In a recent review published in the journal Nutrients, researchers explored the role of an individual’s immunocompetence in the responsiveness to vitamin D.
They discussed the modulation of immunocompetence via the epigenetic programming function of the vitamin D receptor (VDR) and its ligand and highlighted the impact of aging on immunocompetence.
Study: Vitamin D and Aging: Central Role of Immunocompetence. Image Credit: Iryna Imago/Shutterstock.com
Background
Vitamin D plays a crucial role in bone health by regulating calcium homeostasis and preventing conditions like rickets and osteomalacia. However, its influence on immunity extends beyond this function.
Vitamin D deficiency, linked to modern lifestyle factors like limited sun exposure, affects the endogenous production of active vitamin D metabolites.
The inactive vitamin D3 is converted to active 1,25(OH)2D3 in the liver and kidneys, which acts as a hormone and affects various tissues. Notably, various cells, including those of the innate immune system, can produce 1,25(OH)2D3 locally, contributing to auto- and paracrine effects. This compound acts as a ligand of high affinity for VDR, regulating the expression of numerous genes.
The vitamin D status, indicated by serum 25(OH)D3 levels, categorizes individuals into deficient, insufficient, or sufficient groups. Vitamin D responsiveness varies among people due to genetic and epigenetic factors influencing molecular responses.
Low responders, constituting about 25% of the population, may have increased susceptibility to diseases related to compromised immunity. The VDR-based modulation of immunocompetence may contribute to aging and reduce the risk of age-related diseases.
The present review offers insights into the immunomodulatory functions of vitamin D and its impact on various health aspects beyond bone metabolism.
Vitamin D signaling
VDR binds specifically to genomic DNA, recognizing the motif RGKTSA. In complex with retinoid X receptor (RXR), VDR preferentially binds to direct repeat sequences in the euchromatin. Various “pioneer factors” facilitate VDR in opening chromatin, which is crucial for efficient binding.
Chromatin accessibility and VDR binding can be assessed using next-generation sequencing technologies, including ChIP-seq (chromatin immunoprecipitation sequencing) and ATAC-seq (assay for transposase-accessible chromatin using sequencing), especially in peripheral blood mononuclear cells.
Genomic regions of vitamin D target genes demonstrate changes in chromatin accessibility and VDR binding after vitamin D3 supplementation.
Enhancers and transcription start site regions, even at a considerable linear distance, can interact via DNA looping within the same topologically associating domain, influencing gene expression.
VDR's genomic actions involve protein-protein interactions with the Mediator complex and RNA polymerase II, influencing transcription. Vitamin D also exerts epigenomic effects, altering DNA methylation, histone modifications, and chromatin organization, dynamically shaping the cell's epigenetic landscape.
These genomic and epigenomic effects contribute to vitamin D's modulatory role in hematopoiesis and immunocompetence, affecting human immune cells both in vitro and in vivo.
Epigenetic programming of immune cells
Throughout embryogenesis and adult cellular differentiation, stem and progenitor cells undergo epigenetic programming, determining the function of terminally differentiated cells. 1,25(OH)2D3 plays a crucial role in this process, influencing hematopoiesis and the differentiation of immune cells.
Hematopoietic stem cells (HSCs) differentiate into various blood and immune cell types, and 1,25(OH)2D3 regulates embryonic HSC numbers.
Various transcription factors influenced by vitamin D drive the differentiation of myeloid progenitor cells into granulocytes and monocytes. Vitamin D is also the differentiation of monocytes into dendritic cells and macrophages.
Epigenetic programming by vitamin D contributes to innate immune cell adaptation, modulating responses to infections, inflammation, and diseases.
Variability in vitamin D status and response index among individuals affects the epigenetic programming of monocytes and derived cells, emphasizing the potential of optimized vitamin D3 supplementation for supporting proper immune cell epigenetics and overall immunocompetence. However, further research is needed to validate this concept fully.
Decline in immunocompetence during aging
Aging involves accumulating molecular damage, resulting in cellular dysfunction and weakened organs. Immunocompetence, crucial for appropriate immune responses, declines with age, leading to increased susceptibility to infections and diseases.
The thymus atrophies, diminishing the production of T-cells, and “inflammaging” ensues. However, interindividual differences exist, and some individuals may display relatively higher immunocompetence.
Lower immunocompetence correlates with accelerated aging and heightened disease risks. Vitamin D sufficiency may protect against cancers by preserving immunocompetence.
Adequate vitamin D levels could stabilize immune resilience, safeguard against diseases, and contribute to healthy aging by mitigating various hallmarks of aging, including inflammation and cellular stress.
Conclusion
In conclusion, the active form of vitamin D plays a crucial role in modulating the epigenome of immune cells, particularly in monocytes.
The observed associations between vitamin D deficiency, increased disease risk, and accelerated aging may be attributed to diminished immunocompetence.
Considering individual responsiveness, a precautionary daily vitamin D3 dose of 1 µg (40 IU)/kg body mass is suggested, exceeding general recommendations but staying within safe limits to strengthen immunocompetence. The researchers emphasize personalized vitamin D supplementation to safeguard against prevalent diseases and promote healthy aging.
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