European Journal of Cardiovascular Medicine

The immune system is a complex and highly regulated network designed to protect the body against infections and other external threats while maintaining tolerance to self-antigens. Vitamin D3 (cholecalciferol) has recently emerged as a key regulator of immune function, playing a crucial role in both innate and adaptive immunity [1]. Initially recognized for its role in calcium and phosphate homeostasis, Vitamin D3 has now been identified as an essential modulator of immune responses [2].

Overview of Vitamin D3

Vitamin D3 is primarily synthesized in the skin upon exposure to ultraviolet B (UVB) radiation. It can also be obtained through dietary sources, including fatty fish, fortified dairy products, and supplements [3]. Once absorbed, Vitamin D3 undergoes hydroxylation in the liver to form 25-hydroxyvitamin D (25(OH)D), the major circulating form, which is further converted into its active form, 1,25-dihydroxyvitamin D (1,25(OH)2D), in the kidneys and immune cells such as macrophages and dendritic cells [4]. This active form exerts its biological effects by binding to the Vitamin D receptor (VDR), which is widely expressed in immune cells, including T cells, B cells, dendritic cells, and macrophages [5].

Historical Context and Emerging Research

The immunomodulatory effects of Vitamin D3 were first recognized in the early 1980s when researchers observed that its active form could suppress immune responses in vitro [6]. Subsequent studies have confirmed that Vitamin D3 influences various immune pathways, including antigen presentation, cytokine production, and cell differentiation [7]. More recent research has linked Vitamin D3 deficiency

to increased susceptibility to autoimmune diseases, respiratory infections, and chronic inflammatory disorders [8].

Prevalence of Vitamin D3 Deficiency and Global Impact

Vitamin D3 deficiency is a global epidemic with well over 1 billion people affected. It is more common in populations with minimal sun exposure, increased skin pigmentation, and inadequate dietary intake [9]. Epidemiological evidence further indicates that individuals with low levels of Vitamin D3 are at risk of immune incompetency including increased risk of infection and autoimmune diseases [10].

But in the northern latitudes, where sunlight is limited for months on end, deficiency rates are considerably higher. Vitamin D3 synthesis can also be diminished by changes in lifestyle, urbanization and the development of indoor settings for work, as well as their topical use (e.g.: sunscreen) [11].

Role of Vitamin D3 in Immune System Homeostasis

Vitamin D3 is a crucial regulator of the balance of the immune system and modulates the immune response, innate and adaptive [12]. The innate immune system is the first line of defense against pathogens and depends on pathogen recognition receptors (PRRs) like toll-like receptors (TLRs) to sense microbial invaders and trigger immune responses [13].

Influence on Innate Immunity

Vitamin D3 and the innate immune system. It induces the expression of a wide range of AMPs, including cathelicidin and β-defensins, with broad-spectrum antimicrobial activity against bacteria, viruses and fungi [14]. These peptides are important for the clearance of infections and maintaining the integrity of the skin, respiratory tract, and gut mucosa [15].

Moreover, Vitamin D3 modulates the activation and function of macrophages and monocytes, which are also crucial components of the innate immune system. Vitamin D3 has been reported to induce the differentiation of macrophages and to increase their capacity to phagocytose bacteria, while at the same time it is this ability to suppress the production of inflammatory cytokines such as IL-6 and TNF-α [16].

Influence on Adaptive Immunity

Upon conversion to calcitriol, vitamin D3 directs adaptive immunity by adjusting T and B cell function. It favors the differentiation of regulatory T cells (Tregs) that are critical for maintaining immune tolerance and preventing autoimmune diseases [17]. Moreover, Vitamin D3 blocks the development of Th1 and Th17 cells, their promotion is crucial for chronic inflammation and autoimmunity [18].

Regarding B cells, Vitamin D3 has been found to reduce B cell proliferation and antibody production, which may be beneficial in conditions where excessive humoral immunity contributes to disease pathology, such as systemic lupus erythematosus (SLE) [19].

Clinical Significance and Future Research Directions

Growing evidence suggests that Vitamin D3 supplementation may offer therapeutic benefits in various immune-related conditions. Clinical trials have shown that individuals with adequate Vitamin D3 levels have a lower incidence of respiratory infections, improved outcomes in autoimmune diseases, and reduced inflammation [20]. However, the optimal dosage and long-term effects of Vitamin D3 supplementation remain areas of active investigation.

