**3.2 Vitamin D deficiency and systemic lupus erythematosus**

In SLE, the inflammatory milieu drives the development of T cells into proinflammatory pathways, defective function of Tregs, and survival and activation of B cells, which produce autoantibodies [78, 81]. Patients with systemic lupus erythematosus have lower 25(OH)D3 levels compared to controls, suggesting that vitamin D deficiency may be a risk factor for SLE [81, 84, 102–107]. The majority of studies have also found higher SLE disease activity associated with lower levels of 25(OH)D3 [84, 103]. As patients with SLE have often photosensitivity and are advised to avoid direct sun exposure, detecting vitamin D deficiency and replacing 25(OH)D3 with oral supplementation is critical and may impact disease activity [108].

#### **3.3 Vitamin D deficiency and type 1 diabetes mellitus**

Type 1 diabetes mellitus is one of the most prevalent chronic diseases with onset in childhood and is the result of immune-mediated destruction of pancreatic insulin producing β cells. There appears to be a geographic variation in incidence following a gradient in latitude, which is the inverse of the global distribution of ultraviolet B irradiation, critical for the production of vitamin D within the skin [109]. Studies have shown higher incidence of vitamin D deficiency in patients with type 1 diabetes [110–113]. One environmental factor thought to be protective against the development of type 1 diabetes mellitus is early supplementation with vitamin D [114]. A number of large case control studies showed that the risk of type 1 diabetes mellitus was significantly reduced in infants who were supplemented with vitamin D compared to those who were not supplemented [115–117]. Additionally, a lower incidence of type 1 diabetes was observed in infants born to mothers who were administered cod liver oil during pregnancy [118]. A birth cohort study in Finland, now more than 50 years ago, evaluated the effects of vitamin D supplementation on rickets and the development of type 1 diabetes mellitus [85]. All women due to give birth in 1966 were enrolled. There was an 80% reduction in the risk for type 1 diabetes mellitus in children having received >2000 IU vitamin D/day compared to those receiving less or not receiving supplementation with vitamin D. Evidence from both human and animal studies shows that vitamin D may be protective as far as the development of type 1 diabetes mellitus is concerned [68, 71, 76]. Thus, the administration of vitamin D may prevent diabetes mellitus type 1; however, once the destruction of pancreatic beta cells has taken place, it will not act therapeutically to reverse diabetes mellitus type 1.

#### **3.4 Vitamin D deficiency and multiple sclerosis**

Multiple sclerosis is characterized by inflammation, demyelination, axonal or neuronal loss, and astrocytic gliosis in the central nervous system, which can result in disability. Epidemiological studies have suggested that vitamin D insufficiency

may contribute to the risk of multiple sclerosis [62, 63, 75, 119, 120]. Moreover, several genetic studies in multiple sclerosis patients have shown that diverse abnormalities in vitamin D metabolism are related to the risk of the disease. It appears that vitamin D deficiency may interact with genetic and environmental protective and risk factors, such as the allele HLA BRB1\*1501, infections, obesity, smoking, and sexual hormones and may modulate the risk of the disease [63, 74, 80]. Thus, vitamin D deficiency may be a risk modulating factor for the development of multiple sclerosis. Vitamin D acts as an immunomodulatory factor affecting T and B lymphocytes, and it may exert neuroprotector and neurotrophic actions within the central nervous system. Several studies have shown that vitamin D supplementation exerts multiple beneficial immunomodulatory effects in multiple sclerosis [121–124]. On the contrary, a Cochrane review states that there appears to be no benefit from vitamin D supplementation in patients with multiple sclerosis; however, the level of evidence is very low [125]. Nevertheless, it should be noted that robust statistical models used in association studies have already predicted a favorable vitamin D effect reducing relapses by 50–70% [121]. There is little doubt that vitamin D exerts a beneficial action on multiple sclerosis, the inflammatory component in particular, less so the degenerative. Until more information becomes available, vitamin D supplementation of multiple sclerosis patients, using a moderate physiological dose essentially correcting their vitamin insufficiency, is recommended.
