Volume 28, Number 10, October 2006 Parasitic worms and inﬂammatory diseases the destruction of insulin-producing cells. Since insulin regulates glucose uptake into cells from the circulation, its deﬁciency is responsible for glucose accumulation in the blood and ensuing cell starvation (hyperglycaemia, coma, etc.). T1D was considered a death sentence until the early 1920s, when pancreatic extracts were used to correct hyperglycaemia (14). This discovery led to the availability of an effective treatment – insulin injections – and the ﬁrst clinical patient was treated in 1922. Despite the substantial technological improvement for monitoring glycaemia, relatively little progress has been made in terms of therapy; to date, insulin injection remains the only dependable treatment. T1D is an autoimmune polygenic disorder, with numerous gene loci contributing to susceptibility. Historically, the ﬁrst genes associated with T1D were the Human Leukocyte Antigens (HLA) on chromosome 6, in particular the DR and DQ class II regions (15,16). There remains controversy about the relative contributions of DR and DQ on T1D susceptibility with some studies supporting a stronger association for the DQ locus and a secondary role for DR (17). Recently, other genes outside the HLA complex have been associated with predisposition to T1D, including cytotoxic T lymphocyte associated antigen 4 (CTLA-4) and lymphoid tyrosine phosphatase (PTPN22) (18). As mentioned above, genetic components affect the propensity for T1D but the environment appears to play a fundamental role in regulating the onset of the disease. Many different intercepting factors must be taken into account. Within the Caucasian population the incidence of T1D varies between nations. For example Scandinavian countries have the highest incidence of T1D in Europe, whereas relatively under-developed countries like Albania and Romania have some of the lowest (see Table 1). However, these statistics need to be considered in the context of genetics, i.e. the relatively limited genetic diversity seen in Scandinavia (particularly Finland) overlaying and possibly synergizing with the effects of a hygienic environment. Interestingly in Europe, countries with a more agriculture-based economy have lower incidences of T1D (19). This suggests that exposure of the population to a diet containing fewer processed foods and more direct contact with animal-transmitted pathogens such as Salmonella could be a relevant factor in preventing T1D. The North– South gradient also seems to play a role in diabetes incidence. Indeed in Southern European countries the lower socio- economic status and higher temperatures might predispose the inhabitants to infections and contribute to the lower frequency of T1D. Two of the largest islands in the Mediter- ranean, Sicily and Sardinia, present an interesting contrast in T1D incidence and the effects of genetics. These islands are located at similar latitudes and bio-geographical zones, yet Sicily has a low incidence of T1D whereas Sardinia has one of the highest in the world, indicative of a strong genetic modiﬁer (20). If we look now at countries outside Europe (and /or North America) we can see that the inverse correla- tion between poverty and T1D is even more pronounced. Poor sanitation and prevalence of infections seem to protect the inhabitants of developing countries from autoimmune diabetes (see Table 1). A good example is the interdependence between access to clean water, and diseases such as T1D (Figure 1). Indeed many parasitic diseases such as Schisto- somiasis require a freshwater environment for transmission. Overall these considerations strongly suggest that the continuous improvement in sanitation and living standards in developed countries is a key factor for the increase of T1D. According to the IDF database the global incidence of T1D in children and adolescents is increasing, with an estimated overall annual rate of about 3%. Before the 1920s childhood diabetes, although uncommon, was rapid and fatal, therefore it could be argued that the introduction of insulin treatment contributed to a subtle increase in the frequency of T1D susceptibility genes. That said, the dramatic rise of T1D in children under 14 years of age in developed countries cannot be explained by genetic factors alone. The T1D epidemic observed over the last 50 years in Western Europe and North America is predicted to plateau. For example, Norway showed no increase over the last decade (21). The high T1D- incidence areas (with the exception of Finland) in Europe appear to have reached a plateau, but the overall trend is still rising in ex-Eastern Bloc countries and in the Middle East, particularly in Kuwait (22–24). Since changes in the environ- ment seem to play a more signiﬁcant role, predications are that childhood diabetes will not increase exponentially in the high incidence areas but will rather take place in those countries that are gradually seeing an improvement in their living standards and hygiene. For instance, the projections for diabetes incidence in the year 2025 predict a sharp increment in diabetes in the Middle East, South America, Mexico, and South East Asia (see Table 2). ANIMAL MODELS OF HUMAN AUTOIMMUNE DISEASE: THE NOD MOUSE AND SCHISTOSOMA MANSONI INFECTION Since the 1970s the NOD (Non-Obese Diabetic) mouse has provided a good model for the study of T1D. Initially generated in Japan by Makino and co-workers, the NOD mouse has became one of the most popular models to study T1D (25). NOD mice spontaneously develop T1D, with features similar to the human disease. NOD T1D is under polygenic control and, much like the human disease, associates with particular Class II major histocompatibility (MHC) polymorphisms (26). The pancreas of NOD mice become inﬁltrated with mononuclear cells around 6 weeks of age, with cells appearing chieﬂy around the islets and pancreatic ducts. © 2006 The Authors Journal compilation © 2006 Blackwell Publishing Ltd, Parasite Immunology, 28, 515–523 517