Further research is needed to explore the potential of Vitamin D3 in personalized medicine, where treatment plans are tailored to an individual’s genetic background, lifestyle, and existing health conditions. The development of novel formulations, including nanoparticle-based delivery systems, may also enhance the bioavailability and effectiveness of Vitamin D3 in clinical settings.

Mechanisms of Immune Regulation by Vitamin D3

Vitamin D3 Metabolism and Activation in Immune Cells

Vitamin D3 undergoes a two-step hydroxylation process to become biologically active. The first hydroxylation occurs in the liver, where Vitamin D3 is converted to 25-hydroxyvitamin D (25(OH)D). The second hydroxylation takes place in the kidneys and immune cells, where 1,25-dihydroxyvitamin D (1,25(OH)2D) is formed, which is the active form of Vitamin D3. The presence of CYP27B1, an enzyme responsible for this conversion in dendritic cells and macrophages, indicates that immune cells can locally regulate Vitamin D3 levels to influence immune responses.

Vitamin D Receptor (VDR) and Gene Expression

Vitamin D3 mediates its effects on biological function through interaction with the Vitamin D receptor (VDR), a nuclear receptor that is widely expressed in many immune cell types, including T cells, B cells, macrophages and dendritic cells. After its activation, 1,25(OH)2D covalently binds to the vitamin D receptor (VDR), and the VDR + RXR complex promotes the transcription of genes involved in immune regulation. Presence of VDREs in the promoter regions of these genes down regulate anti-inflammatory cytokines (for example, IL-10) and suppress expression of pro-inflammatory cytokines (for example, IL-6, TNF-α, IL-17).

Modulation of Innate Immunity

Vitamin D3's importance to innate immune defense lies in its ability to upregulate macrophages and monocytes' antimicrobial function and balance vagal inflammatory responses.

Antimicrobial Peptide Induction

It upregulates antimicrobial peptides, such as cathelicidin (LL-37) and β-defensins, which help destroy bacteria, viruses, and fungi. These peptides attack microbial membrane and protect pathogens from survival and propagation. Cathelicidin upregulation has been recognized as a key mediator of the host defense-enhancing effects of Vitamin D3, especially in the respiratory tract, skin, and gastrointestinal tract.

Effects on Macrophages and Monocytes

Macrophages and monocytes express high levels of VDR and CYP27B1, allowing them to generate 1,25(OH)2D within these cells. This autocrine secretion augments their ability to:

• Recognize and engulf pathogens via increased phagocytic activity.
• Suppress excessive inflammation by downregulating IL-6, IL-1β, and TNF-α, which are pro-inflammatory cytokines associated with chronic inflammatory diseases.
• Balance immune responses by inducing anti-inflammatory cytokines like IL-10, preventing overactivation that could lead to autoimmune reactions.

Modulation of Dendritic Cells

Dendritic cells (DCs) are crucial antigen-presenting cells that initiate adaptive immune responses. Vitamin D3 regulates dendritic cell activity by:

• Inhibiting dendritic cell maturation, reducing their ability to activate T cells excessively.
• Promoting tolerogenic dendritic cells, which increase regulatory T cell (Treg) differentiation, essential for maintaining immune tolerance and preventing autoimmunity.
• Suppressing pro-inflammatory cytokine release, thereby preventing prolonged immune activation in chronic inflammatory conditions.

Modulation of Adaptive Immunity

Vitamin D3 has profound effects on T and B cell function, ensuring that adaptive immune responses remain balanced and non-pathogenic.

T Cell Regulation

T cells play a crucial role in cell-mediated immunity, and Vitamin D3 modulates their function in several ways:

• Inhibiting Th1 and Th17 responses: Vitamin D3 suppresses the differentiation of Th1 cells (which produce IFN-γ and TNF-α) and Th17 cells (which produce IL-17 and IL-22), both of which are involved in autoimmune diseases like multiple sclerosis and rheumatoid arthritis.
• Promoting Treg cell differentiation: Regulatory T cells (Tregs) are essential for immune tolerance and preventing autoimmunity. Vitamin D3 enhances the expression of FoxP3, a key transcription factor in Tregs, leading to increased production of IL-10, an anti-inflammatory cytokine.
• Reducing inflammatory T cell responses: By decreasing the activation of pro-inflammatory Th1 and Th17 cells, Vitamin D3 prevents excessive immune activation and tissue damage in chronic diseases.

