ReviewVitamin D in autoimmune rheumatic diseases: A view inside gender differences
Graphical abstract
Introduction
An adequate vitamin D status is nowadays considered to be essential in order to maintain good health and wellbeing, beside calcium-phosphate homeostasis and bone metabolism regulation.
Skin exposure to sunlight and ultraviolet B (UVB) radiation is the main source of vitamin D, while diet and dietary supplements help to gain a hormone optimal status when the sunlight is not sufficient. Adequate hormone levels should be ensured by this dual source in order to warranty health homeostasis. Nevertheless, severe vitamin D insufficiency is now emerging as a global health problem, leading to different acute and chronic illnesses [1], [2]. Past and recent literature has pointed out the link existing between vitamin D deficiency and the onset/maintenance of several diseases. Vitamin D seems to exert such an important pleiotropic effect, likely due to its fine immunomodulatory features. Vitamin D receptor (VDR) agonists, indeed, have been recognized as powerful immunomodulating agents, able to counteract inflammation which, in turn, has been shown to be the “common soil” of several pathologies, including rheumatic diseases (RD) [3]. Thus, it is not surprising that vitamin D inadequacy associates with metabolic and cardiovascular illnesses, some types of neoplasia, adverse pregnancy or birth outcomes, neurocognitive disorders, autoimmune and, relevant for this review, RD [4], [5], [6], which consist of many different disorders mainly of autoimmune origin. Great scientific interest is addressed to vitamin D and RD, which, like most of autoimmune diseases, are characterized by an important gender bias toward females, from clinical presentation to onset, progression and outcome.
To date, autoimmune response underlying RD seem to be under the control of vitamin D and sexual hormones. The present review aims to offer an oversight on the association between vitamin D status and RD related to gender and sex hormones, highlighting vitamin D inadequacy as factor involved in disease pathogenesis and vitamin D supplementation as potential tool in disease prevention or treatment.
With this purpose, the following paragraphs will first summarize how vitamin D regulates the immune response and how male and female immune systems differ in relation to sex hormones.
Section snippets
Vitamin D
The term vitamin D comprehends a group of natural molecules named “calciferols”, including cholecalciferol, or vitamin D3, ergocalciferol, or vitamin D2 and their intermediate and final metabolites, [25(OH)D] and [1,25(OH)2D], respectively.
The exposure of epidermis to wavelength UVB light (290–315 nm) converts the precursor 7-dehydrocholesterol in previtamin D3; non enzymatic processes originate vitamin D3, that circulates in blood transported by the specific vitamin D binding protein (DBP).
Sexual dimorphism and (auto)immunity
It is well known that diseases of autoimmune origin, including RD, take place from a disruption of immune tolerance to self-antigens, characterized by cell- and antibody-mediated response, and end in systemic or/and organ damage [54], [55].
Remarkably, sexual dimorphism seems to play a pivotal role in development and maintenance of autoimmune diseases, in addition to numerous other factors, including genetic background, environment, epigenetic mechanisms, X and Y chromosome significant influence
Rheumatic diseases and sexual dimorphism
The term RD largely encompasses over one hundred inflammatory, degenerative and autoimmune conditions which in their most complicated form display joint damage, severe pain, disability and death [93]. Commonly, in RD there is also a detrimental involvement of skeletal muscle which worsens disease disability [94]. In the 2010 World Health Organization (WHO) Global Burden of Disease Study, RD have been, indeed, reported to be the second leading cause of disability worldwide [95].
As previously
Vitamin D and rheumatic diseases
As previously addressed, a consistent part of literature suggests a correlation between some autoimmune RD, such as SLE, RA, SSc, Polymyositis/Dermatomyositis (PM/DM) and low plasma vitamin D levels [142], [143]. In fact, although some discrepancy reported by some epidemiological studies [144], the role for vitamin D insufficiency in the pathogenesis of certain RD is supported by epidemiologic, genetic and basic science studies [25], [145], [146]. Adequate vitamin D levels result in a more
Conclusion
As previously addressed, the key event for therapeutic use of VDR agonists relies on restoring immune homeostasis substantially through its inhibitory effects on DC maturation and activation.
In view of the tight link existing with RD progression, recently recommendations for daily vitamin D intake have been provided.
I.e., in UCTD 1.0 μg/day alfacalcidol for 5 weeks repairs the Treg/Th17 balance and raise the capacity of Treg cells to suppress the proliferation of autologous CD4+CD25− cells [182]
Acknowledgments
The authors wish to thank Dr. Francesco Marampon, Department of Movement, Human and Health Sciences, University of Rome Foro Italico, for his critical support during manuscript reviewing.
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These authors contributed equally.