Vitamin D, sun and multiple sclerosis - Prue Hart, Robyn Lucas, Anderson Jones
UV-B phototherapy for participants with an early form of multiple sclerosis.
We have an NHMRC-funded trial to give UV-B phototherapy to participants with Clinically Isolated Syndrome, a pre MS condition. We propose that UV-B phototherapy may prevent or dampen any progression to MS. But how may UV-B phototherapy regulate immune responses? We propose that there is an epigenetic imprinting by signals from UV-irradiated skin on bone marrow macrophage and dendritic cell progenitor cells. In turn, the daughter cells differentiating from these progenitor cells have altered immunological functions.
Latitude gradients for the incidence of multiple sclerosis are well established, with more disease at higher latitudes when there is reduced sun. Exposure to sun has been linked with the initiation and progression of MS, and there is evidence that sun exposure is important at all stages of life for MS pathogenesis, even in utero. Many believe that a lack of UV-induced vitamin D is responsible, but vitamin D supplementation trials have not shown the reduced disease progression that was hoped for. We propose that UV via vitamin D-independent pathways may be responsible. We have initiated a trial of narrow band UV-B phototherapy for participants diagnosed with their first demyelinating event in the last 120 days. Participants are randomised to receive, or not receive, UV-B phototherapy (24 sessions over 8 weeks). Blood is taken for phenotyping of immune cell subsets in their blood, and biobanking, over a 12 month period. We believe that this is the first trial in the world of UV-B phototherapy for participants with Clinically Isolated Syndrome. The trial is called PhoCIS as it is Phototherapy for participants with Clinically Isolated Syndrome. Funded by NHMRC
The Sun Exposure and Vitamin D Supplementation Study is recruiting Australian adults to a 12 month intervention study of supplementation with sun exposure or vitamin D to test whether there are non-vitamin D benefits of sun exposure, and whether sun exposure can be safely used to raise vitamin D levels.
The SEDS Study is an intervention study whereby participants are randomly allocated to receive different doses of vitamin D (or placebo) and different advice on how much sun exposure to have. Participants complete a questionnaire, measure their sun exposure, and have blood taken four times over the 12 months of participation.
Vitamin D metabolites and risk of multiple sclerosis in the Ausimmune Study
MS Research Australia Project Grant (14-041).Chief Investigators: Lucas RM, Ponsonby A-L, Taylor BV, Black L, Clarke M. 2015
Many research studies from around the world have shown that people with multiple sclerosis, or at high risk of developing multiple sclerosis, have lower vitamin D levels than their healthy peers. In reality, we do not measure vitamin D levels, or the active part of vitamin D in the blood - we measure an intermediate chemical because there is more of it, it is easier to measure, and the levels fluctuate less rapidly than the active form of vitamin D. In a major Australian study, the Ausimmune Study, we showed that people with a first neurological event that may progress to multiple sclerosis had lower levels of this intermediate chemical than healthy people of the same age and sex. But although we found an effect, it was not very strong. Some evidence suggests that levels of the active form of vitamin D, or of breakdown products may be a stronger risk factor than levels of the intermediate form. In addition, most of the vitamin D in our blood is strongly attached to a protein. Recent research suggests that it is the level of the vitamin D that is bioavailable (free in blood or loosely bound to a blood protein) that is important. New assays for vitamin D are now available that allow us to measure the active form, other forms of vitamin D, and this bioavailable vitamin D. This new work will measure these other forms of vitamin D on blood stored as part of the Ausimmune Study. The results will provide new insights into the role of vitamin D in the risk of multiple sclerosis, and possibly guide the form of vitamin D that is provided as a supplement to people at high risk of multiple sclerosis, or lead to development of vitamin D analogues of the optimal form, to lower the risk of developing multiple sclerosis.
