Immune Response: Investigating the role of vitamin D in asthma

Results in mice suggest that vitamin D reduces the symptoms of asthma by controlling an immune response that leads to inflammation of the airways.
  1. Siddhant Sharma
  2. Mayank Garg  Is a corresponding author
  1. Department of Biology, Ashoka University, India
  2. Simons Ashoka Fellowship Program, Trivedi School of Biosciences, Ashoka University, India
  3. Koita Centre for Digital Health, Trivedi School of Biosciences, Ashoka University, India

Vitamin D deficiency has burgeoned into a major public health concern, exacerbated by dietary habits and pollution among other factors (Cui et al., 2023). While vitamin D is well known to be important for maintaining healthy bones, it has also been linked with various immune disorders, including asthma.

Supplements of vitamin D are being increasingly used to treat immune-related conditions. However, it remains unclear precisely how vitamin D is able to improve the outcome of these disorders (Scragg, 2018). Now, in eLife, Scott Weiss, Ardu Halu and co-workers – including Ayşe Kiliç as joint first author with Halu – report how vitamin D regulates an immune response that is a major contributor to asthma (Kiliç et al., 2023).

First, the team – who are based at Brigham and Women’s Hospital and Harvard Medical School, and institutes in Germany, Japan, Russia, and the United States – revisited the findings of a clinical trial called the Vitamin D Antenatal Asthma Reduction Trial (VDAART). In the trial, pregnant women who had a history of Asthma or allergies (or whose partner, the other biological parent, had a similar history), were given low or high doses of vitamin D during pregnancy. Analyses of the data found that higher vitamin D supplementation did not significantly reduce asthma in the offspring (Litonjua et al., 2016; Litonjua et al., 2020). However, a more nuanced reanalysis – which adjusted for baseline vitamin D levels to account for factors such as dietary intake – reported a reduced risk of asthma in the offspring of women who received a higher dose of vitamin D during pregnancy (Wolsk et al., 2017).

Kiliç et al. set out to find the genetic underpinnings of this protective effect, focusing their attention on chromosome 17, which contains regions strongly associated with asthma and other immune diseases (Bansal et al., 2021). Across chromosome 17 are sites where the receptor for vitamin D (known as VDR) can bind. Bioinformatic analysis revealed that some of these VDR binding sites overlapped with genetic variants associated with diseases triggered by the immune response mediated by T helper type 2 cells. These immune cells (known as Th2 for short) are a subset of white blood cells which respond proactively to invading pathogens like helminths, as well as recurrent exposures. Th2 cells act by producing inflammatory mediators as well as by modulating the activity of other cells in the immune system. They are also activated by allergens, such as mites and pollens, which can lead to allergic inflammation and disorders like asthma.

A detailed exploration of these overlapping regions suggested that VDR can trigger a cascade that regulates genes involved in the Th2 immune response. This genetic regulation could either promote or repress the Th2 response, depending on other genetic variants present in the proximity.

With a hypothesis established, the researchers tested their findings in mice which had been exposed to extracts from house dust mites to mimic the asthma phenotype (Figure 1A). They found that mice deficient in vitamin D or lacking VDRs displayed a more severe phenotype. Further experiments revealed that house dust mite exposure also caused the Th2 cells to express higher levels of VDR. When these Th2 cells were exposed to calcitriol (the active form of vitamin D), the VDRs bound to the calcitriol and migrated from the cytosol into the nucleus (Figure 1B).

The vitamin D receptor and its role in inflammation of the airways.

(A) To mimic the symptoms of asthma, Kiliç et al. treated a lab-grown strain of mice (known as C57Bl/6) with extracts from house dust mites (HDM). This activated a group of immune cells called T helper type 2 (Th2; green) in the lungs of the mice, leading to inflammation of their airways. (B) Kiliç et al. found that exposure to dust mites also caused the Th2 cells to produce more vitamin D receptors (purple). When the cells were treated with calcitriol, the active form of vitamin D (blue circles with black lines), the receptors migrated from the cytosol to the nucleus. Once there, the receptor can regulate the expression of genes involved in the Th2 response, including the gene Ikzf3 which suppresses the inflammatory response triggered by Th2 cells.

© 2024, BioRender Inc. Figure 1 was created using, and is published under a CC BY-NC-ND license. Further reproductions must adhere to the terms of this license.

These findings suggest that VDR acts like a lock waiting for its key. Access to the key (vitamin D), and migration of the VDR into the nucleus, possibly unlocks the transcriptional regulation required to modulate the immune pathways. Furthermore, VDR expression was contingent upon baseline vitamin D levels, suggesting that this vitamin has both a preventive and therapeutic potential. Kiliç et al. also found that one of the genes that VDR regulates (called Ikzf3) is a major factor in suppressing the Th2 immune response (Figure 1B). This effect is likely mediated through the STAT signaling axis, which is a critical pathway regulating inflammation (Hu et al., 2021).

