P. Zaccone et al. Table 1 Inverse correlation between Type 1 diabetes (T1D) and hygiene conditions Parasite Immunology T1D incidence per thousand, 0–14 yrs Sanitation (% of households without access to improved sanitation) H O (% of 2 households with access to improved H2O supply) Low mortality infectious neglected diseases (prevalence) Country Europe Finland Sweden UK Romania Albania North America USA Canada Africa Tanzania Ghana Western Paciﬁc China Vietnam Singapore Australia New Zealand East Mediterranean and Middle East Egypt Saudi Arabia Kuwait Yemen Afghanistan South/Central America Brazil Argentina Venezuela Peru South East Asia India Nepal Bangladesh 0·9 No data 37·4 28 18·9 5 3·6 13·8 24·1 0·6 0·3 2·5 17·8 15·2 8 12·3 20·9 2·5 1·2 8 6·4 0·1 0·4 4·2 0·6 4·2 0 0 0 47 9 0 0 10 28 60 53 0 0 0 24 18 32 29 72 72 52 2 0 No data 62 88 100 100 100 58 97 100 100 68 73 75 77 100 100 100 87 94 83 80 84 88 97 97 95 No data 69 13 Absent Absent Absent Absent Absent Absent Absent Endemic Endemic Frequent Frequent Rare/Absent Rare/Absent Rare/Absent Rare/Absent Rare/Absent Rare/Absent Endemic Frequent Endemic Rare/Absent Rare/Absent Rare/Absent Endemic Endemic Endemic Broadly-speaking there is an inverse relationship between the incidence of T1D and hygiene as gauged by levels of sanitation, access to clean water, and the presence of low mortality infectious diseases (ﬁlariasis, leprosy, onchocerciasis, schistosomiasis, soil-transmitted helminths, and trachoma). Adapted from the IDF e-Atlas, http://www.eatlas.idf.org/, © International Diabetes Federation, Brussels. By 8–12 weeks of age the inﬁltrate progresses to the islets, causing destruction of the β cell mass. Pathology is primarily cell-mediated, with dendritic cells (DC), macrophages (MΦ) and B cells responsible for the initiation of the autoimmune process by presentation of pancreatic antigen and secretion of inﬂammatory mediators (27,28). Subsequently, CD8+ and CD4+ T cells enter the pancreas, inﬁltrate the islet area and β cell destruction arises through a Th1-mediated immune response (29) (Figure 2). After 12 weeks of age the clinical signs of disease start to manifest with polydypsia and glycosuria and by the age of 30 weeks 80–100% of female mice are diabetic. NOD mice show a distinct gender difference with female NOD mice developing T1D at a much higher incidence 518 than the males (10–20%). There are variations between colonies and the conditions under which NOD mice are kept appear to greatly inﬂuence the rate and frequency of onset of diabetes. It rapidly became clear that NOD mice kept under germ-free conditions developed diabetes at a much faster rate and higher incidence than mice kept under conventional conditions (30). This observation, made independently in many different laboratories, provoked immunologists to consider the possibility that infection and/or exposure to microbial products was responsible for the reduction of T1D incidence in some animal colonies. Experiments designed to test this hypothesis and elucidate the mechanisms of T1D prevention, revealed that infections © 2006 The Authors Journal compilation © 2006 Blackwell Publishing Ltd, Parasite Immunology, 28, 515–523