th17 differentiation and disease pathology. In the same study, it was shown that vitamin D supplementation of wildtype mice reduced disease severity. 1,25D treatment also slows the progression of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS) (Lemire and Archer, 1991). The protective effects of 1,25D in EAE pathogenesis was abrogated by selective deletion of the Vdr in T cells (Mayne et al., 2011). Dietary intake of 1,25D in mice also prevented or abrogated symptoms associated with two murine models of arthritis (Cantorna et al., 1998). Similarly, dietary intake of 1,25D in combination with intraperitoneal injections attenuated the symptoms of a mouse model mimicking human systemic lupus erythematosus (SLE) (Lemire et al., 1992). Low vitamin D status is also a risk factor for conditions such as asthma, allergic rhinitis, and wheezing (Bener et al., 2014), where Th2 cells play a pathogenic role. Mice fed a vitamin D deficient diet had increased T cell dependent antibody titers associated with enhanced Th2 responses in a mouse model of allergic airway hypersensitivity to chicken egg ovalbumin (OVA) (Heine et al., 2014). Therefore, vitamin D signaling controls autoinflammatory disease progression in models with distinct pathogenic mechanisms.
Numerous pre-clinical and clinical studies have linked decreased vitamin D levels to increased incidence of type 1 diabetes (T1D) (Daskalopoulou et al., 2022; Soltesz et al., 2007), which is characterized by autoimmune destruction of insulin-producing beta cells of the pancreas. Non obese diabetic (NOD) mice, which have mutations in a variety of loci encoding proteins that regulate T cell activation, are the most common murine model of T1D (Chen et al., 2018). Results of studies examining the role of vitamin D signaling in incidence of autoimmune diabetes in NOD mice are conflicting. Early evidence suggested that vitamin D supplementation in female NOD mice reduced the incidence of disease from 56% to 8% (Mathieu et al., 1994). Another study found that both male and female mice fed a vitamin D-depleted diet in the first 100 days of life led to increased T1D incidence during adulthood (Giulietti et al., 2004). Unexpectedly, Vdr-deficient NOD mice developed diabetes at the same rate as control NOD mice (Gysemans et al., 2008). Thus, more investigation of vitamin D signaling in disease incidence in the NOD mouse model is merited. It is important to note that vitamin D signaling in pancreatic beta cells is important for their proliferation and survival (Wang et al., 2016). Collectively, poor vitamin D status is linked to the pathogenesis of multiple models of autoinflammatory disease, mirroring clinical findings made in humans. However, the potential therapeutic benefits of 1,25D supplementation in the prevention and treatment of human autoimmune diseases is still under investigation.
Given the current literature, it is highly probable that 1,25D signaling in both arms of the immune system is involved in autoinflammatory disease initiation and progression. In addition, other evidence exists that vitamin D signaling in non-immune cells may shape the immune response. Adoptive transfer of T cells into recombinase activating gene (RAG) deficient mice results in T cell driven intestinal inflammation and mortality. Interestingly, in reciprocal bone marrow chimera experiments, wildtype T cells that developed in Vdr deficient hosts were far more pathogenic than Vdr KO T cells that developed in wildtype mice when adoptively transferred into RAG KO mice (Giulietti et al., 2004). Furthermore, Vdr KO T cells that developed in wildtype hosts did not have significantly differences in weight loss when compared to wildtype T cells that developed in wildtype mice. This data strongly argues for the involvement of non-hematopoietic cell types in long lasting phenotypic changes observed in T cells.
While vitamin D signaling in keratinocytes and other non-immune stromal cell types has been carefully examined, vitamin D action in stromal cells of the thymus, which shapes T cell development, has been largely overlooked until recently. The thymus regulates the maturation of bone marrow derived T cell precursors into mature naïve T cells. Critical developmental checkpoints including MHC restriction, lineage commitment, and the negative selection of highly autoreactive T cells, all of which occur in waves through interactions between the TCR and peptide-MHC expressed by antigen presenting thymic epithelial cells (TECs) (Shichkin and Antica, 2022). Importantly, defects in negative selection result in compromised central tolerance and the escape of autoreactive T cells into the circulation, which leads to autoimmunity. The activity of the transcription factor autoimmune regulator (AIRE) is critical to the process of negative selection, as it induces the ectopic expression of tissue restricted antigen (TRA) in medullary TECs (mTECs) (Marx et al., 2021). Loss of AIRE function in humans results in autoimmune polyendocrinopathy candidiasis ecto-dermal dystrophy (APECED), a multifaceted autoimmune disorder. Thus far, it has been shown that thymocyte development in the absence of 1,25D signaling is largely normal, with little to no differences in the proportion of major thymocyte subsets (Artusa et al., 2024; Yu and Cantorna, 2011). However, the intra-thymic development of regulatory innate-like immune cells including iNKT and CD8aa-intraepithelial lymphocytes is defective in Vdr deficient mice (Artusa et al., 2024; Yu and Cantorna, 2008; 2011).
We found that the Vdr and Cyp27b1 are expressed in multiple non-lymphoid cell types in the thymus, notably Aire+ mTECs, and that 1,25D signaling was intact in TECs (Artusa et al., 2023). Notably, 1,25D treatment induced Aire and TRA gene expression, suggesting that vitamin D signaling may regulate key aspects of central tolerance. Consistent with this, the proportion of Aire+ mTECs and TRA gene expression was reduced in the thymus of Vdr and Cyp27b1 deficient mice (Artusa et al., 2024). Moreover, markers of T cell negative selection were diminished in Cyp27b1 deficient mice. Evidence of spontaneous autoimmunity could be observed in the pancreas and stomach of Cyp27b1 deficient mice. Additionally, we found that thymi were significantly smaller in Cyp27b1-deficient mice by 8 weeks of age, and that loss of vitamin D signaling led to a premature thymic aging phenotype. These results are noteworthy as aging increases susceptibility to infection and cancer due to accumulated defects in immune function (Liang et al., 2022). This is in part attributable to loss of thymic function, as thymic activity peaks in our infancy and childhood. This suggests that vitamin D signaling contributes to thymic function by promoting tissue longevity and the development of self-tolerant T cell repertoire.
AIRE regulates the expression of thousands of genes, but it is poorly understood how it is recruited to chromatin due to the absence of a sequence-specific DNA-binding domain. To date it’s been shown that distinct domains of AIRE recognize H3K4me0 marks on chromatin, bind to methylated CpG islands, or are anchored to Z-DNA (Fang et al., 2024; Org et al., 2008; Waterfield et al., 2014). While these interactions contribute to Aire activity, disruption of their interactions do not alter the breadth of AIRE targets, suggesting that other recruitment mechanisms are active. The presence of 4 conserved LXXLL motifs, nuclear receptor binding sites, in AIRE strongly suggests that it can bind to nuclear receptors in vivo (Nagamine et al., 1997). We found that AIRE was a coactivator of the Vdr in a model in vitro system and that the two proteins are recruited to chromatin in a 1,25D- dependent manner in primary murine mTECs. This supports the notion that AIRE may interact with and be recruited to DNA by its interaction partners, which include the Vdr and potentially other nuclear receptors (Artusa et al., 2023). Since nuclear receptors target genes also number in the thousands, such interactions may function to enhance the breadth of Aire targets.

Vitamin D and its analogues in immune-related disorders.

