Vitamin D and allergic rhinitis: A mini-review

Abstract

Allergic rhinitis (AR) is an increasingly common inflammatory disease mediated by immunoglobulin E in response to environmental allergens, substantially impacting the quality of life and healthcare systems worldwide. Recent research has drawn attention to the role of vitamin D, a corticosteroid hormone with immunomodulatory properties, in influencing the onset and severity of allergic diseases, including AR. Vitamin D exerts regulatory effects and inherent and tailored immunity, including suppressing pro-inflammatory cytokines and enhancing regulatory T cell function. A contrary connection among serum 25-hydroxyvitamin D levels has been suggested in observational studies of AR prevalence, particularly among children and male adults. However, interventional studies/ research into the therapeutic effects of vitamin D supplementation in AR have yielded mixed results, with benefits possibly dependent upon baseline vitamin D levels, gender, age, and concomitant therapies. Although emerging evidence implies a link between vitamin D shortage and augmented threat or severity of AR, definitive statements regarding its therapeutic role have not been made. Further high-quality randomized controlled trials are required to clarify the immunological mechanisms engaged and establish standardized clinical guidelines. This mini-review underscores the potential of vitamin D as an adjunctive approach in AR and highlights the need for individual strategies tailored to each patient's profile. This mini-review aims to synthesize evidence about the bond between vitamin D levels and AR, exploring epidemiological findings and underlying immunological mechanisms.

Key Words: Vitamin D; Allergic rhinitis; 1,25-dihydroxycholecalciferol; Immunoglobulin E; Immunomodulation; Inflammation

Core Tip: Allergic rhinitis (AR) is an increasingly common inflammatory disease mediated by immunoglobulin E in response to environmental allergens, substantially impacting the quality of life and healthcare systems worldwide. Recent research has drawn attention to the role of vitamin D, a corticosteroid hormone with immunomodulatory properties, in influencing the onset and severity of allergic diseases, including AR.

INTRODUCTION

Allergic rhinitis (AR) is a prevalent immunoglobulin E (IgE)-mediated inflammatory disorder of the nasal mucosa, provoked by exposure to airborne allergens. It significantly impairs quality of life, affecting sleep, work, and social interactions. The global prevalence of AR varies, with studies indicating rates ranging from 16.9% to 28.5% in Europe and from 8.7% to 24.1% in major Chinese cities[1]. Vitamin D, previously very well-known for its role in bone metabolism, is a vital immunomodulator. Its active form, 1,25-dihydroxyvitamin D3, leverages the duty of diverse immune cells, including T cells, B cells, dendritic cells (DCs), monocytes, and macrophages[1]. Vitamin D deficiency has been implicated in the pathogenesis of numerous allergic situations, particularly AR[2]. Epidemiological research has followed an opposite liaison between serum vitamin D levels and the prevalence of AR. For instance, a study in Australia discovered that vitamin D deficiency related to increased AR severity[3]. However, findings are inconsistent, with some studies reporting no significant association[4]. Experimental research suggests that vitamin D utilizes immunomodulatory effects that could influence AR development. It promotes regulatory T cell differentiation, suppresses inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor-alpha, and inhibits IgE production[2-5]. These mechanisms highlight the capability role of vitamin D in adjusting allergic responses.

Clinical trials that have investigated vitamin D supplementation as a therapeutic approach for the treatment of AR have produced mixed results. Vitamin D supplementation may reduce symptoms of AR, but the differences were not statistically significant in a meta-analysis of randomized controlled trials (RCTs), and considerable heterogeneity among studies was observed[2-5]. Factors such as concomitant corticosteroid use and participant sex appeared to influence the potency of vitamin D complement.

This mini-review will analyze the current literature on the association between vitamin D and AR. It will examine the immunological functions of vitamin D, review the epidemiological and clinical evidence linking vitamin D status to AR, and discuss the potential curative implications of vitamin D supplementation in treating AR. By summarizing existing research, we aim to elucidate the role of vitamin D in AR and identify areas for future investigation.

