Vitamin D and Demyelinating Diseases: Neuromyelitis Optica (NMO) and Multiple Sclerosis (MS)

Figure 1

A roadmap of vitamin D production and putative roles in autoimmune demyelinating disease. Once activated to calcitriol by liver 25-hydroxylases and kidney 1α-hydroxylases, vitamin D can execute a variety of immunologic functions. Calcitriol binds the VDR receptor which acts as a transcription factor when complexed with nuclear retinoid X receptor. The VDR-RXR heterodimer then binds to DNA sequences within gene promoter regions (vitamin D response elements) and facilitates the expression of gene products which may be classified as neuroprotective, anti-inflammatory, and proinflammatory. Vitamin D increases estrogen production (stimulation of aromatase (CYP19) converts testosterone to estrogen). Estrogen preserves vital components of the CNS attacked in autoimmune disease and regulates vitamin D production (inhibits degradation by 24-hydroxylase (CYP24A1). Vitamin D suppresses autoimmunity by promotion of anti-inflammatory T cell subsets: T helper 2 (Th2) and regulatory T (Treg) cells. Vitamin D downregulation of proinflammatory cytokines IL-1 and IL-21 (not depicted) and T cell subsets: T helper 1 (Th1) and 17 (Th17) prevents macrophages and other leukocytes from exerting cell mediated toxic effects on myelin. B cell proliferation and antibody production are also inhibited, knocking out the key mediators of humoral mediated demyelinating damage. Th2 cells are pathologically involved in the induction of B cells producing self-antibodies in MS, but a higher ratio of Th2 to Th1 is associated with reduced inflammation. M1 macrophages release proinflammatory cytokines, metalloproteases and free radicals and carry out phagocytosis of myelin (early stage of MS) that leads to CNS destruction while M2 macrophages repair inflammatory damage (late stage of MS). In NMO, macrophages may scavenge the byproducts of astrocyte cytotoxicity and eosinophil/neutrophil infiltration (not depicted). Created with https://Biorender.com.