Several publications have alluded to connections between seasonality of infectious diseases and fluctuating vitamin D metabolite levels. However, the seasonality of vector-borne infections also correlates with climatic conditions favoring their replication (Coussens, 2017). Nonetheless, as presented above, the expression of the VDR and CYP27B1 in immune cells is widespread, and there is growing preclinical evidence for roles of vitamin D signaling in controlling innate immune and inflammatory responses (Fig. 4). As a result, there have been numerous clinical trials to test the potential benefits of vitamin D supplementation to prevent or attenuate the incidence or severity of immune-related disorders. The ultimate test of the efficacy of vitamin D supplementation is the randomized, double blind, placebo-controlled trial (RCT). However, RCTs with vitamin D supplementation are fraught with complications because vitamin D is a nutrient and not a drug, and assessment of vitamin D intake is complicated by the cutaneous synthesis that occurs in the presence of adequate solar UVB. Finally, as it is unethical to leave a patient vitamin D deficient, placebo wings frequently include low-dose vitamin D supplementation (often 400IU/day). As a result, many trials are conducted on vitamin D-sufficient populations. Moreover, as described below, dosing schedules appear to be key for efficacy.

Vitamin D supplementation in bacterial infections.
In vitro studies described above showed that vitamin D signaling in humans induces expression of the genes encoding antimicrobial peptides CAMP and HBD2, as well as the secretion of antimicrobial activity (Wang et al., 2004). In an RCT of patients treated with placebo or 1,000 IU/day of vitamin for 90 days, supplementation enhanced antimicrobial activity of lung airway surface liquid (ASL) (Vargas Buonfiglio et al., 2017). Moreover, supplementation eliminated seasonal variations in ASL antimicrobial activity consistent with fluctuating vitamin D metabolite levels. Moreover, ASL antimicrobial activity was inhibited by a blocking antibody recognizing the active form of CAMP, LL37 (Vargas Buonfiglio et al., 2017). These studies thus link vitamin D status to mucosal antibacterial activity in humans.
Consistent with a role of vitamin status in controlling antibacterial activity, several crosssectional and observational studies as well as RCTs link low vitamin D status to dental caries (Ismailova and White, 2024; Li et al., 2023; Olczak-Kowalczyk et al., 2021; Suarez-Calleja et al., 2021). These were supported by umbrella analyses of systematic reviews and meta-analyses (Hujoel, 2013; Theodoratou et al., 2014). One, encompassing a broad array health outcomes, singled out an inverse association of dental caries with vitamin D status (Theodoratou et al., 2014). While the quality and reliability of trials varied considerably, the study noted that “restricting the analysis to studies with nonbiased treatment assignment increased the percent reduction in caries rate from 47% to 54%” (Theodoratou et al., 2014). Robust innate immune responses, including AMP production, are important for oral health (Dale et al., 2006; Ozturk et al., 2010). Notably, CAMP/LL-37 is efficacious against bacterial species, such as Streptococcus mutans, present in plaque (Yoshida et al., 2019), and its concentrations in saliva correlate positively with vitamin D status (Gyll et al., 2018). Another study found an inverse correlation with salivary 25D levels and severity of caries (Nireeksha et al., 2024). Vitamin D status has also been linked with AMP levels in other diseases of oral health such as gingivitis and chronic periodontitis (Bayirli et al., 2020).
Bacterial infections of the urinary tract (urinary tract infections, UTI) are also linked to low serum vitamin D levels. Vitamin D signaling induces CAMP expression in the urinary bladder (Hertting et al., 2010), and urinary LL-37 levels are correlated with vitamin D metabolite levels in young children (Georgieva et al., 2019). Clinically, recurrence of UTI in infants, children, and premenopausal women are linked to low vitamin D status (Gan et al., 2023; Georgieva et al., 2019; Hacihamdioglu et al., 2016; Nseir et al., 2013; Tekin et al., 2015). These findings are supported by a meta-analysis of 9 studies and 1921 participants, which confirmed the correlation between rates of UTI and low vitamin D status (Deng et al., 2019). Numerous publications have also linked poor vitamin D status to severity of bacterial sepsis, and correlations have been made between seasonal variations in vitamin D status and seasonality of sepsis, whose incidence is highest in the winter and lowest in the fall (Danai et al., 2007; Kempker et al., 2012). Moreover, in the US, seasonal variations increase with latitude (Danai et al., 2007). A systematic review of observational cohort studies encompassing 9,715 critically ill patients concluded that low serum vitamin D levels increased the risk of sepsis and mortality in critically ill patients (de Haan et al., 2014). Subsequent studies reached similar conclusions, including one in neonates (Seok et al., 2023; Upala et al., 2015; Workneh Bitew et al., 2021). In a small RCT (20 patients only) in new-onset sepsis patients, high-dose vitamin D supplementation trial raised 25D levels by 5-15 ng/mL (200,000 and 400,000 IU, respectively) and increased circulating levels of LL- 37, but did not analyze sepsis-related outcomes (Quraishi et al., 2015). Unfortunately, this trial is typical of other intervention trials, which were underpowered to assess effects of supplementation on clinical outcomes in sepsis patients. Clearly, larger RCTs, to assess the efficacy of supplementation with vitamin D or one of its analogues, are warranted.

Vitamin D supplementation in viral infections.
There has been widespread interest in the potential protective effects of vitamin D in respiratory infections, many of which are viral in origin. In an RCT conducted on Japanese school children (Urashima et al., 2010), vitamin D supplementation reduced the rates of seasonal influenza A, with the most striking effects in children who had not previously received supplements. While these results are compelling, globally, the results of intervention trials are mixed. Adrian Martineau and coworkers have published two meta-analyses of studies examining the potential benefits of vitamin D supplementation on incidence and severity of acute respiratory tract infections (ARIs) (Jolliffe et al., 2021; Martineau et al., 2017). The findings are important for several reasons. Both the 2017 study and its 2021 update highlighted the fact that daily dosing of vitamin D, as opposed to bolus dosing, was efficacious in reducing the incidence of ARIs. The 2021 update noted “No significant effect of vitamin D supplementation on the risk of having one or more ARIs was observed for any of the subgroups defined by baseline 25(OH)D concentration.” (Jolliffe et al., 2021). As pointed out in a recent viewpoint article (Giustina et al., 2024), of mega supplementation trials in New Zealand, Australia and the U.S., two employed monthly bolus dosing schedules, which other studies have found are not efficacious. There is thus a need for population-based RCTs of daily vitamin D supplementation that are sufficiently powered to detect any effects of vitamin D on a variety of indications, immune-related or otherwise. There is also a need for further analysis of individual participant data from existing trials aimed at subgroup analysis to assess the potential benefits of supplementation of individual with low vitamin D levels (25D levels <25nM) (Giustina et al., 2024).
The growing links between vitamin D signaling and antiviral innate immunity (White, 2022) spurred an interest in a potential role of vitamin D status and incidence and outcome of COVID-19, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS CoV2) infection. Immune evasion strategies by SARS CoV2 can be accompanied by elevated proinflammatory cytokine release, pneumonia (Wang et al., 2020), sepsis and potentially fatal acute respiratory distress syndrome (Zhou et al., 2020), symptoms whose incidence is also associated with poor vitamin D status (Quesada- Gomez et al., 2020; Tsujino et al., 2019; Zhou et al., 2019). It is noteworthy that 1,25D was identified as a repurposed drug for treatment of H5N1 influenza A virus-induced lung injury, whose clinical features are similar to those of COVID-19 (Huang et al., 2021). During the pandemic, numerous clinical studies were conducted to determine the potential relationship between vitamin D status and COVID- 19 incidence and outcome. A recent systematic review and meta-analysis of 16 studies assessed the potential protective role of vitamin D supplementation in COVID-19 incidence, mortality, and patient intensive care unit admission (Sartini et al., 2024). Significantly, the analysis, which included a mix of RCTs, as well as prospective, retrospective and cohort studies with different dosing regimens, concluded that supplementation has a protective effect against COVID-19 incidence in RCTs and against both incidence and intensive care unit admission in other study types. While these results are encouraging, further large-scale RCTs will be necessary to firmly establish the protective effects of vitamin D in COVID-19.

