Although the exact cause of multiple sclerosis (MS) is unknown, a number of genetic and environmental factors are thought to influence MS susceptibility. One potential environmental factor is sunlight and the subsequent production of vitamin D. A number of studies have correlated decreased exposure to UV radiation (UVR) and low serum 25-hydroxyvitamin D 3 [25(OH)D 3 ] levels with an increased risk for developing MS. Furthermore, both UVR and the active form of vitamin D, 1α,25-dihydroxyvitamin D 3 , suppress disease in the experimental autoimmune encephalomyelitis (EAE) animal model of MS. These observations led to the hypothesis that UVR likely suppresses disease through the increased production of vitamin D. However, UVR can suppress the immune system independent of vitamin D. Therefore, it is unclear whether UVR, vitamin D, or both are necessary for the putative decrease in MS susceptibility. We have probed the ability of UVR to suppress disease in the EAE model of MS and assessed the effect of UVR on serum 25(OH)D 3 and calcium levels. Our results indicate that continuous treatment with UVR dramatically suppresses clinical signs of EAE. Interestingly, disease suppression occurs with only a modest, transient increase in serum 25 (OH)D 3 levels. Further analysis demonstrated that the levels of 25(OH) D 3 obtained upon UVR treatment were insufficient to suppress EAE independent of UVR treatment. These results suggest that UVR is likely suppressing disease independent of vitamin D production, and that vitamin D supplementation alone may not replace the ability of sunlight to reduce MS susceptibility.calcium | immune | multiple sclerosis | sunlight

Handunnetthi and Ramagopalan have questioned the validity of the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS) (1), the model we have used in our studies relating to MS (2). As with any animal model of human disease, the EAE model has its limitations. For example, in the mice, the disease is induced through immunization, as opposed to occurring spontaneously, as is the case with MS. Despite these problems, the EAE model has been instrumental in MS research. The EAE model has provided insight into the underlying mechanisms of MS pathology. Preclinical work in the EAE model has directly led to the development of three different treatment modalities for MS, including glatiramer acetate, mitoxantrone, and natalizumab (3). The EAE model also allows researchers the manipulation of mice genetically that simply is not possible with human subjects. Therefore, although studies in the EAE model cannot be "unequivocally extrapolated" to answer questions relating to MS, they certainly provide a starting point for the exploration of whether UV radiation, vitamin D, or both are involved in determining MS susceptibility.When studying the effect of UV radiation itself, the problem is that UV radiation also produces vitamin D. We analyzed the effect of UV on circulating 25-OH-D 3 levels and the effect of 25-OH-D 3 levels on EAE independent of UV radiation. Clearly, the level of 25-OH-D 3 required to suppress EAE was much greater than the level reached by our UV treatment.In our experiments "suppression" means that the treatment group showed a significant decrease in the average clinical scores compared with its control group. We used two different diets in the studies we reported. In our hands, mice fed a chow diet consistently had higher EAE scores than mice fed a purified diet.Thus, the untreated control animals on the chow diet had a higher score than the controls on the purified diet.1,25-(OH) 2 D 3 is effective only when delivered at doses that cause hypercalcemia (4). In addition, hypercalcemia independent of vitamin D can suppress EAE (5). Thus, calcium plays a critical role in the protective mechanisms underlying 1,25-(OH) 2 D 3 treatment. In contrast, treatment with UV radiation had no effect on serum calcium levels. This observation, coupled with the fact that UV radiation does not cause hypercalcemia in human populations exposed to large amounts of sunlight, argues against vitamin D being the sole cause of protection against MS. However, it is possible that localized production of 1,25-(OH) 2 D 3 may be important for protection. To address this issue we are currently carrying out experiments in mice lacking the 1α-hydroxylase and/or vitamin D receptor gene.Although we agree that the most conclusive evidence elucidating the role of vitamin D and UV will come from clinical trials, we caution against disregarding evidence simply because it was derived from studies using the EAE model. As stated by Steinman and Zamvil, "To study a disease such as MS, without support from available animal ...