SEARCH STRATEGY

This mini-review used a narrative approach to synthesize current literature regarding the relationship between vitamin D and AR. Relevant articles published in English from 2000 to 2024 were identified through comprehensive searches of electronic databases including PubMed, Scopus, and Web of Science. The search strategy utilized combinations of keywords such as "vitamin D", "allergic rhinitis", "immunomodulation", "25-hydroxyvitamin D", and "supplementation". Both epidemiological studies and interventional clinical trials were considered, as well as mechanistic studies exploring vitamin D’s role in immune function. Priority was given to RCTs, meta-analyses, and systematic reviews; however, observational and experimental studies were included to provide a broader understanding. Studies were selected based on relevance, methodological quality, and contribution to understanding vitamin D's immunological effects in the context of AR. Data were extracted and thematically categorized into sections covering immunological mechanisms, clinical efficacy, and potential therapeutic implications.

VITAMIN D'S IMMUNOLOGICAL/IMMUNOMODULATORY FUNCTIONS

Vitamin D exerts its immunomodulatory effects by acting on multiple immune cell types. It facilitates the development of tolerogenic DCs, which stimulate the production of regulatory T cells-key players in promoting immune tolerance and reducing allergic reactions.

Over and above its classical role in bone health, vitamin D is a key immune system modulator, influencing inherited and tailored immune responses[6]. Its active metabolite, 1,25-dihydroxyvitamin D3 (calcitriol), interfaces with vitamin D receptors found on various immune cells, including T lymphocytes, B lymphocytes, DCs, and monocytes, orchestrating several immunological processes (Table 1).

Table 1 Immune response in normal vs allergic rhinitis individuals.

Features	Normal immunity	Allergic rhinitis
Th cell balance	Balanced Th1/Th2	Th2 skewed dominance
IgE production	Low IgE levels	High IgE levels promoting hypersensitivity
Epithelial barrier	Strong, intact	Impaired, leaky barrier facilitates allergen entry
Inflammation	Controlled, self-limited	Chronic, persistent nasal inflammation
Mast cell activation	Minimal under normal conditions	Heightened activation and mediator release
Clinical outcome	No allergic symptoms	Sneezing, itching, rhinorrhea, congestion

IgE: Immunoglobulin E; Th: T-helper.

Vitamin D's effect on innate immunity modulation

In innate immunity, vitamin D enhances the pathogen-fighting capabilities of monocytes and macrophages. It stimulates these cells to produce antimicrobial peptides, such as cathelicidin, crucial to defense against pathogens[7]. Additionally, vitamin D influences DCs by promoting a tolerogenic phenotype, which can modulate T cell responses and maintain immune tolerance.

Vitamin D's effect on adaptive immunity regulation

Vitamin D significantly affects adaptive immunity by influencing T cell responses[8]. It inhibits the output of pro-inflammatory cytokines by T-helper (Th) 1 and Th17 cells, such as interferon-γ and IL-17, while encouraging the secretion of anti-inflammatory cytokines from Th2 cells, including IL-4 and IL-10. This shift favors a Th2-dominant response generally associated with humoral immunity and allergic reactions.

Vitamin D's effect on the regulation of autoimmune responses

Vitamin D's immune-modulating properties are also apparent in autoimmune diseases. A deficiency of vitamin D has been associated with an increased risk of developing autoimmune diseases, for instance, type 1 diabetes mellitus and multiple sclerosis[9]. Vitamin D supplementation has shown promise in modulating immune responses, potentially reducing disease activity and promoting immune tolerance[10].

Vitamin D's impact on inflammatory processes

Beyond its roles in immunity, vitamin D influences inflammatory pathways[11]. It has been observed to reduce the output of pro-inflammatory cytokines and upregulate the manufacture of anti-inflammatory cytokines, thereby helping resolve inflammation. This balance is crucial in preventing the advancement of perennial seditious status and maintaining overall immune homeostasis[12].

Vitamin D's multifaceted immunological roles underscore its importance as a crucial regulator of inherited and tailored immune responses. Its capacity to modulate immune cell function and influence inflammatory pathways highlights its potential as a therapeutic agent in various immune-mediated conditions. Ongoing research unravels the complexities of vitamin D's effects on the immune system, offering promising avenues for clinical applications in immunology.