Inflammatory Bowel Diseases.
Crohn’s disease (CD) is a relapsing-recurring form of IBD arising from defective intestinal innate immune homeostasis (White, 2018). The incidence of CD is rising worldwide (Ng et al., 2017), and, notably, its frequency increases with increasing latitude. In addition, there is an association of CD risk with low sun exposure early in life (Holmes et al., 2019; Jantchou et al., 2014). Given the roles of vitamin D signaling in enhancing innate immunity and suppression of inflammatory immune responses in general, and the relevance of its target gene regulation to CD specifically, there has been considerable interest in vitamin D (analogue) supplementation in CD therapy (Vernia et al., 2022). Sidechain analogues of 1,25D, BXL-62 [1a,25(OH)2-16-ene-20-cyclopropyl-vitamin D3], TX 527 [19- nor-14,20-bisepi-23-yne-1,25(OH)2D3] and ZK-191784 (with a cyclopropane- and oxazole-substituted sidechain) have demonstrated efficacy in reducing inflammatory markers and maintaining barrier integrity in preclinical or ex vivo models of IBD (Laverny et al.; Martinesi et al., 2014; Stio et al., 2007). A number of generally small intervention trials have, collectively, supported a role for supplementation in reduction of disease activity (White, 2018). Meta-analyses of observational studies and RCTs linked poor vitamin D status to increased disease activity and confirmed the benefits of supplementation in reducing rates of clinical relapse (Gubatan et al., 2019; Li et al., 2018; Valvano et al., 2024). It is important to note, however, that, in some CD patients, supplementation is complicated by intestinal malabsorption after bowel resections or ostomy procedures associated with CD management. For example, in one study, patients who did not respond to oral supplementation benefitted from highdose sublingual vitamin D2 treatment (McCullough and Heaney, 2017). Moderate UVB exposure is also an alternative in these cases (Koutkia et al., 2001).
It is likely that therapeutic benefit of vitamin D supplementation of CD patients also arises from the effects of vitamin D sufficiency on composition of the gut microbiome (Cantorna and Arora, 2024). A healthy microbiome contributes to normal immune system development, extraction of energy and nutrients from dietary components, and competitive displacement of pathogens. It also appears that the nature of microbial colonization that occurs early in life is important for immune system development and may affect disease risk later in life (Rinninella et al., 2019). CD is characterized by dysbiosis of the gut microbiome, with an enrichment of species associated with inflammation (Kaakoush Nadeem et al., 2020; Marie et al., 2011; Seksik et al., 2003). In an RCT conducted on healthy adults, serum 25D levels were associated with enrichment of beneficial bacteria at the expense of pathogenic species. Notably, supplementation led to a dose-dependent increase in species associated with decreased IBD activity (Charoenngam et al., 2020). Given all of the above, it would be important to undertake larger scale RCTs to determine optimum dosing schedules for supplementation and to assess the potential interactions of supplementation with other CD therapeutics (Cantorna and Arora, 2024).

Vitamin D and allergies.
Allergies arise from an overreaction of the immune system to allergens due to genetic, environmental, and nutritional factors. The pathogenesis of allergic reactions can be attributed to excessive type 2 responses with participation from TH2 cells, mast cells, basophils, eosinophils, and IgE secreting B cells (Zhang et al., 2024). In addition to less common excessive responses to food allergens, allergic diseases including asthma, allergic rhinitis, and atopic dermatitis can place a heavy burden on the affected persons and the healthcare system. While allergies are not strictly geographically restricted, there are observations of increased frequencies of allergies in populations at higher latitudes (Camargo et al., 2007; Mullins et al., 2009). Moreover, there is data suggesting that sunlight exposure may be critical in the first two years of life to reduce the risk of developing food allergies, asthma, allergic rhinitis, and atopic dermatitis (Hwang et al., 2016). This suggests that vitamin D status early in life may be an important factor in preventing childhood onset of allergic diseases.
Studies examining asthma risk in healthy and asthmatic individuals have found that vitamin D status is negatively correlated with asthma risk and severity in both children (Bener et al., 2012; Kolokotroni et al., 2015), and adults (Chang et al., 2023; Niruban et al., 2015; Zhu et al., 2022). Various studies have reported an inverse relationship between vitamin D status and rates of atopic dermatitis in children and adults (Baek et al., 2014; Cicek and Kole, 2023; Ng and Yew, 2022). Similarly, the majority of studies are in agreement that vitamin D levels are lower in atopic rhinitis patients than in healthy controls (Coban et al., 2021; Restimulia et al., 2018; Saad et al., 2020). However, a number of studies have found no links between vitamin D status and the risk of developing atopic dermatitis or allergic rhinitis, in both adults and children (Baiz et al., 2014; Berents et al., 2016; Cheng et al., 2014; Wu et al., 2017). Thus, more work is required firmly establish a relationship between low vitamin D status and disease risk. We note that differences in risk for each of these diseases have also been attributed to gender, race, ethnicity, genetics, and lifestyle choices.

Vitamin D and autoimmunity
Poor vitamin D status is implicated in all major autoimmune diseases (Bouillon et al., 2019). Intriguingly, the incidence of T1D and MS are associated with latitude (Bach, 2018). A study of white army recruits in the U.S. found that 25D levels of less than 50 nmol/L at the time of recruitment were linked to an almost twofold increased risk of MS later in life (Munger et al., 2006). Maternal 25D levels of less than 30 nmol/L were associated with a 1.9-fold increased risk of development of MS in the offspring of Finnish women (Munger et al., 2016). Increased MS risk in multiple studies was also correlated with genetic variants predisposing to lower circulating 25D levels (Mathieu et al., 2005). A low frequency variant of CYP2R1 which conferred a large effect on circulating 25D levels was associated with a 1.4-fold increased risk of developing MS (Manousaki et al., 2017). A meta-analysis of cohort studies conducted in the U.S. and Sweden analyzing the effects of single nucleotide polymorphisms associated with decreased 25D levels also concluded that poor vitamin D status was a risk factor for MS (Rhead et al., 2016).
In a study identifying 310 T1D cases (along with 613 controls) found that 25D levels > 100nmol/L were associated with a 44% lower risk of T1D in non-Hispanic US military personnel. In contrast, those in the bottom 20% of 25D status had the highest risk of developing T1D (Munger et al., 2013). Several retrospective studies found that vitamin D supplementation in the first year of life lowered the risk of later development of T1D. A large cohort study of 10,366 children born in northern Finland in 1966 and published in 2001 found that vitamin D supplementation was associated with dramatically decreased incidence of T1D (Hypponen et al., 2001). Specifically, the relative risk of regular versus no supplementation was 0.12. In addition, children who took the recommended 2,000 IU per day dose had a relative risk of 0.22 compared to those who received lower doses. Finally, children displaying symptoms of rickets had a 3.0 increased relative risk of developing T1D (Hypponen et al., 2001). These findings are significant as interpretation of many studies is complicated by the effects of sun exposure on vitamin D status. However, sun exposure is not a significant source of vitamin D in northern Finland due to the year-round vitamin D winter.

