Elsevier

Pharmacological Research

Volume 117, March 2017, Pages 228-241
Pharmacological Research

Review
Vitamin D in autoimmune rheumatic diseases: A view inside gender differences

https://doi.org/10.1016/j.phrs.2016.12.038Get rights and content

Abstract

A large body of evidence highlights the role for vitamin D deficiency/insufficiency in rheumatic diseases, a group of different pathologies mostly of autoimmune origin. Vitamin D and vitamin D receptor agonists exquisitely modulate the immune system against over-reactivity towards tolerance; on this basis, vitamin D could be a good therapeutic candidate to control autoimmune processes in rheumatic diseases. Similarly, to other autoimmune pathologies, rheumatic diseases show a significant female bias. This sexual dimorphism seems, in part, to rely on the different sex hormone-induced regulation on male and female immune systems. Females, in fact, retain greater immune reactivity and competence likely due to estrogens, which, at variance with androgens, are associated with a greater resilience to infections but also to a higher risk for autoimmunity. In this scenario, there is growing interest on vitamin D supplementation for prevention or therapy in rheumatic diseases in relation to gender and sexual hormones.

The purpose of the review is to overview vitamin D status in rheumatic diseases, related to gender and sex hormones. In particular, the main vitamin D immunoregulatory properties are summarized with some sex hormone-driven immune activities, in females and males immune systems. Topics onto vitamin D receptor agonists as potential therapeutic agents in rheumatic disease are addressed, especially in view of the role of vitamin D inadequacy in the pathogenesis of rheumatic diseases. So far, further clinical and basic studies should be encouraged to confirm the high potential power of vitamin D receptor agonists as novel pharmacological tools in rheumatic diseases particularly in light of personalized gender-related therapeutic strategies.

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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