IMPORTANCE OF AR

AR is a prevalent IgE-mediated inflammatory disorder characterized by rhinal mucosal inflammation upon exposure to airborne allergens. It significantly impacts quality of life and is associated with comorbid conditions such as asthma and sinusitis. Understanding the pathophysiology of AR is crucial for developing effective therapeutic strategies (Table 2).

Table 2 Vitamin D and allergic rhinitis.

Classification
AR	An immunoglobulin E-mediated inflammatory condition
	Triggered by exposure to airborne allergens
Vitamin D	A hormone with immunomodulatory properties
	Deficiency in vitamin D has been implicated in the pathogenesis of AR
Immunological mechanisms	Modulates both innate and adaptive immune responses
	Suppresses the production of pro-inflammatory cytokines
	Enhances the development and function of regulatory T cells
Clinical evidence	Studies on vitamin D supplementation have yielded mixed results
	Some evidence suggests potential improvement in AR symptoms

AR: Allergic rhinitis.

PATHOPHYSIOLOGY OF AR

The pathogenesis of AR is the consequence of a compound interaction among genetic susceptibility, ambient exposures, and immune system dysregulation (Table 1). Upon allergen exposure, antigen-presenting cells such as DCs capture and process the allergen, leading to the mobilization of naïve Th cells. In individuals with AR, there is a skewing toward a Th2-dominant immune response, classified by cytokine production, including IL-4, IL-5, and IL-13. IL-4 and IL-13 promote class switching of B cells to produce IgE antibodies, while IL-5 is crucial to help recruit and activate eosinophils, leading to tissue inflammation and damage[13].

Typically, early-phase and late-phase answers are distinguished in the clinical manifestations of AR. The early phase response occurs within a few minutes of exposure to the allergen. It is mediated by cross-linking of IgE on mast cells, releasing histamine and other mediators that cause instant symptoms such as sneezing, itching, and rhinorrhea. The late-phase response develops hours later and is characterized by the infiltration of inflammatory cells, including eosinophils, basophils, and Th2 cells, leading to sustained nasal congestion and mucosal edema[14].

Up-to-date studies have highlighted the duty of epithelial-derived cytokines such as thymic stromal lymphopoietin, IL-25, and IL-33 in initiating and amplifying Th2 responses at mucosal surfaces. These cytokines are produced by airway epithelial cells in response to allergen exposure and act as alarmins to activate DCs, thereby promoting Th2 polarization. Additionally, impaired epithelial barrier function, as evidenced by decreased expression of tight junction proteins like occludin and zonula occludens-1, has been observed in patients with AR, suggesting a compromised mucosal defense that facilitates allergen entry and sensitization[15].

Furthermore, the actuation of histamine receptors beyond the traditional H1 and H2 receptors, specifically the H4-histamine receptor, has been compromised in the pathophysiology of AR. The H4 receptor is expressed on various immune cells, including eosinophils and mast cells, and its activation contributes to the recruitment and activation of these cells, thereby exacerbating inflammation[16].

The investigation of AR has elucidated a multifaceted pathophysiological landscape involving immune dysregulation, epithelial barrier dysfunction, and altered mediator signaling (Table 1). These findings pave the way for novel therapies targeting specific allergic cascade components, including Th2 cytoinhibitors and epithelial alarmin modulators. Continued research into the molecular mechanisms underlying AR will be indispensable for processing personalized and effective treatments for this widespread condition.

EPIDEMIOLOGICAL AND CLINICAL EVIDENCE LINKING VITAMIN D STATUS TO AR

The connection between vitamin D status and AR has been a subject of extensive research, yielding varied findings across different study designs.

EPIDEMIOLOGICAL OBSERVATIONS

A systematic review and meta-analysis of 19 studies found reduced vitamin D levels related to a greater frequency of AR in children, with a clustered odds ratio of 0.75 (95%CI: 0.58–0.98). Nevertheless, this association was not observed in adults. Additionally, the study found that the clustered mean vitamin D level in AR patients was lower than that of controls only in children[17]. Another meta-analysis of 21 observational studies examined the relationship between vitamin D status and aeroallergen sensitization and AR. The findings indicated that children with serum 25-hydroxyvitamin D [25(OH)D] levels ≥ 75 nmol/L had significantly lowered odds of aeroallergen sensitization. However, neither prenatal vitamin D uptake nor infant complementarity was related to a reduced risk of AR[18].