Vitamin D analogues in inflammatory disorders
In addition to their therapeutic applications for indications associated with disrupted calcium homeostasis such as osteoporosis and chronic kidney disease (CKD)(Maestro et al., 2019), vitamin D analogues have demonstrated efficacy for the treatment of various inflammatory disorders. Numerous classes of analogues have shown superior efficacy relative to 1,25D in the suppression of inflammation and modification of immune population phenotypes. Evidence is derived from pre-clinical studies using human PBMCs and mouse models, in addition to clinical data examining their effects on psoriatic lesions. One of the earliest analogues whose immune regulatory function was described was alfacalcidol. In agreement with its potential anti-inflammatory properties, alfacalcidol treatment attenuated disease severity in a rat model of type II collagen-induced arthritis (Tsuji et al., 1994). In the clinic, one case report claimed that alfacalcidol treatment cured psoriatic lesions (Berth-Jones and Hutchinson, 1992). Two studies in humans undergoing hemodialysis for chronic kidney disease oral administration of alfacalcidol for four weeks enhanced IL-2 production and lymphoproliferative responses of isolated PBMCs, respectively (Tabata et al., 1988; Tabata et al., 1986). These findings are intriguing as they are in contrast to our current understanding of the function of vitamin D signaling in suppression of IL2 transcription and T cell proliferation. However, it is unclear how the diseased state in CKD patients affected these outcomes.
Newer vitamin D analogues have yielded results consistent with our current understanding of vitamin D biology. Topical application of calcipotriol (Fig. 3) on psoriatic lesions reduced epidermal differentiation, the production of pro-inflammatory cytokines such as IL-6 and attenuated the recruitment of T cells and neutrophils. Treatment of human PBMCs with calcipotriol reduced LPS- dependent IL-1 production, and in separate work, attenuated IgM, IgG, and IgA antibody production in mitogen stimulated cells (Berth-Jones and Hutchinson, 1992). In the clinic, topical calcipotriol is an efficacious treatment of psoriasis vulgaris (Kragballe et al., 1991) and is currently one of the most commonly prescribed medications alongside betamethasone, a corticosteroid (Patel et al., 2008). Importantly, calcipotriol is efficacious without causing hypercalcemia - a major limitation for usage of naturally occurring 1,25D at therapeutic dosages. Mechanistically, this appears to be due to reduced affinity for DBP and more rapid clearance (Berth-Jones and Hutchinson, 1992) (see also section 4 on vitamin D analogues). While highly efficacious, up to 20% of patients treated with topical calcipotriol experience cutaneous irritation when applied to the face or intertriginous areas. Notably, a comparative clinical study assessing the safety and efficacy of calcipotriol versus calcitriol found that patients using calcitriol had a significantly greater improvement due to effects on flexural region without any clinically significant hypercalcemia observed.
As such, newer analogues such as tacalcitol and maxacalcitol were developed. Tacalcitol (1a,24-dihydroxyvitamin D3) is hydroxylated at the 24 position but lacks other sidechain modifications. Its topical application was effective at reducing PMN, T cell, and monocyte numbers in psoriatic lesions while inhibiting epidermal cell proliferation. While less cutaneous irritation was reported in humans, there is evidence that tacalcitol may also be less efficacious as a therapy. Maxacalcitol (Fig. 3) suppressed keratinocyte proliferation in vitro significantly better than both calcipotriol and tacalcitol (Barker et al., 1999). Furthermore, once-daily topical application of maxacalcitol markedly improved or cleared psoriasis in 55% of participants, compared to 46% for those receiving calcipotriol (Barker et al., 1999). Maxacalcitol also has also demonstrated efficacy in treating palmoplantar pustulosis, a chronic inflammatory skin condition characterized by pustules on the palms and soles (Yamamoto, 2019). Pre-clinical studies using murine models have demonstrated that topical maxacalcitol treatment on imiquimod-induced psoriatic skin inflammation reduced MHC-II+ cell infiltration, expression of pro- inflammatory cytokines IL-17, IL-22, IL-12p40, TNFa, and IL-6 mRNA in the skin, and significantly increased FoxP3+ regulatory T cell infiltration and IL-10 expression when compared to betamethasone ointments or vehicle controls (Hau et al., 2018). Interestingly, maxacalcitol uniquely suppressed the expression of IL-23p19, which is elevated in psoriatic lesions and contributes to the stabilization of pathogenic Th17 signature secretion. This is noteworthy as pro-inflammatory Th17 cells are pathogenic in a variety of autoimmune and autoinflammatory conditions (Yasuda et al., 2019), providing a clear rationale for investigating the use of vitamin D and its analogues in the treatment of such diseases. Notably, one study found that oral maxacalcitol treatment significantly reduced markers of arthritis and systemic lupus erythematosus in autoimmune MRL/lpr mice without elevating serum calcium (Abe et al., 1990), and separately, it was shown that oral maxacalcitol had a smaller effect on serum calcium in mice receiving doses even 30X higher than that of 1,25D. Therefore, oral maxacalcitol therapy could be a promising drug candidate for use in humans with autoimmune disease.
Maxacalcitol, tacalcitol, calcipotriol, alfacalcidol, and doxercalciferol are currently approved for topical use to treat psoriasis in various countries including Canada, the United States, Europe, and Japan (Leyssens et al., 2014). However, efficacy in diverse pre-clinical disease models has been shown for several other vitamin D analogues yet to be used clinically. Systemic administration of MC- 1288, a C20 epimer of 1,25D, suppressed the development of type I collagen induced arthritis in mice when given before the onset of disease and reduced the severity of joint inflammation when given at the onset of disease, without causing hypercalcemia (Larsson et al., 1998). KH-1060, another C20 epimer of 1,25D with an extended sidechain bearing an ether, was shown to prevent the onset of T1D in NOD mice at non-hypercalcemic doses (Mathieu et al., 1995). Another study showed that KH-1060 bound to the VDR with a similar affinity as 1,25D but more potently suppressed IL-2 production by mitogen stimulated human PBMCs. Furthermore, KH-1060 was 633,000 times more potent than 1,25D at suppressing murine thymocyte proliferation, albeit with a 1.3-fold increased calcemic effect (Binderup et al., 1991b).
Several analogues have been tested for efficacy in treatment of gut inflammation and have shown promising results. ZK191784, a secosteroidal sidechain analogue, suppressed Th1 mediated colitis (Daniel et al., 2006; Strauch et al., 2007) in mice and modulated NF-kB signaling in murine preadipocytes and macrophages while suppressing their pro-inflammatory phenotype (Zhu and Wilding, 2020). In human PBMCs, ZK191784 demonstrated improved suppression of IFNy, TNFa, IL- 1p, while enhancing induction of IL-4 and IL-10 (Daniel et al., 2005), consistent with its antiinflammatory effects in murine disease models. Similarly, 1a,25-dihydroxy-16-ene-20-cyclopropyl-24- oxo-vitamin D3 exhibited significantly enhanced suppression of IL-6, IL-12, IFNy, TNFa production in human PBMCs compared to 1,25D, while super-inducing CYP24A1 and CAMP (Laverny et al., 2009).
Furthermore, it was markedly less calcemic than 1,25D when administered in vivo to mice (Lemire et al., 1994). Importantly, data from primary lamina propria mononuclear cells derived from IBD patients revealed that this analogue inhibited pro-inflammatory cytokine production more efficaciously than 1,25D (Laverny et al., 2010).
While the analogues described above consist of primarily of 1,25D-like secosteroids with various side-chain modifications, non-secosteroid analogues have also been generated and investigated for clinical efficacy. Compound A, a non-secosteroid with a diarylpentane core identical to those of LG190178 and LY2108491, appeared to act in a cell-specific manner; it promoted an antiinflammatory phenotype in activated human PBMCs, characterized by enhanced Th2 cytokine secretion and diminished Th1 and Th17 cytokine secretion without strongly inducing vitamin D- responsive genes in human intestinal cell lines (Na et al., 2011). Importantly, mouse studies demonstrated that Compound A is not hypercalcemic in vivo at high doses and is more efficacious than 1,25D at diminishing EAE severity (Na et al., 2011). Collectively, the increased efficacy and decreased calcemic effects of vitamin D analogues relative to natural vitamin D metabolites support the utility in the clinic. Currently approved analogues are utilized for topical treatment of psoriasis, however, promising results with these and the other analogues suggest they may represent efficacious treatments for other autoinflammatory human diseases.

