Environmental influences on multiple sclerosis and other autoimmune disorders

The risk of autoimmune disorders such as multiple sclerosis (MS) may be influenced by environmental factors early in life. This epidemiological thesis provides new knowledge on the role of early life environmental factors in MS in particular, for which the specific aetiology is unknown. Two main potential environmental determinants of MS, ultraviolet radiation (UVR) and infections, are explored through an analysis of their timing of action in the life course and a consideration of their possible protective effects. Other organ-specific autoimmune disorders whose aetiology is also unknown, including type 1 diabetes and rheumatoid arthritis (RA), are also assessed for links with UVR for comparison with MS. Two existing national Australian datasets provided the outcome data for the analyses. The 1995 Australian National Health Survey (NHS) provided summary prevalence estimates for ecological (population-level) analysis of four immune disorders other than MS. The 1981 Australian MS Survey, used for the largest part of the thesis, provided individual-level MS-case data for 1981 throughout Australia, and was further modified to construct a longitudinal MS-rates study dataset for analysis of timing of birth. Ecological analysis of the 1995 NHS data showed that geographic latitude was positively associated, and regional ambient UVR inversely associated, with the prevalence of type 1 diabetes in Australia. Ambient UVR exposure may thus be a protective factor against such disease at the population level. The association supports previous ecological findings for MS in Australia and adds to the evidence that UVR exposure might be a modifiable determinant for autoimmune disease generally. Longitudinal analysis of the reconstructed 1981 Australian MS Survey dataset showed that increased MS risk of around 30% was evident in Australians born in November to December (southern hemisphere early summer) compared with those born in May to June (early winter). This MS-risk pattern, indicating environmental factor(s) acting around the time of birth, mirrored (seasonally) that seen for MS in the northern hemisphere, suggesting globally similar perinatal environmental determinants modifying the risk of MS onset. Most importantly, this Australian pattern was found to be fully accounted for by individual, regional (state) and seasonal ambient UVR levels specific to the prenatal period seven to eight months before birth. Low ambient (maternal) UVR exposure in the first trimester of pregnancy thus appears to be associated with a higher risk of MS in the offspring. Birth-order analysis of cases in the 1981 MS Survey further showed that early birth order was independently associated with MS risk, MS cases being more likely to be one of the older siblings in their sibships. Consistent with the hygiene hypothesis, this result suggests that a lack of microbial exposure in early childhood may increase MS risk later in life. Population health implications of these findings are discussed. In particular, safe sun exposure and/or vitamin D supplementation during early pregnancy may help prevent subsequent onset of high-morbidity, long-duration and presently incurable autoimmune disorders such as MS in the offspring

Low maternal exposure to ultraviolet radiation in pregnancy, month of birth, and risk of multiple sclerosis in offspring: longitudinal analysis

Objectives To investigate the distribution of month of birth in people with multiple sclerosis in Australia. To use the large regional and seasonal variation in ambient ultraviolet radiation in Australia to explore the association between exposure to ultraviolet radiation during pregnancy and subsequent risk of multiple sclerosis in offspring

Ecologic analysis of some immune-related disorders, including type 1 diabetes, in Australia: latitude, regional ultraviolet radiation, and disease prevalence

The apparent immune-suppressive effect of ultraviolet radiation (UVR) has suggested that this environmental exposure may influence the development of immune-related disorders. Self-reported prevalence rates of type 1 diabetes mellitus, rheumatoid arthritis (RA) , eczema/dermatitis, and asthma, from the 1995 Australian National Health Survey, were therefore examined by latitude and ambient level of UVR. A positive association of type 1 diabetes mellitus prevalence was found with both increasing southern latitude of residence (r = 0.77 ; p = 0.026) and decreasing regional annual ambient UVR (r = -0.80 ; p = 0.018) ; a 3-fold increase in prevalence from the northernmost region to the southernmost region was evident. In contrast, asthma correlated negatively with latitude (r = -0.72 ; p = 0.046) , although the change in asthma prevalence from the north to the south of Australia was only 0.7-fold. For both RA and eczema/dermatitis, there were no statistically significant associations between latitude/UVR and disease prevalence. These ecologic data provide some support for a previously proposed beneficial effect of UVR on T-helper 1-mediated autoimmune disorders such as type 1 diabetes. The inverse association of type 1 diabetes prevalence with UVR is consistent with that previously reported for another autoimmune disease, multiple sclerosis, in Australia, and also with type 1 diabetes latitudinal gradients in the Northern Hemisphere. The finding also accords with photoimmunologic evidence of UVR-induced immunosuppression and may suggest a beneficial effect of UVR in reducing the incidence of such autoimmune conditions. In light of this study, analytic epidemiologic studies investigating risk of immune disorders in relation to personal UVR exposure in humans are require

