In addition, the disease is affecting younger children; two recent reports from a Finish and a European cohort fully support these preoccupying conclusions [8,9]. This trend is not only valid for autoimmune diabetes. RO4929097 mouse In fact, over the past

three decades, in industrialized countries the prevalence of allergic and autoimmune diseases has increased tremendously [10]. Over the same period of time there has been an obvious decrease in these countries of the incidence of many infections due to the improvement of hygiene standards and of medical care (use of antibiotics, vaccination campaigns and better socio-economic conditions). In northern European countries, in particular, rheumatic fever and hepatitis A are good examples to illustrate this tendency. Intestinal infections are another interesting example; their frequency has decreased significantly in developed countries, especially in young children, and it has been proved that there are major quantitative and qualitative differences in the intestinal flora in developed countries versus less-developed

environments; i.e. colonization with Gram-negative bacteria occurs later. Major parasitic infections such as plasmodia or schistosoma are mostly non-existent in developed countries, and even infestation with minor parasites such as Enterobius vermicularis (pinworms) has decreased significantly over the last 10–20 years LEE011 in vitro [11]. The working hypothesis proposing a causal link between the increasing incidence of allergic diseases and the decrease of infections was referred to as the ‘hygiene hypothesis’, coined by Strachan Ergoloid in 1989 [12], and has been extended to autoimmune diseases [10].

As formulated in its original inception, the hypothesis predicts that increased hygienic living conditions, the use of antibiotics and sterile food preparation will result in the continued segregation of the immune system from positive microbial exposure, thus favouring an increased susceptibility to immune-mediated disorders. The best direct evidence in support of the hygiene hypothesis has been collected from experimental animal models. In susceptible strains of mice or rats, spontaneous autoimmune diseases develop faster and with a higher incidence in animals bred in a specific pathogen-free environment compared to those bred in conventional facilities. This is true in NOD mice and in BB rats and in rats with collagen or adjuvant-induced arthritis [10]. Disease is prevented in NOD mice by infecting the young mice with bacteria, viruses or parasites (i.e. mycobacteria, lymphocytic choriomeningitis virus, murine hepatitis virus, lactate dehydrogenase virus, schistosoma, filariae) [10]. Similarly, infection of lupus-prone New Zealand black (NZB) mice or NZB–New Zealand white (NZB–NZW) F1 hybrid mice with lactate dehydrogenase virus or Plasmodium berghei prevents disease very effectively [10].