Vitamin D analogues and their potential as adjuncts to cancer immunotherapy.

The potential association between vitamin D status and increased cancer risk was first proposed in a seminal study that found increased colon cancer mortality in populations residing in the northeast of the United States, which has less UV exposure year-round, than those living in the south (Garland and Garland, 1980). Other data demonstrating an association between low serum vitamin D levels and increased risk of prostate, colorectal and breast cancers further supported this hypothesis (Ahonen et al., 2000; Bertone-Johnson et al., 2005; Garland et al., 1989). A series of studies published in 2010 analyzing serum 25D concentrations and risk of developing rarer cancers, including endometrial, esophageal, gastric, kidney, non-Hodgkin lymphoma, ovarian, and pancreatic cancer, did find a reduced risk of developing cancer in those with serum 25D >30ng/mL. However, whether low vitamin D levels are causative or merely associative is still under debate.
Numerous studies have noted the antiproliferative and pro-differentiation effects of 1,25D on cancer cells (Deeb et al., 2007; Fleet et al., 2012), leading to an interest in vitamin D and its analogues as potential cancer therapeutics. As discussed above, vitamin D also has many immune-modulatory functions, which suggests that its regulation of immune cell function may affect cancer surveillance or control. Several RCTs of vitamin D supplementation have been conducted to test the potential anticancer efficacy of vitamin D. A post-hoc analysis of the AMATERASU trial, which included colorectal cancer patients receiving placebo or 2,000 lU/day of vitamin D3, found a significant benefit for relapse- free survival in the treatment group (Urashima et al., 2019). The SUNSHINE trial, which compared the effect of high-dose vitamin D3 treatment (8,000 lU/day for 2 weeks, then 4,000 lU/day) to 400 lU/day in advanced colorectal cancer patients receiving chemotherapy did not find a significant difference in progression-free survival but a decreased risk of death (Ng et al., 2019). Similarly, a meta-analysis of 10 RCTs did not find any benefit of vitamin D supplementation on total cancer incidence. However, the same study found an association between supplementation and reduced total cancer mortality, which was largely attributable to supplementation by daily dosing and not infrequent bolus dosing (Keum et al., 2019).
Clinical trials utilizing calcitriol as a single agent or in combination with other drugs have shown varying levels of success. The anti-tumor efficacy of calcitriol is best observed when it is used at high concentrations. While this raises concerns for dose-limiting hypercalcemia, available data indicates that it is safe when administered intermittently (Woloszynska-Read et al., 2011), since mild to moderate hypercalcemia is rapidly reversible. Moreover, oral daily administration in prostate cancerpatients could be safely given for up to 15 months (Gross et al., 1998; Woloszynska-Read et al., 2011). While calcitriol may be administered safely in humans, its efficacy as an anti-cancer therapeutic agent is limited at non-toxic doses. As discussed previously, many vitamin D analogues exhibit increased efficacy relative to calcitriol while largely avoiding hypercalcemic side effects. Inecalcitol (TX-522, 19- nor-14-epi-23-yne-1,25-(OH)2D3), a side-chain analogue of calcitriol, more potently decreased tumor growth in various cancer models including breast (Verlinden et al., 2000), squamous cell (Ma et al., 2013), and prostate (Okamoto et al., 2012) compared to calcitriol. Furthermore, in these mouse experiments inecalcitol induced tumor regression without significantly affecting serum calcium levels (Ma et al., 2013; Okamoto et al., 2012). Phase I trials in a cohort of 54 advanced prostate cancer patients using inecalcitol in combination with the chemotherapy docetaxel resulted in hypercalcemia in two of four patients receiving 8,000 pg of inecalcitol, which normalized after a few days of drug removal (Medioni et al., 2014). The maximum tolerated dose was determined to be 4,000 pg, 100- times that of calcitriol when in combination with docetaxel (Beer and Myrthue, 2004). Seocalcitol (EB1089; Fig. 3) also had potent antiproliferative effects in vitro and significantly decreased tumor growth in vivo in animal models of head and neck squamous cell carcinoma (Prudencio et al., 2001). Seocalcitol and paricalcitol have been examined in phase I and phase II trials. However, neither demonstrated significant anti-tumor efficacy as monotherapies in pancreatic (Evans et al., 2002), hepatocellular carcinoma (Dalhoff et al., 2003) or prostate cancer patients (Schwartz et al., 2008). This may be, in part, because of acquired tumor resistance to vitamin D and its analogues in vivo. Intriguingly, resistant cells retain active vitamin D signaling, providing a rationale for potential use of vitamin D analogues in combination therapy, which has become the norm in cancer treatment.
There has been a recent surge in interest in links between vitamin D status and response to immunotherapy, and the potential use of vitamin D and its analogues as adjuncts for cancer immunotherapy (Fig 5). Immune checkpoint inhibition (ICI), a kind of immunotherapy, functions by blocking interactions between cancer cells and inhibitory receptors expressed on T cells, eliciting anticancer T cell activity. This is achieved through the administration of monoclonal antibodies targeting inhibitory receptors expressed on T cells such as programmed-death 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4). One study analyzed the relationship between PD-1 ICI efficacy and serum 25D levels in 77 advanced lung cancer patients and found that the baseline 25D levels of partial response patients was significantly higher than that of non-responders. Moreover, overall survival was significantly improved in patients with 25D > 20 ng/mL versus 10-20 ng/mL or < 10 ng/mL (You et al., 2023). In a survey of 703 primary melanoma biopsies, elevated VDR expression was correlated with a reduced risk of melanoma-related death (Muralidhar et al., 2019), along with upregulation of pathways mediating anti-tumor immunity. It was also associated with increased levels of tumor-infiltrating lymphocytes. These results suggest that VDR expression may be useful as a biomarker for response to immunotherapy. In a clinical study with 200 advanced melanoma patients receiving anti-PD-1 immunotherapy, vitamin D3 supplementation significantly increased the response rate to immune checkpoint inhibition (36.2% in those with 25D < 30 ng/mL and not-supplemented versus 56.0% in supplemented and with 25D > 30 ng/mL; p =0.01)(Galus et al., 2023). Importantly, progression free survival (5.75 versus 11.25 months; p=0.03) and overall survival (27 versus 31.5 months; p = 0.39) was higher in the supplemented group. These data strongly suggest that vitamin D status is associated with, and supplementation increases, ICI efficacy and prognosis in patients with advanced cancers.
ICI has revolutionized the cancer treatment field, but like many therapies, treatment comes with unintended off-target effects. In this context, ICI is associated with immune-related adverse effects (irAEs), which cause organ-specific toxicities due to disrupted T cell tolerance and reactivation of autoreactive T cells, thus mimicking autoimmune diseases. Importantly, vitamin D status was shown to correlate negatively with irAE occurrence in anti-PD-1 treated lung cancer patients (You et al., and significantly reduced the chances of developing ICI-induced colitis in melanoma patients receiving PD-1 or CTLA-4 inhibitors (Grover et al., 2020). Moreover, in a case-report of a man with dermatological irAEs resistant to topical steroid treatment, phototherapy with UV-B light resolved his symptoms (Donaldson et al., 2018), suggesting that the synthesized vitamin D suppressed ongoing inflammation. Collectively, vitamin D in combination with ICI therapy has shown promising results in both bolstering ICI efficacy while managing immune-related side effects.
These results suggest that vitamin D analogues may be useful adjuncts to ICI therapy because they are efficacious at concentrations where they do not induce hypercalcemia. We have exploited the combinatorial effects of vitamin D analogues and histone deacetylase inhibitors (HDACi) in 1,25D- resistant cancer models (Banwell et al., 2004; Rashid et al., 2001) to develop analogues that integrate HDACi into the backbone of a non-secosteroidal VDR agonist (Barbier et al., 2022; Sarmadi et al.,
. Histone deacetylases (HDACs) regulate the acetylation of histones, transcription factors, and cofactors in the nucleus in addition to some cytoplasmic proteins. The nuclear actions of HDACs have significant effects on regulation of gene expression, and HDACi such as SAHA (suberoylanilide hydroxamic acid; vorinostat) are used clinically as therapies for cutaneous and peripheral T cell lymphoma and multiple myeloma (Sun et al., 2018). VDR agonist/HDACi hybrids are robustly bifunctional in vitro in a series of cancer models and are bioavailable (Aslakson and Miller, 1992). The most recently developed analogue, ZG-126 (Fig. 3), reduced tumor size more than 1,25D or SAHA in B16-F10 melanoma tumors while displaying comparable efficacy to gemcitabine, a chemotherapeutic agent (Sarmadi et al., 2024). Importantly, high dose ZG-126 treatment in the 4T1 mouse model of triple negative breast cancer reduced tumor burden and metastases more than the combination of 1,25D with SAHA, supporting the benefit of bifunctional compounds relative to traditional combination therapy (Sarmadi et al., 2024). In addition, published (Barbier et al., 2022) and unpublished gene expression profiling studies have provided evidence that hybrid compounds such as ZG-126 should render cancer cells more susceptible to immune checkpoint inhibitor therapy. For example, ZG-126 treatment reduced the accumulation and gene signature of anti-inflammatory macrophages in 4T1mouse tumors (Sarmadi et al., 2024). Collectively, the above studies suggest that it would be important to investigate the potential of vitamin D analogues as adjuncts of immune checkpoint inhibitor therapy.