The study by Kiliç, Halu, Weiss and colleagues sheds light on how vitamin D offers protective benefits against asthma. However, several pathophysiological pathways can lead to the characteristic airway inflammation associated with asthma (Moore and Bleecker, 2014). Subgroup analysis during clinical trials, along with targeted exploration of relevant biomarkers, could help identify who would benefit most from vitamin D supplements. The latest findings also underscore the importance of vitamin D in a wider sense, as the Th2 response is associated with several other chronic inflammatory diseases.

That being said, it is essential to be mindful of the broader biological role of vitamin D, as it influences both the innate and the adaptive immune system via a number of different cell types (Colotta et al., 2017). This complexity may be why scientific literature on vitamin D is marred by contradictory findings: for instance, a previous study has even shown loss of VDR to be protective against asthma (Wittke et al., 2004). However, this complexity should not deter researchers from trying to develop a deeper mechanistic understanding of vitamin D effects. Such an understanding could, in the future, enable personalized treatment strategies for individuals with immune disorders such as asthma.


Article and author information

Author details

  1. Siddhant Sharma

    Siddhant Sharma is in the Department of Biology, Ashoka University, Sonipat, India

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1768-1802
  2. Mayank Garg

    Mayank Garg is on the Simons Ashoka Fellowship Program and at the Koita Centre for Digital Health, Trivedi School of Biosciences, Ashoka University, Sonipat, India

    For correspondence
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1919-1818

Publication history

  1. Version of Record published: April 3, 2024 (version 1)


© 2024, Sharma and Garg

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.


  • 263
    Page views
  • 28
  • 0

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Siddhant Sharma
  2. Mayank Garg
Immune Response: Investigating the role of vitamin D in asthma
eLife 13:e97031.

Further reading

    1. Genetics and Genomics
    Pianpian Zhao, Zhifeng Sheng ... Hou-Feng Zheng
    Research Article

    The ‘diabetic bone paradox’ suggested that type 2 diabetes (T2D) patients would have higher areal bone mineral density (BMD) but higher fracture risk than individuals without T2D. In this study, we found that the genetically predicted T2D was associated with higher BMD and lower risk of fracture in both weighted genetic risk score (wGRS) and two-sample Mendelian randomization (MR) analyses. We also identified ten genomic loci shared between T2D and fracture, with the top signal at SNP rs4580892 in the intron of gene RSPO3. And the higher expression in adipose subcutaneous and higher protein level in plasma of RSPO3 were associated with increased risk of T2D, but decreased risk of fracture. In the prospective study, T2D was observed to be associated with higher risk of fracture, but BMI mediated 30.2% of the protective effect. However, when stratified by the T2D-related risk factors for fracture, we observed that the effect of T2D on the risk of fracture decreased when the number of T2D-related risk factors decreased, and the association became non-significant if the T2D patients carried none of the risk factors. In conclusion, the genetically determined T2D might not be associated with higher risk of fracture. And the shared genetic architecture between T2D and fracture suggested a top signal around RSPO3 gene. The observed effect size of T2D on fracture risk decreased if the T2D-related risk factors could be eliminated. Therefore, it is important to manage the complications of T2D to prevent the risk of fracture.

    1. Genetics and Genomics
    Songyuan Wu, Xiaoling Tong ... Fangyin Dai
    Research Article

    The color pattern of insects is one of the most diverse adaptive evolutionary phenotypes. However, the molecular regulation of this color pattern is not fully understood. In this study, we found that the transcription factor Bm-mamo is responsible for black dilute (bd) allele mutations in the silkworm. Bm-mamo belongs to the BTB zinc finger family and is orthologous to mamo in Drosophila melanogaster. This gene has a conserved function in gamete production in Drosophila and silkworms and has evolved a pleiotropic function in the regulation of color patterns in caterpillars. Using RNAi and clustered regularly interspaced short palindromic repeats (CRISPR) technology, we showed that Bm-mamo is a repressor of dark melanin patterns in the larval epidermis. Using in vitro binding assays and gene expression profiling in wild-type and mutant larvae, we also showed that Bm-mamo likely regulates the expression of related pigment synthesis and cuticular protein genes in a coordinated manner to mediate its role in color pattern formation. This mechanism is consistent with the dual role of this transcription factor in regulating both the structure and shape of the cuticle and the pigments that are embedded within it. This study provides new insight into the regulation of color patterns as well as into the construction of more complex epidermal features in some insects.