B Cell Regulation

Vitamin D3 also modulates B cell function, impacting antibody production and immune memory:

• Suppressing B cell proliferation: Vitamin D3 downregulates B cell activation, limiting excessive antibody production, which is beneficial in autoimmune diseases where antibodies target self-tissues (e.g., systemic lupus erythematosus).
• Reducing memory B cell formation: By limiting the development of memory B cells, Vitamin D3 helps control long-term autoimmune reactions that may lead to chronic disease progression.
• Inhibiting autoantibody production: Autoantibodies contribute to many autoimmune disorders. Vitamin D3 prevents excessive autoantibody formation, thereby reducing the risk of autoimmune flare-ups.

Vitamin D3 and Cytokine Balance

Cytokines are signaling molecules that mediate immune responses. Vitamin D3 plays a key role in balancing pro-inflammatory and anti-inflammatory cytokines:

This cytokine modulation is particularly relevant in conditions such as chronic inflammatory diseases, infections, and autoimmunity, where an imbalance in cytokine production leads to pathology.

Role of Vitamin D3 in Immune Tolerance and Autoimmunity

One of the most crucial roles of Vitamin D3 is maintaining immune tolerance, preventing the immune system from attacking self-tissues. Through its effects on Tregs, dendritic cells, and B cells, Vitamin D3 helps reduce autoimmunity risk by:

• Suppressing autoreactive T cells, preventing them from attacking self-antigens.
• Enhancing Treg function, which helps maintain peripheral immune tolerance.
• Reducing antigen presentation by dendritic cells, thereby lowering the likelihood of autoimmune reactions.

Search Strategy

This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive literature search was performed using electronic databases, including PubMed, Scopus, Web of Science, and Google Scholar, covering studies published between 2000 and 2024. The search strategy included Medical Subject Headings (MeSH) terms and free-text keywords, such as:

• "Vitamin D3 and immune system"
• "Vitamin D and autoimmunity"
• "Vitamin D deficiency and infections"
• "Vitamin D receptor (VDR) and immune modulation"

Boolean operators (AND, OR) were used to refine search results. Additionally, references from selected studies were manually screened to identify additional relevant research.

Inclusion and Exclusion Criteria

Inclusion Criteria:

• Studies investigating the role of Vitamin D3 in immune system regulation.
• Randomized controlled trials (RCTs), cohort studies, meta-analyses, and systematic reviews.

• Studies evaluating Vitamin D3 supplementation and immune-related health outcomes.
• Studies published in English.
• Peer-reviewed articles with full-text availability.

Exclusion Criteria:

• Non-peer-reviewed articles, editorials, case reports, and opinion pieces.
• Animal or in-vitro studies that do not provide clinical relevance.
• Studies that do not specifically analyze Vitamin D3’s effects on immunity.
• Duplicate publications or incomplete studies.

Data Extraction and Synthesis

Two independent reviewers conducted the selection of articles. Titles and abstracts were initially screened to identify relevant studies, followed by a full-text review for eligibility. Discrepancies were resolved through discussion or consultation with a third reviewer. Data were extracted using a standardized format that included:

• Study design and population
• Intervention type (Vitamin D3 supplementation, dietary intake, or sun exposure)
• Immune parameters assessed (cytokine levels, immune cell function, infection rates, autoimmune markers, etc.)
• Main findings and conclusions

Quality Assessment

The methodological quality of selected studies was evaluated using appropriate tools:

• Cochrane Risk of Bias Tool for randomized controlled trials (RCTs).
• Newcastle-Ottawa Scale (NOS) for observational cohort and case-control studies.
• GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) framework for assessing overall evidence quality.

PRISMA Flowchart

The PRISMA flowchart below outlines the study selection process, including the number of studies identified, screened, and included in the final review.

Statistical Analysis

For studies providing quantitative data, statistical analyses were conducted where applicable. The meta-analysis in the Review Manager (RevMan) software was used, and the effect sizes and confidence intervals were calculated. We utilized the I² statistic to assess heterogeneity among studies, where I² values greater than 50% were classified as moderate to high heterogeneity. Relevant data were used to assess publication bias by means of funnel plots and Egger’s test.

Ethical Considerations

No ethical approval was necessary as this review was conducted on previously published studies. However, all included studies were critically evaluated for reporting on ethical guidelines including informed consent and institutional review board (IRB) approval as applicable.

Limitations of the Study

While this systematic review provides a comprehensive analysis of Vitamin D3’s role in immune regulation, certain limitations must be acknowledged:

• Variability in study methodology may contribute to heterogeneity among findings.
• Variations in the vitamin D3 doses used and how long supplementation was given makes direct comparison difficult.
• Insufficient data in the literature regarding the long-term effects of vitamin D3 supplementation in certain types of patients
• Excluding non-English studies might cause language bias.