Concluding statement.

Since 1,25D was discovered as the biologically active mediator of vitamin D signaling in 1971 (Holick et al., 1971a; Holick et al., 1971b), its therapeutic application in human health has been subject of vigorous investigation (Fig. 6). Initially used solely as a drug for diseases derived from perturbations in calcium homeostasis, the anti-proliferative, pro-differentiation, and immunoregulatory activities of 1,25D are now well-recognized. This has resulted in clinical success in the treatment of various inflammatory disorders by 1,25D and its analogues, particularly for the treatment psoriasis vulgaris. Notably, utilization of vitamin D analogues have expanded the potential for vitamin D-targeted therapies in the clinic due to their increased efficacy and diminished calcemic effects. Thus, future applications of vitamin D analogues may endeavor to elicit systemic activity through oral administration to target and treat complex internal inflammatory disorders including autoimmune diseases or cancer as either single agents or combination therapies.

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Shinkyo R, Sakaki T, Kamakura M, Ohta M and Inouye K (2004) Metabolism of vitamin D by human microsomal CYP2R1. Biochemical and Biophysical Research Communications 324:451-457.
Soltesz G, Patterson CC, Dahlquist G and Group ES (2007) Worldwide childhood type 1 diabetes incidence--what can we learn from epidemiology? Pediatr Diabetes 8 Suppl 6:6-14.
St-Arnaud R (1999) Targeted inactivation of vitamin D hydroxylases in mice. Bone 25:127-129.
St-Arnaud R, Messerlian S, Moir JM, Omdahl JL and Glorieux FH (1997) The 25-hydroxyvitamin D 1- alpha-hydroxylase gene maps to the pseudovitamin D-deficiency rickets (PDDR) disease locus. Journal of Bone and Mineral Research 12:1552-1559.
Stio M, Martinesi M, Bruni S, Treves C, Mathieu C, Verstuyf A, d’Albasio G, Bagnoli S and Bonanomi AG (2007) The Vitamin D analogue TX 527 blocks NF-kB activation in peripheral blood mononuclear cells of patients with Crohn's disease. The Journal of Steroid Biochemistry and Molecular Biology 103:51-60.
Strauch UG, Obermeier F, Grunwald N, Dunger N, Rath HC, Scholmerich J, Steinmeyer A, Zugel U and Herfarth HH (2007) Calcitriol analog ZK191784 ameliorates acute and chronic dextran sodium sulfate-induced colitis by modulation of intestinal dendritic cell numbers and phenotype. World J Gastroenterol 13:6529-6537.
Suarez-Calleja C, Aza-Morera J, Iglesias-Cabo T and Tardôn A (2021) Vitamin D, pregnancy and caries in children in the INMA-Asturias birth cohort. BMC pediatrics 21:1-9.
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Swamy N, Head JF, Weitz D and Ray R (2002) Biochemical and preliminary crystallographic characterization of the vitamin D sterol-and actin-binding by human vitamin D-binding protein. Archives of biochemistry and biophysics 402:14-23.
Szymczak I and Pawliczak R (2016) The Active Metabolite of Vitamin D3 as a Potential Immunomodulator. Scand J Immunol 83:83-91.
Tabata T, Shoji T, Kikunami K, Matsushita Y, Inoue T, Tanaka S, Hino M, Miki T, Nishizawa Y and Morii H (1988) In vivo effect of 1 alpha-hydroxyvitamin D3 on interleukin-2 production in hemodialysis patients. Nephron 50:295-298.
Tabata T, Suzuki R, Kikunami K, Matsushita Y, Inoue T, Inoue T, Okamoto T, Miki T, Nishizawa Y and Morii H (1986) The effect of 1 alpha-hydroxyvitamin D3 on cell-mediated immunity in hemodialyzed patients. J Clin Endocrinol Metab 63:1218-1221.
Takahashi, K., Nakayama, Y., Horiuchi, H., Ohta, T., Komoriya, K., Ohmori, H. and Kamimura, T. (2002) Human neutrophils express messenger RNA of vitamin D receptor and respond to 1 a, 25-dihydroxyvitamin D3. Immunopharmacology and immunotoxicology 24:335-347.
Tavera-Mendoza LaW, J.H. (2007) Cell defenses and the sunshine vitamin. Scientific American 297:62-72.
Tekin M, Konca C, Celik V, Almis H, Kahramaner Z, Erdemir A, Gulyuz A, Uckardes F and Turgut M (2015) The association between vitamin D levels and urinary tract infection in children. Hormone research in paediatrics 83:198-203.
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Tsuji M, Fujii K, Nakano T and Nishii Y (1994) 1 alpha-hydroxyvitamin D3 inhibits type II collagen- induced arthritis in rats. FEBS Lett 337:248-250.
Tsujino I, Ushikoshi-Nakayama R, Yamazaki T, Matsumoto N and Saito I (2019) Pulmonary activation of vitamin D3 and preventive effect against interstitial pneumonia. Journal of clinical biochemistry and nutrition 65:245-251.
Umesono K, Murakami KK, Thompson CC and Evans RM (1991) DIRECT REPEATS AS SELECTIVE RESPONSE ELEMENTS FOR THE THYROID-HORMONE, RETINOIC ACID, AND VITAMIN- D3 RECEPTORS. Cell 65:1255-1266.
Upala S, Sanguankeo A and Permpalung N (2015) Significant association between vitamin D deficiency and sepsis: a systematic review and meta-analysis. BMC Anesthesiology 15:84.
Urashima M, Ohdaira H, Akutsu T, Okada S, Yoshida M, Kitajima M and Suzuki Y (2019) Effect of Vitamin D Supplementation on Relapse-Free Survival Among Patients With Digestive Tract Cancers: The AmATERASU Randomized Clinical Trial. JAMA 321:1361-1369.
Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y and Ida H (2010) Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. The American Journal of Clinical Nutrition 91:1255-1260.