Conversely, a Mendelian randomization study utilizing genetic variants associated with vitamin D synthesis found no causal relationship between serum 25(OH)D levels and the risk of AR or allergic sensitization. This suggests that previous observational associations might be influenced by confounding factors[4,19].

CLINICAL EVIDENCE: INTERVENTION TRIALS

There have been mixed results from clinical trials investigating the effect of vitamin D supplementation on AR symptoms. A meta-analysis of five RCTs found that vitamin D supplementation eased AR symptoms compared to placebo; however, the disparities were not statistically significant, and significant heterogeneity among studies was noted[20]. In a randomized, double-blind, placebo-controlled trial involving children sensitive to grass pollen, daily supplementation of 1000 IU of vitamin D during the pollen season significantly lowered symptoms and medication scores. The vitamin D group also showed increased regulatory T cells (CD4+CD25+Foxp3+ cells), suggesting an immunological effect[21].

Another randomized controlled clinical investigation involving 80 patients diagnosed with AR and concurrent vitamin D deficiency evaluated the impact of vitamin D supplementation on symptom severity. After 8 weeks, 35 patients in the intervention group and 33 patients in the control group completed follow-up, with no significant age difference between groups (mean age approximately 29 years, P > 0.05). Baseline serum vitamin D levels were similar in both groups (14 ng/mL vs 14.67 ng/mL, P = 0.189). However, after 8 weeks of supplementation, the study group exhibited a significant increase in vitamin D levels (24.08 ng/mL, P < 0.001). Although symptom severity scores did not differ significantly between groups at baseline or at week 4 (P = 0.073), a notable improvement was observed by week 8 in the intervention group compared to baseline (P = 0.007). These findings suggest that vitamin D supplementation and antihistamines may significantly improve AR symptoms among patients with documented vitamin D deficiency[22].

However, another study reported that vitamin D supplementation did not significantly affect AR incidence or total rhinal symptom scores, indicating that the impact of supplementation may vary based on study design, population, and supplementation parameters[20,23].

The epidemiological and clinical evidence linking vitamin D status to AR is complex and sometimes contradictory. While several studies suggest a liaison between lower vitamin D levels and increased AR prevalence, particularly in children, other research, including Mendelian randomization studies, does not support a cause-and-effect relationship. Clinical trials on vitamin D complement's efficacy in treating AR symptoms have yielded mixed outcomes, with some studies reporting benefits and others finding minimal effects. These discrepancies may arise from study methodologies, populations, and supplementation protocol variations. Further well-designed, RCTs are essential to clarify vitamin D's role in AR prevention and management (Table 2).

POTENTIAL THERAPEUTIC IMPLICATIONS OF VITAMIN D SUPPLEMENTATION IN AR MANAGEMENT

Vitamin D, typically acknowledged for its role in bone health, has emerged as a significant modulator of immune responses, suggesting potential therapeutic applications in AR. The impacts of vitamin D supplementation on AR symptoms and underlying immunological mechanisms have been investigated in various studies.

Clinical observations

A randomized, double-blind, placebo-controlled trial including children with grass pollen sensitivity assessed the impact of daily vitamin D supplementation (1000 IU) during the pollen season. The results indicated a significant reduction in AR symptoms/medication score in the vitamin D group, like that of the placebo. Additionally, there was a notable rise in the percentage of regulatory T cells (CD4+CD25+Foxp3+), which are crucial for immune tolerance, suggesting an immunomodulatory effect of vitamin D[21,24].

Another study observed that vitamin D supplementation, alongside antihistamine treatment, significantly improved AR symptoms after eight weeks[22,25]. This improvement was particularly evident in contributors with vitamin D deficiency at baseline, highlighting the potential benefit of supplementation in deficient individuals[22,26].

Meta-analyses and systematic reviews

A meta-analysis of five RCTs examined the efficacy of vitamin D supplementation in alleviating AR symptoms. While the overall effect was not statistically significant, subgroup analyses revealed that vitamin D complementation might be more efficient when used concomitantly with non-corticosteroid medications. Factors such as the proportion of female participants also appeared to influence the reply to vitamin D supplementation[20]. In addition, in a systematic review and meta-analysis focusing on children with allergic diseases, vitamin D supplementation reduced symptom medication scores in children with AR[27]. This indicates that vitamin D may be essential in managing symptoms of AR in children (Table 3)[28].