Repeated periods of vitamin D deficiency in childhood are associated with increased risk for asthma and related conditions: findings from a high-risk birth cohort - Elysia Hollams
Human studies investigating whether low vitamin D is a risk factor for asthma or allergy in childhood have yielded conflicting results; the majority of these studies have taken a single 25(OH)D measure per child, at ages that vary greatly between studies. We hypothesized that inadequate vitamin D during childhood promotes development of asthma by increasing susceptibility to two major asthma risk factors: allergic sensitisation and severe respiratory infection. We measured 25(OH)D from plasma samples collected at eight specific ages between birth and age 10 years in children within the high-risk Childhood Asthma Study (CAS) cohort and conducted cross-sectional and longitudinal analyses relevant to this hypothesis.
Vitamin D, sun and type 1 diabetes - Kate Tan, Aveni Haynes, Prue Hart and Robyn Lucas
The association between maternal ultraviolet radiation exposure and vitamin D status during pregnancy and subsequent risk of Type 1 diabetes mellitus in offspring
In 2015, 7,404 Australian children had Type 1 diabetes (1). Type 1 diabetes occurs mostly in childhood and adolescence and has a significant impact on quality of life and life expectancy. Currently, there is no cure or known way of preventing the development of Type 1 diabetes (2). Current research suggests that ensuring adequate levels of vitamin D intake during pregnancy and early infancy may be one of the most promising interventions for preventing the disorder (3). The aim of this study is to determine whether higher levels of ultraviolet (UV) radiation exposure and/or maternal vitamin D status during pregnancy are associated with a reduced risk of Type 1 diabetes in the offspring.
This retrospective population-based case control study will involve the linkage of routinely collected data from pre-existing administrative datasets with NASA satellite data to determine UV radiation exposure during pregnancy and at the time of offspring diagnosis of Type 1 diabetes.
Serum 25 hydroxyvitamin D (25(OH)D) levels will also be obtained for pregnant mothers, and for children at the time of diagnosis of Type 1 diabetes, for a subset of the cohort to determine the correlation between serum levels of 25(OH)D and UV radiation exposure in these two specific populations. This study responds to calls for further research into the area and will provide a critical body of knowledge.
This study will contribute important evidence on whether higher levels of maternal UV radiation exposure and 25(OH)D levels before or during pregnancy can reduce subsequent risk of Type 1 diabetes in offspring or extend the age of onset of the disease. By measuring a wide range of UV exposures for a whole population we will gain valuable insight into what levels are required to be protective.
Vitamin D, sun and preclinical models of Crohns disease - Simon Ghaly, Prue Hart
The effect of vitamin D and UV radiation on a preclinical model of Crohn's disease Low vitamin D levels have been associated with increased incidence of Crohn's disease. However supplementation trials have not generally been successful. It is possible that low vitamin D levels merely reflect low sun exposure and that exposure to UV may be a more realistic treatment strategy. A preclinical model of Crohn's Disease has been established using dextran sulphate delivered in drinking water. Mice are fed deficient, sufficient and excessive levels of vitamin D in their diets, and this is superimposed with UV phototherapy (low dose twice weekly). The mice on the diet containing the highest levels of vitamin D have the worst pathology. Assessment of all the tissues removed from the mice is ongoing in order to understand why the vitamin D-high diet is pathogenic.
Funded by special grant to Simon Ghaly by Gastroenterology Society of Australia
A "vitamin D hypothesis" has been proposed to explain the increased prevalence of eczema in regions with higher latitude. There is evidence that vitamin D acts through multiple pathways that influence the risk of eczema development. Most notably, this includes effects on skin barrier function, early immune development and bacterial defense. These biological effects are in keeping with observational studies that have indicated a link between vitamin D status and eczema outcomes, including lower serum vitamin D concentrations associated with increased incidence and severity of eczema symptoms. Measurements of cord blood 25-hydroxyvitamin D [25(OH)D] concentrations in infants, with a hereditary risk of allergic disease, have found a higher cord blood 25(OH)D concentration appears to be associated with reduced risk of eczema in early childhood. This has now been observed in two separate Australian cohorts, in Adelaide (n=270) at lattitude of 35⁰ South and in Perth (n=231) at lattitude of 32⁰ South. In these two Australian cohorts, no associations between cord blood 25(OH)D concentrations and development of allergic sensitisation, allergic rhinitis or asthma in early childhood until 3 years of age were found. Several randomised controlled trials of early life vitamin D supplementation for the prevention of eczema in infancy are now underway.