Valvano M, Magistroni M, Cesaro N, Carlino G, Monaco S, Fabiani S, Vinci A, Vernia F, Viscido A and Latella G (2024) Effectiveness of vitamin D supplementation on disease course in inflammatory bowel disease patients: systematic review with meta-analysis. Inflammatory Bowel Diseases 30:281-291.
Vargas Buonfiglio LG, Cano M, Pezzulo AA, Vanegas Calderon OG, Zabner J, Gerke AK and Comellas AP (2017) Effect of vitamin D<sub> <sub>3</sub> </sub> on the antimicrobial activity of human airway surface liquid: preliminary results of a randomised placebo-controlled double-blind trial. BMJ Open Respiratory Research 4.
Verboven C, Rabijns A, De Maeyer M, Van Baelen H, Bouillon R and De Ranter C (2002) A structural basis for the unique binding features of the human vitamin D-binding protein. Nature structural biology 9:131-136.
Verlinden L, Verstuyf A, Van Camp M, Marcelis S, Sabbe K, Zhao XY, De Clercq P, Vandewalle M and Bouillon R (2000) Two novel 14-Epi-analogues of 1,25-dihydroxyvitamin D3 inhibit the growth of human breast cancer cells in vitro and in vivo. Cancer Res 60:2673-2679.
Vernia F, Valvano M, Longo S, Cesaro N, Viscido A and Latella G (2022) Vitamin D in inflammatory bowel diseases. Mechanisms of action and therapeutic implications. Nutrients 14:269.
Verway M, Bouttier M, Wang TT, Carrier M, Calderon M, An BS, Devemy E, McIntosh F, Divangahi M, Behr MA and White JH (2013) Vitamin D induces interleukin-1beta expression: paracrine macrophage epithelial signaling controls M. tuberculosis infection. PLoS Pathog 9:e1003407.
Victor CY, Delsert C, Andersen B, Holloway JM, Devary OV, Naar AM, Kim SY, Boutin J-M, Glass CK and Rosenfeld MG (1991) RXRp: a coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements. Cell 67:1251-1266.
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Wang Y, He D, Ni C, Zhou H, Wu S, Xue Z and Zhou Z (2016) Vitamin D induces autophagy of pancreatic beta-cells and enhances insulin secretion. Mol Med Rep 14:2644-2650.
Waterfield M, Khan IS, Cortez JT, Fan U, Metzger T, Greer A, Fasano K, Martinez-Llordella M, Pollack JL, Erle DJ, Su M and Anderson MS (2014) The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance. Nat Immunol 15:258265.
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Respiratory Tract Infections and Antibiotic Resistance: A Protective Role for Vitamin D? - March 2021

Front. Nutr., 24 March 2021 Volume 8 - 2021 | https://doi.org/10.3389/fnut.2021.652469
Emma J. Derbyshire1*Philip C. Calder,Philip C. Calder2,3

1Nutritional Insight, London, United Kingdom
2Faculty of Medicine, School of Human Development and Health, University of Southampton, Southampton, United Kingdom
3National Institute for Health Research Southampton Biomedical Research Center, University Hospital Southampton National Health Service Foundation Trust and University of Southampton, Southampton, United Kingdom

Upper and lower respiratory tract infections are among the most common infections globally, and in the United Kingdom, they account for about half of all oral antibiotics prescribed. Antibiotic overuse and the emergence of “superbugs” that are resistant to their effects is a global problem that is becoming a serious concern. Considering this, the potential role of immunonutrition as a “prehabilitation” in helping to tackle bacterial infections and reduce over-reliance on antibiotic usage is gaining interest. This narrative mini-review summarizes current knowledge on the roles of certain nutrients in helping to modulate immune function, with particular focus on vitamin D. Vitamin D supplementation appears to reduce the risk of acute respiratory tract infections and thus could have a valuable role to play in reducing over-reliance on antibiotics. Investment in high-quality trials is needed to further explore this field.
No such attachment on this page

VitaminDWiki – Immunity category contains

275 items in Immunity category

see also

Virus category listing has 1401 items along with related searches

Overview Influenza and vitamin D
Vitamin D helps both the innate and adaptive immune systems fight COVID-19 – Jan 2022
Vitamin D aids the clearing out of old cells (autophagy) – many studies
600,000 IU of Vitamin D (total) allowed previously weak immune systems to fight off a virus antigen - Nov 2020
Search for treg OR "t-cell" in VitaminDWiki 1440 items as of Jan 2020
228 VitaminDWiki pages contained "infection" in title (June 2024)
Search VitaminDWik for BACTERIA in title 25 items as of Aug 2019
Vitamin D and the Immune System – chapter Aug 2019
7X less risk of influenza if Vitamin D levels higher than 30 ng – Oct 2017
Common cold prevented and treated by Vitamin D, Vitamin C, Zinc, and Echinacea – review April 2018
Vitamin D improves T Cell immunity – RCT Feb 2016
Immune system - great 11-minute animated video - Aug 2021
Only the brain is more complex, nothing about Vitamin D
18 titles in VitaminDWiki contained INNATE or ADAPTIVE as of Jan 2023
Increasing publications on vitamin D and Infection

52 studies are in both Immunity and Virus categories

VitaminDWiki – Over 727 Virus studies have Vitamin D in the title

VitaminDWiki - 12 studies in both categories Immunity and Vitamin D Receptor

This list is automatically updated

VitaminDWiki - 2 studies in both categories Immunity and Vitamin D Binding Protein

This list is automatically updated

VitaminDWiki – Cancer category contains:

Cancers get less Vitamin D when there is a poor Vitamin D Receptor

Vitamin D Receptor pages in VitaminDWiki with CANCER in title 86 as of July 2023
Cancer and the Vitamin D Receptor, a primer – Sept 2017
Vitamin D Receptor (Cancers OR Viruses) - many studies
Risk of Cancer increased if poor Vitamin D Receptor – meta-analysis of 73 studies Jan 2016
Cancer (general) and VDR 23 articles
Breast Cancer and VDR 24 articles
Colon Cancer and VDR 13 articles
Prostate Cancer and VDR 7 articles
Skin Cancer and VDR 10 articles
- Note some Health problems, such as some Cancers, protect themselves
  by actively reducing Receptor activation

VitaminDWiki – Autoimmune category contains

204 items in Autoimmune category
Vitamin D and MS Asthma RA Diabetes Gut Allergy Hay Fever Lupus Psoriasis
Predicted 95% autoimmune cured by HIGH-DOSE vitamin D - 2014
10% of the UK have Autoimmune Diseases - Lancet May 2023 PDF is behind a paywall
- Increase in 20 years : coeliac disease 2.19 X. Sjogren's syndrome 2.09, and Graves' disease 2.07
- All 43 references are FREE on-line
Autoimmune diseases fought by Vitamin D, especially if have more than 40 ng – Sept 2022
The BEST Nutrient for Autoimmune Conditions (Vitamin D) - video May 2022
The number 1 Deficiency behind All Autoimmune Diseases (Vitamin D) video - Dec 2023
Autoimmune disease clusters run in families having low D
How Vitamin D reduces inflammation, improves immunity and fights autoimmunity – review Dec 2018
120 doctors and 20,000 MS patients using high dose Vitamin D Dec 2018
Vitamin D has treated Multiple Sclerosis and autoimmune diseases for 16 years – Coimbra April 2018
Vitamin D Receptor is associated in over 58 autoimmune studies
More autoimmune disease if higher pollution or lower UVB - Feb 2023
Many autoimmune diseases associated with low vitamin D or poor Vit D genes – July 2019

See also web: consensus that ~50 diseases are autoimmune, ~50 more are suspected:

VitaminDWiki – CYP27B1 category contains

The CYP27B1 gene activates Vitamin D in the Kidney, Skin, Lungs, Brain, Eyes Breasts etc.
Poor CYP27B1 is assocated with COVID, Miscarriage, Lupus, Alz, Parkinson, MSA, Rickets

CYtochrome P450 family 27 subfamily B member 1 = 25-Hydroxyvitamin D3 1-alpha-hydroxylase

63 items in CYP27B1 category
344 articles in the Genetics
530 articles in Vitamin D Receptor
178 articles in Vitamin D Binding Protein
CYP27B1 and other genes are less activated in seniors
CYP27B causes many health problems – March 2020
Every Parkinson’s brain had a poor CYP27B1 gene

What can be done if have a poor CYP27B1

Larger doses of Vitamin D
More Bio-available: Gut-friendly form, Topical form, taken with fatty meal, taken with evening meal
Additional sources: UV
Increase Vitamin D metabolism: additional Magnesium, Omega-3
- All cytochrome P450 enzymes require Mg++ as a cofactor
Increase the amount of Vitamin D in the blood that gets to cells: increase activation of VDR
- See: Reasons for low response to vitamin D

Vitamin D blood test misses CYP27B1 and other genes
in Visio for 2023

VitaminDWiki – Genetics category contains

344 articles in the Genetics category

see also

Vitamin D Receptor has 530 items
Vitamin D Binding Protein = GC has 178 items
CYP27B1 has 63 items
CYP24A1 in title of 39+ items
CYP2R1 25+ items
Calcidiol has 48 items
Calcitriol has 62 items
Topical Vitamin D
Nanoemulsion Vitamin D may be a substantially better form
1289 genes changed with higher doses of Vitamin D - RCT Dec 2019
CYP3A4 (7 as of Dec 2022)
Getting Vitamin D into your body

Vitamin D blood test misses a lot
in Visio for 2023

Vitamin D from coming from tissues (vs blood) was speculated to be 50% in 2014, and by 2017 was speculated to be 90%
Note: Good blood test results (> 40 ng) does not mean that a good amount of Vitamin D actually gets to cells
A Vitamin D test in cells rather than blood was feasible (2017 personal communication) Commercially available 2019
- However, test results would vary in each tissue due to multiple genes
Good clues that Vitamin D is being restricted from getting to the cells
1) A vitamin D-related health problem runs in the family
    especially if it is one of 51+ diseases related to Vitamin D Receptor
2) Slightly increasing Vitamin D shows benefits (even if conventional Vitamin D test shows an increase)
3) DNA and VDR tests - 100 to 200 dollars $100 to $250
4) PTH bottoms out ( shows that parathyroid cells are getting Vitamin d)
   Genes are good, have enough Magnesium, etc.
5) Back Pain
   probably want at least 2 clues before taking adding vitamin D, Omega-3, Magnesium, Resveratrol, etc

Vitamin D, genes, analogues and Immune System - Dec 2024

Vitamin D and Its Analogues in Immune System Regulation Patricio Artusa, John H. White

Detailed Table of Contents (PDF contains many charts and tables)

A Brief History of Vitamin D

Introduction to Vitamin D Metabolism and Signaling.

The Vitamin D Receptor.

Development of Vitamin D Analogues.

Vitamin D Signaling in the immune system.

Vitamin D and its analogues in immune-related disorders.

Vitamin D analogues and their potential as adjuncts to cancer immunotherapy.

Concluding statement.

324 References

Respiratory Tract Infections and Antibiotic Resistance: A Protective Role for Vitamin D? - March 2021

VitaminDWiki – Immunity category contains

VitaminDWiki – Over 727 Virus studies have Vitamin D in the title

VitaminDWiki - 12 studies in both categories Immunity and Vitamin D Receptor

VitaminDWiki - 2 studies in both categories Immunity and Vitamin D Binding Protein

VitaminDWiki – Cancer category contains:

VitaminDWiki – Autoimmune category contains

VitaminDWiki – CYP27B1 category contains

VitaminDWiki – Genetics category contains

Attached files

Health Problems and D

Vitamin D, genes, analogues and Immune System - Dec 2024

Vitamin D and Its Analogues in Immune System Regulation Patricio Artusa, John H. White

Detailed Table of Contents (PDF contains many charts and tables)

A Brief History of Vitamin D

Introduction to Vitamin D Metabolism and Signaling.

The Vitamin D Receptor.

Development of Vitamin D Analogues.

Vitamin D Signaling in the immune system.

Vitamin D and its analogues in immune-related disorders.

Vitamin D analogues and their potential as adjuncts to cancer immunotherapy.

Concluding statement.

324 References

Respiratory Tract Infections and Antibiotic Resistance: A Protective Role for Vitamin D? - March 2021

VitaminDWiki – Immunity category contains

VitaminDWiki – Over 727 Virus studies have Vitamin D in the title

VitaminDWiki - 12 studies in both categories Immunity and Vitamin D Receptor

VitaminDWiki - 2 studies in both categories Immunity and Vitamin D Binding Protein

VitaminDWiki – Cancer category contains:

VitaminDWiki – Autoimmune category contains

VitaminDWiki – CYP27B1 category contains

VitaminDWiki – Genetics category contains

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Attached files

Health Problems and D