**2.2 Vitamin D and autoimmunity**

The natural history of autoimmunity remains largely unknown. However, the theory is that both genetic susceptibility and environmental factors play a role in the development of clinical autoimmune disease. Vitamin D has known immunomodulatory effects on a wide range of immune cells, including T and dendritic cells [44, 45]. Each of these immune cells expresses VDR and produces the enzymes 1-α-hydroxylase and 24-hydroxylase and is therefore capable of locally producing active 1,25(OH)2D3 [46–49]. Activation of CD4+ T cells results in a significant increase in VDR expression enabling regulation of many genes responsive to 1,25(OH)2D3 [50]. 1,25(OH)2D3 suppresses T-cell receptor induced T cell proliferation and changes their cytokine expression. The overall shift is away from T helper Th1 phenotype toward a more tolerogenic Th2 response [51–53]. Vitamin D appears to directly inhibit Th1 cells and may additionally modulate a skewing toward a Th2 response [54]. Th17 cells are a subset of CD4+ T cells involved in organ-specific autoimmunity playing a role in maintaining inflammation, which can lead to tissue damage. 1,25(OH)2D3 suppresses autoimmunity and tissue destruction by inhibiting the Th17 response at several levels [55, 56]. Altogether, the evidence suggests an important role for vitamin D in influencing T-cell responses and in tempering inflammation and tissue damage.

Vitamin D appears to have a direct effect on B cells and inhibits immunoglobulin production [57]. Additionally, differentiation of B cells is interrupted when exposed to 1,25(OH)2D3. 1,25(OH)2D3 also has effects on dendritic cells. Dendritic cells have important functions in maintaining both protective immunity and self-tolerance [58, 59]. Physiologic levels of 1,25(OH)2D3 inhibit maturation of dendritic cells and maintain an immature and tolerogenic phenotype with inhibition of activation markers such as MHC class II, CD40, and others and upregulation of inhibitory molecules [60, 61]. Thus, it appears that the maturational state of dendritic cells can be modulated by 1,25(OH)2D3, making it possible that the vitamin D status of an individual is likely to have important immunologic consequences.
