The role of vitamin D in autoimmune diseases: could sex make the difference?

Abstract

Over the last decades, a central role for vitamin D in immune modulation has been well established. The active form of vitamin D, i.e., 1,25-dihydroxyvitamin D, through the interaction with vitamin D receptor, exerts different activities on the innate and adaptive immune system, among which suppression of inflammation and promotion of tolerogenic responses. Vitamin D insufficiency has been linked to autoimmune disorders that commonly display significant differences between females and males due to genetic, epigenetic, hormonal, and environmental factors. Notably, a number of studies recently showed a cross-talk between vitamin D and the sex hormone estrogen. Estrogen-mediated effects on immune response may favor a Th1 profile or a Th2 profile, depending on hormone concentration. Thus, estrogen-mediated effects appear to be variable on autoimmunity depending on its concentration but also on the pathogenic mechanisms underlying the different autoimmune diseases (i.e., Th1- or Th2-mediated diseases). Notably, estrogen has been demonstrated to enhance vitamin D function favoring its accumulation, and increasing the expression of vitamin D receptor, thus resulting in a more potent anti-inflammatory response in females than males. On the other hand, vitamin D has been shown to downregulate in immune cells the expression of aromatase, which converts testosterone to estrogen, leading to a decrease in estrogen level. Overall, available data allow us to hypothesize a higher protective effect of vitamin D-based therapeutic approaches in women, at least in fertile age, than in men. Future studies are needed to expand current knowledge on the immunomodulatory role of vitamin D in a sex and gender perspective, paving the way to a more personalized therapeutic approach in autoimmune diseases.

Keywords: Autoimmunity; Estrogen; Gender; Multiple sclerosis; Rheumatoid arthritis; Sex; Sex hormones; Systemic lupus erythematosus; Vitamin D.

Fig. 1

Cross-talk between vitamin D and estrogen and vitamin D effects on immune response. Estrogen decreases the expression of CYP24A1, which is involved in the inactivation of vitamin D, and increases the expression of VDR gene. 1,25(OH)2D downregulates aromatase expression, decreasing estrogen level. 1,25(OH)2D also regulates immune cell subsets, interfering with antigen presentation and cytokine production