Mechanisms by which Vitamin A and D may Contribute to (Oral) Tolerance Induction

Abstract

Vitamin A and D are fat soluble vitamins that have different functions in the body: vitamin A is important for eye sight while vitamin D is necessary for bone maintenance. However, lately has it been demonstrated that both vitamins may have a pivotal role in the immune system, especially in tolerance induction. Diseases as inflammatory bowel disease (IBD), food allergy and asthma have broken tolerance which results in an improperly working immune system, and therefore symptoms of disease. Vitamin A and D however could be a possible treatment or prevention for these diseases. Vitamin A’s metabolite retinoic acid (RA) will bind its intracellular receptor retinoid X receptor (RXR) in the T-cell directly or in a dendritic cell (DC) and subsequently inhibit T helper cell 1 (Th1) or Th17 cell differentiation by reducing TGF-β, IL-6 and IL-23 expression. Furthermore will RA stimulate forkhead box P3 (FOXP3) expression which results in regulatory T-cell (Treg) differentiation. RA can also stimulate a Th2 response by inducing IL-2 and IL-4. Vitamin D metabolites bind the intracellular vitamin D receptor (VDR) which will form a heterodimer with RXR. This complex can bind specific vitamin D response elements (VDRE) on the genes of different cytokines and in this way skew towards a Treg or a Th2 response. The cytokines that are affected by vitamin D are especially IL-10 (up-regulation), IL-12 (down-regulation) and the most important, vitamin D affects the Treg marker FOXP3 (up-regulation). Tolerance, in relation to the described diseases, is the stimulation of Treg cell differentiation, resulting in a balance between Th1 and Th2 cells, inhibition of inflammatory reaction and a maintenance of mucosal homeostasis. Both vitamin A and D will contribute to oral tolerance induction as they stimulate Treg differentiation. The induction of oral tolerance by vitamin A and D may be important for the treatment of IBD, food allergy and asthma, as tolerance is broken in these diseases. Different animal and human studies have been performed to research the relation between vitamin A and D and the described diseases. There are no conclusive results, however the supplementation of vitamin D in both IBD and asthma appear to be promising. Furthermore is it striking that vitamin A demonstrates contradicting results in both human and animal studies regarding the diseases of interest, there is not one disease that shows a conclusive picture. Therefore more research is necessary for both vitamins, in both humans and animals for all diseases. In conclusion, in immune system function vitamin A and D are pivotal as they both stimulate Treg differentiation and therefore tolerance. However both animal and human studies with regard to the diseases of interest did not demonstrate a conclusive picture which means more research is necessary.