Insights Into the Role of Vitamin D as a Biomarker in Stem Cell Transplantation

Abstract

Vitamin D was discovered 100 years ago and since then multiple studies have consistently proved its effect on bone health and mineral metabolism. Further research has also explored its so-called "non-classical" biological effects, encompassing immune regulation and control of cell proliferation and differentiation. Vitamin D downregulates pro-inflammatory immune cells and subsequently their cytokine production, while enhancing the anti-inflammatory subsets, thus mediating inflammation and fostering a more tolerogenic environment. Its biological action is exerted through the vitamin D receptor, a nuclear receptor that mediates gene transcription and is expressed in most cells from the innate and adaptive immunity. Owing to its immune-modulatory properties, its role in cancer pathophysiology, hematology disorders and stem cell transplantation has also been investigated. Vitamin D deficiency causes immune imbalance and cytokine dysregulation, contributing to some autoimmune diseases. In the hematopoietic stem cell transplant setting this could lead to complications such as acute and chronic graft-versus-host disease, ultimately impacting transplant outcomes. Other factors have also been linked to this, including specific polymorphisms of the vitamin D receptor in both stem cell donors and recipients. Nevertheless, studies thus far have shown conflicting results and the use of vitamin D or its receptor as biomarkers has not been validated yet, therefore there are no evidence-based consensus guidelines to guide clinicians in their day-today practice. To gain more insight in this topic, we have reviewed the existent literature and gathered the current evidence. This is an overview of the role of serum vitamin D and its receptor as biomarkers for clinical outcomes in patients undergoing hematopoietic stem cell transplantation. Further prospective studies with larger cohorts are warranted to validate the viability of using serum vitamin D, and its receptor, as biomarkers in potential stem cell donors and patients, to identify those at risk of post-transplant complications and enable early therapeutic interventions.

Causal Links between Hypovitaminosis D and Dysregulation of the T Cell Connection of Immunity Associated with Obesity and Concomitant Pathologies

“…Vitamin D is a fat-soluble secosteroid, 70–80% of which is synthesized in a photolysis reaction in the skin [ 20 ]. Under the influence of ultraviolet radiation (UV) from the B spectrum of the sun, the process of photosynthesis in the epidermis is activated.…”

“…The synthesis of vitamin D 3 takes up to 3 days from the time the skin is exposed to UV rays. This process is the main source of vitamin D and it depends on the intensity of UV radiation (latitude, season, time of day), skin pigmentation and air pollution [ 20 , 21 , 22 ] ( Figure 1 ).…”

“…The kidney also contains the enzyme 24-hydroxylase (CYP24A1), which converts 25(OH)D 3 to 24,25(OH) 2 D 3 by hydroxylation at C-24 (carbon 24) [ 29 ]. Furthermore, 1,25(OH) 2 D 3 is converted to calcitroic acid, which is functionally inactive [ 20 , 25 ]. These toxic metabolites are excreted in the bile, feces and urine [ 20 ].…”

The Crossroads between Infection and Bone Loss

“…As mentioned before, vitamin D is a major player in calcium metabolism and consequently in bone mineralization. Another increasingly recognized role of vitamin D is the regulation of both innate and adaptative immunity [ 108 ]. Even though vitamin D itself has an impact on bone homeostasis, here, we will focus on the role of vitamin D during infection as an immune modulator and its consequences for bone homeostasis.…”

“…Vitamin D is hydroxylated in the body, by the enzyme CYP27B1, forming its active form, calcitriol [ 109 ]. CYP27B1 expression has been shown to be upregulated during infection by Mycobacterium tuberculosis , the causative agent of tuberculosis, leading to the increased synthesis of calcitriol [ 108 , 110 ]. Calcitriol also promotes the production of the anti-inflammatory cytokines IL4, IL5, and IL10, while decreasing the production of pro-inflammatory cytokines such as IFNγ, IL6, TNFα [ 111 , 112 ].…”