Table 3 Standard protocols in clinical randomized controlled trials on vitamin D supplementation for allergic rhinitis.

Protocol component	Details
Patient selection	Clinical diagnosis of allergic rhinitis. Confirmed vitamin D deficiency (< 20 ng/mL). Exclusion: Chronic systemic illness, immunodeficiency, high-dose steroids
Supplementation regimen	Vitamin D3 (cholecalciferol): 1000–2000 IU/day. Oral route preferred. Duration: 8-12 weeks
Concomitant treatments	Standard antihistamines (e.g., cetirizine, loratadine). Some trials include intranasal corticosteroids. Medications maintained at stable doses
Outcome measures	Symptom scores (e.g., total nasal symptom scores, visual analog scale) at baseline and end of study. Serum 25-hydroxyvitamin D levels pre-intervention and post-intervention
Immunological assessments	(In select trials) CD4+CD25+Foxp3+, Treg levels, cytokine profiling (e.g., IL-4, IL-10, interferon-γ)
Monitoring and follow-up	Follow-ups every 4 weeks. Supplement compliance via pill count/self-report. Monitoring for side effects/toxicity

IL: Interleukin.

Considerations and future directions: AR is a globally prevalent, IgE-mediated inflammatory condition that significantly impacts the quality of life and presents a growing public health burden. While its pathogenesis is multifactorial, involving environmental triggers and immune dysregulation, growing evidence points toward a potential immunological link with vitamin D status. Vitamin D, traditionally linked to bone health, has demonstrated significant regulatory effects on both innate and adaptive immunity, positioning it as a promising modulator in allergic disease pathways.

While existing studies imply that vitamin D supplementation may offer therapeutic benefits for AR, results are not universally consistent, and some studies report minimal effects. Variations in study design, supplementation protocols, and participant characteristics contribute to these discrepancies. Therefore, further research, including large-scale, multicenter RCTs, is essential to conclusively define the efficacy of vitamin D supplementation in AR management and to elucidate the underlying mechanisms of action. Vitamin D supplementation holds promise as a therapeutic adjunct in managing AR, particularly in individuals with vitamin D deficiency. Its potential to modulate immune responses offers a novel approach to alleviating AR symptoms. However, due to variability in current research findings, further studies are warranted to understand its role fully and improve its application in the clinical setting.

Mechanistic studies provide a plausible biological rationale for vitamin D's therapeutic role, highlighting its influence on dendritic cell maturation, Treg cell induction, cytokine modulation, and maintenance of epithelial barrier integrity-all critical in allergic inflammation[29]. However, the absence of standardized protocols and the influence of confounding factors in many studies underscore the need for more rigorously designed clinical trials. By synthesizing the current body of literature, this review underscores vitamin D’s potential role as an adjunctive therapy in AR management, particularly in subgroups with demonstrable deficiency or immune imbalance. Future investigations should focus on large-scale, randomized, placebo-controlled studies with stratified patient cohorts to determine optimal dosing strategies, duration of supplementation, and long-term outcomes. In addition, integrative approaches examining gene-environment interactions, vitamin D receptor polymorphisms, and the role of microbiota may further clarify individual variations in response to supplementation. While vitamin D is unlikely to serve as a stand-alone cure for AR, its immunomodulatory properties suggest it may be a valuable component of a personalized, multifaceted treatment strategy. Establishing clear clinical guidelines for its use could significantly enhance therapeutic outcomes for patients suffering from AR.

CONCLUSION

Epidemiological data suggest a contrary connection between serum 25(OH)D levels and the prevalence of AR, especially in pediatric populations, although findings in adults remain inconsistent. Moreover, intrusive studies exploring vitamin D supplementation in AR patients have reported varying outcomes-some indicating symptomatic relief and immunological benefits, particularly in vitamin D-deficient individuals. In contrast, others report minimal or no therapeutic effect. These discrepancies may be attributed to heterogeneity in population demographics, supplementation dosage, duration, and concurrent therapies.