Ecologic analysis of some immune-related disorders, including type 1 diabetes, in Australia: latitude, regional ultraviolet radiation, and disease prevalence.

The apparent immune-suppressive effect of ultraviolet radiation (UVR) has suggested that this environmental exposure may influence the development of immune-related disorders. Self-reported prevalence rates of type 1 diabetes mellitus, rheumatoid arthritis (RA), eczema/dermatitis, and asthma, from the 1995 Australian National Health Survey, were therefore examined by latitude and ambient level of UVR. A positive association of type 1 diabetes mellitus prevalence was found with both increasing southern latitude of residence (r = 0.77; p = 0.026) and decreasing regional annual ambient UVR (r= -0.80; p = 0.018); a 3-fold increase in prevalence from the northernmost region to the southernmost region was evident. In contrast, asthma correlated negatively with latitude (r = -0.72; p = 0.046), although the change in asthma prevalence from the north to the south of Australia was only 0.7-fold. For both RA and eczema/dermatitis, there were no statistically significant associations between latitude/UVR and disease prevalence. These ecologic data provide some support for a previously proposed beneficial effect of UVR on T-helper 1-mediated autoimmune disorders such as type 1 diabetes. The inverse association of type 1 diabetes prevalence with UVR is consistent with that previously reported for another autoimmune disease, multiple sclerosis, in Australia, and also with type 1 diabetes latitudinal gradients in the Northern Hemisphere. The finding also accords with photoimmunologic evidence of UVR-induced immunosuppression and may suggest a beneficial effect of UVR in reducing the incidence of such autoimmune conditions. In light of this study, analytic epidemiologic studies investigating risk of immune disorders in relation to personal UVR exposure in humans are required

Fungal entomopathogens: new insights on their ecology

An important mechanism for insect pest control should be the use of fungal entomopathogens. Even though these organisms have been studied for more than 100 y, their effective use in the field remains elusive. Recently, however, it has been discovered that many of these entomopathogenic fungi play additional roles in nature. They are endophytes, antagonists of plant pathogens, associates with the rhizosphere, and possibly even plant growth promoting agents. These findings indicate that the ecological role of these fungi in the environment is not fully understood and limits our ability to employ them successfully for pest management. In this paper, we review the recently discovered roles played by many entomopathogenic fungi and propose new research strategies focused on alternate uses for these fungi. It seems likely that these agents can be used in multiple roles in protecting plants from pests and diseases and at the same time promoting plant growth

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Education and diversity: values education and cross-cultural learning through Socratic dialogue and the visual arts

This chapter addresses the relationship between values education and interfaith and intercultural understanding. It draws upon the experience of the Melbourne Interfaith and Intercultural cluster, a group of five schools in Victoria, Australia, whose membership is composed of a Jewish school, an Islamic school, two Catholic schools and one Government school. The main objective of the cluster is to provide opportunities for young people from different schools, cultures and faith traditions to come together and discuss issues such as values, national identity, social cohesion and citizenship. The purpose of the cluster’s work came out of a desire to respond to some of the disturbing and negative activities in the community, in particular the Cronulla riots in Australia in 2005. It was hoped that the work of the cluster could contribute to fostering positive relationships among young people of different cultures and faiths and in so doing contribute to a stronger sense of community and social cohesion among the students and within society more broadly