Future research should focus on large-scale, well-controlled trials to establish more definitive conclusions regarding Vitamin D3’s optimal dosage and long-term immunomodulatory effects.

Overview of Included Studies

A total of 120 studies were included in the systematic review, covering a wide range of research on the

immunomodulatory effects of Vitamin D3. These studies encompassed randomized controlled trials (RCTs), cohort studies, systematic reviews, and meta-analyses. The majority of the studies focused on Vitamin D3’s role in autoimmune diseases, respiratory infections, inflammatory conditions, and its impact on cytokine regulation [21].

Effects of Vitamin D3 on Innate Immunity

Multiple studies have shown that Vitamin D3 is a key modulator of the innate immune response due to upregulating antimicrobial peptide expression, like cathelicidin and β-defensins, which are important for the clearance of both bacteria and viruses [22]. Moreover, Vitamin D3 increases macrophage phagocyting activity and alters the expression of toll-like receptors (TLRs) [23], which can recognize pathogens and activate the immune system.

A meta-analysis of 15 RCTs of Vitamin D3 supplementation in subjects with chronic infectious disease demonstrated that subjects with adequate Vitamin D3 levels were 30-40% less likely than subjects with deficient levels to be severely infected [24]. Furthermore, an observational study showed that patients with low Vitamin D3 were significantly more likely to experience chronic inflammatory diseases such as sepsis and tuberculosis [25].

Effects of Vitamin D3 on Adaptive Immunity

Vitamin D3 has been shown to exert significant regulatory effects on the adaptive immune system, particularly in the modulation of T cell and B cell responses [26].

• T Cells: Vitamin D3 enhances the differentiation of regulatory T cells (Tregs), which are essential for immune tolerance and preventing autoimmunity. It also inhibits Th1 and Th17 responses, thereby reducing inflammatory cytokine production [27].
• B Cells: Vitamin D3 plays a role in suppressing B cell proliferation, thereby reducing excessive antibody production, which is relevant in conditions like systemic lupus erythematosus (SLE) and multiple sclerosis (MS) [28].

A randomized trial involving MS patients revealed that Vitamin D3 supplementation led to a significant

decrease in pro-inflammatory cytokine levels, including IL-6 and TNF-α, while increasing anti-inflammatory IL-10 expression [29].

Vitamin D3 and Cytokine Regulation

Vitamin D3 influences immune system regulation by modulating the balance between pro-inflammatory and anti-inflammatory cytokines. This balance is critical in preventing immune hyperactivation, which is often observed in autoimmune diseases and chronic infections.

Vitamin D3 deficiency has been correlated with higher circulating levels of IL-6 and TNF-α, which are key drivers of chronic inflammatory diseases, including rheumatoid arthritis (RA) and inflammatory bowel disease (IBD).

Summary of Findings

• Vitamin D3 enhances innate immunity by promoting antimicrobial peptide production and macrophage activation.
• Vitamin D3 regulates adaptive immunity by suppressing pro-inflammatory Th1/Th17 responses and promoting Treg activity.

The Broader Implications of Vitamin D3 in Immunoregulation

New studies have emphasized the role of Vitamin D3 in modulating immune response by reducing cytokines that induce inflammation, helping to avoid the immune storm and improving immune resilience. Due to its involvement in the modulation of both innate and adaptive immune cells, vitamin D3 deficiency may play a role in immune system compromise as well as elevated susceptibility to infections and autoimmune disease [30].

Vitamin D3 Deficiency and Chronic Inflammation

A lack of vitamin D3 has been associated with chronic inflammatory conditions such as rheumatoid arthritis, multiple sclerosis, type 1 diabetes and inflammatory bowel disease. Low levels of Vitamin D3 are associated with increased pro-inflammatory cytokines including IL-6, TNF-α and IFN-γ driving autoimmune and chronic inflammatory processes [31].

A meta-analysis showed that patients with autoimmune diseases and Vitamin D3 supplementation exhibited significantly decreased inflammatory biomarkers and improved clinical outcomes in contrast to deficient patients [32]. These results support the therapeutic application of Vitamin D3 in immune-mediated disorders.

Clinical Benefits of Vitamin D3 Supplementation in Immune Disorders

Several randomized controlled trials (RCTs) have investigated Vitamin D3 supplementation in autoimmune diseases, infections, and inflammatory conditions:

• Multiple Sclerosis (MS): Patients supplemented with high-dose Vitamin D3 exhibited reduced disease activity, fewer relapses, and improved regulatory T cell function [33].
• Rheumatoid Arthritis (RA): Studies indicate that Vitamin D3 modulates Th1/Th17-mediated inflammation, resulting in lower joint inflammation and improved pain management in RA patients [34].
• Respiratory Infections: Vitamin D3 has been associated with lower susceptibility to respiratory tract infections, including influenza and COVID-19, due to its role in enhancing innate immune defenses [35].