Vitamin D, sun and immune responses including those to vaccination - Robyn Lucas, Shelley Gorman
National Research Foundation of South Africa Research Development Grant:Sun protection to improve vaccine effectiveness and immune response for South African children. Chief Investigators: Wright C, Mathee A, Lucas RM. 2015: 223,000R
Our group has previously shown that higher levels of exposure to sunlight on the day of vaccination result in a reduced immune (protective) response to the vaccination. This project is an intervention study testing whether the provision of sun protection in infants receiving their measles booster vaccination is associated with an improved immune response compared to infants who do not receive sun protection. The study is being undertaken in South Africa, where levels of UV radiation are high and children often travel to the immunisation clinic, and wait in the sun, for extended periods immediately prior to receiving the vaccination. There have been several measles epidemics in South Africa over recent years - sun protection may be an inexpensive method of improving the effectiveness of vaccination in this setting.
Effect of UV irradiation of skin on the glycolytic activity of dendritic cells and macrophages generated by culture from the bone marrow. Is an epigenetic event involved? - Terry McGonigle, Royce Ng, Prue Hart
We have previously shown that signals sent from skin irradiated with erythemal UV to the bone marrow stimulate the development of dendritic cells that are poorly immunogenic and cannot induce a strong immune response. Similar responses have been detected following multiple exposures to sub-erythemal UV radiation. The phenotype and function of cells generated by culture from the bone marrow of animals administered a single inflammatory dose of UV, or multiple lower doses of UV radiation, were analysed. We studied that metabolism of dendritic cells generated from the bone marrow of UV-irradiated mice. Contrary to our hypothesis, we believe that the cells differentiated from the bone marrow of UV-irradiated mice versus those from non-irradiated control mice have increased glycolytic activity, with no difference observed in mitochondrial respiratory function. This suggests that metabolism and function of dendritic cells may be linked. Mice were also given the demethylating agent, 5-Aza-2-deoxycytidine, at the time of UV irradiation of skin. As the function of bone marrow-derived dendritic cells was restored in mice given 5-Aza-2-deoxycytidine, we believe that an epigenetic event was involved.
Funded in 2014 by Asthma Foundation WA, Scott Kirkbride Melanoma Research Foundation
Effect of a short Prostaglandin E2 pulse on bone marrow cells engrafted into chimeric mice - Terry McGonigle, Will Kermode, Naomi Scott, Prue Hart
Regulatory dendritic cells are generated by culture of bone marrow cells from UV-irradiated mice or mice exposed to subcutaneous pellets releasing prostaglandin E2. To determine whether prostaglandin E2 acts directly on bone marrow cells, or indirectly via an effect on other cells, the outcome of a 60 minute pulse of bone marrow cells with a stabilised derivative of prostaglandin E2, namely 16,16-dimethyl prostaglandin E2 (dmPGE2) , was investigated. Dendritic cells differentiating from bone marrow given a dmPGE2-pulse were similarly poor at inducing new immune responses. Then, to remove the potential artificial effect of bone marrow cell culture, we established chimeric mice with bone marrow cells pulsed with dmPGE2. The efficiency of the engrafted dendritic cells was sought with increasing time after bone marrow cell engraftment (CD45.1 into CD45.2 mice). After 2-3 weeks, the differentiating dendritic cells had poor priming ability but after 16 weeks, this effect was no longer detected. This suggested that the effect of PGE2 may be dose-dependent and reversible. In experiments in which the recipient mice, not the donor mice, were UV-irradiated, no differences were detected and suggested that the effect of PGE2 was direct on haemopoietic progenitors in the bone marrow.
Funded by Asthma Foundation WA, Scott Kirkbride Melanoma Research Foundation, Multiple Sclerosis Research Australia