Vitamin D3 and Immunosenescence

Aging is associated with immune system dysregulation (immunosenescence), leading to reduced immune surveillance and chronic inflammation. Vitamin D3 plays a protective role in aging-associated immune dysfunction by:

• Enhancing Treg cell function to maintain immune tolerance [36].
• Reducing chronic low-grade inflammation, a hallmark of aging (termed “inflammaging”) [37].
• Improving immune responses in elderly individuals, particularly in reducing infection rates and vaccine responsiveness [38].

Studies have shown that elderly individuals with sufficient Vitamin D3 levels have better immune responses to vaccinations and lower incidence of age-related inflammatory diseases [39].

Vitamin D3 and Gut Microbiota Interactions

The gut microbiota has a major role in regulating the immune system and there are emerging findings that infer a modulatory role of vitamin D3 on gut microbiome composition. Research has shown that:

• Vitamin D3 helps develop anti-inflammatory bacterial species, including Faecalibacterium prausnitzii, which play a role in immune homeostasis [40].
• Vitamin D3 deficiency has been associated with dysbiosis (microbial imbalance), which leads to the induction of intestinal inflammation and autoimmunity disorders [41].
•  Only 0.1% of individuals received supplementation, which has been shown to restore gut microbiota diversity in people with IBD and metabolic disease [42].

These findings suggest that Vitamin D3’s role extends beyond direct immune modulation, influencing the immune system through gut-immune interactions.

Future Research Directions and Therapeutic Implications

While significant progress has been made in understanding Vitamin D3’s immunomodulatory effects, future research should address the following key areas:

1. Personalized Vitamin D3 supplementation – Research should focus on determining the optimal dosage based on genetic predisposition, baseline levels, and immune health status [43].
2. Long-term safety and efficacy – Large-scale longitudinal studies are needed to evaluate the long-term effects of Vitamin D3 supplementation in different populations [44].
3. Combination therapies – Investigating the synergistic effects of Vitamin D3 with other immunomodulatory agents, such as probiotics, anti-inflammatory diets, and biologics, in managing autoimmune diseases [45].
4. Advanced delivery mechanisms – Development of nanotechnology-based Vitamin D3 formulations to enhance bioavailability and efficacy in patients with absorption disorders [46].
5. Precision medicine approaches – Utilizing artificial intelligence (AI) and genomic analysis to tailor personalized immune interventions based on Vitamin D3-related gene variants [47].

While significant progress has been made in understanding Vitamin D3’s immunomodulatory effects, future research should address the following key areas:

SUMMARY OF DISCUSSION

• Vitamin D3 deficiency contributes to chronic inflammation and autoimmune disease susceptibility.
• Supplementation has shown clinical benefits in MS, RA, and respiratory infections, supporting its therapeutic potential [32-35].
• Aging-related immune dysfunction can be mitigated through adequate Vitamin D3 levels, reducing chronic inflammation and improving immune resilience [36-39].
• Gut microbiota plays a key role in Vitamin D3-mediated immune regulation, influencing inflammatory and autoimmune conditions [40-42].
• Future research should focus on personalized dosing, combination therapies, and novel delivery mechanisms to maximize therapeutic benefits [43-47].

Vitamin D3 plays a pivotal role in immune system regulation by modulating both innate and adaptive immunity. Its influence on T cells, B cells, macrophages, and cytokine production highlights its importance in maintaining immune balance and preventing excessive inflammatory responses. Deficiency in Vitamin D3 has been strongly associated with autoimmune diseases, chronic inflammation, and increased susceptibility to infections.

Clinical research supports the benefits of Vitamin D3 supplementation in managing conditions such as multiple sclerosis, rheumatoid arthritis, and respiratory infections, demonstrating it’s anti-inflammatory and immune-modulatory properties. Moreover, Vitamin D3 plays an essential role in aging-related immune decline and interacts with the gut microbiota, further influencing immune function. Despite its promising potential, challenges remain regarding optimal dosing, long-term safety, and population-specific effects. Future studies should focus on personalized supplementation strategies, advanced delivery mechanisms, and combination therapies to maximize the therapeutic benefits of Vitamin D3 in immune health.

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