**2. Evidence of the hygiene hypothesis**

As described in Introduction, the prevalence of asthma, T1D, MS, and inflammatory bowel diseases (IBD) has been increasing in developed countries in an inverse relation to the declining prevalence of infectious diseases (Bach, 2002). In addition to the chronological trend, the geographical distribution of some autoimmune diseases seems to support the hygiene hypothesis. MS and T1D have a similar geographical distribution pattern known as a "North-south gradient", with a high prevalence in northern European (Scandinavian) countries (= relatively hygienic) and low prevalence in southern European countries (= relatively non-hygienic) (Bach, 2002; Shapira et al., 2010a). This pattern could be explained by the hygiene hypothesis, but also attributable to differences in genetic background. For example, the single nucleotide polymorphism (SNP) PTPN22 is associated with high risk of T1D and distributed more in the northern regions than southern regions of Europe (Shapira et al., 2010a). Another factor that might explain the "North-south gradient" of MS and T1D is the amount of sun exposure. Vitamin D, production of which is dependent on exposure to UV, has been reported to have immunomodulatory effects, and insufficient production of vitamin D might be responsible for the higher incidence of autoimmune disorders in northern European countries (Shoenfeld et al., 2009; Ponsonby et al., 2002).

There is epidemiological evidence of the importance of non-hygienic conditions in the prevention of autoimmune or atopic disorders. For instance, a significant difference in allergen-specific IgE level was reported between people of neighboring regions sharing the same ethnic background; Finland (relatively hygienic) and Russian Karelia (relatively nonhygienic) (Seiskari et al., 2007). Enteroviral infections were found to protect the children in Karelia from atopy. Moreover, there are reports that offspring of immigrants from developing countries acquire a higher incidence of autoimmune diseases, such as T1D and MS, than the population of their parents' motherland countries (Bach, 2002; Bodansky, 1992). These findings clearly indicate the importance of environmental factors (including hygienic standards) rather than genetic background in the pathogenesis of autoimmune disorders.

The "sibling effect", that children with more siblings have a lower risk of developing atopic disorders (Strachan, 1989), is the basic finding that the hygiene hypothesis comes from. The sibling effect on atopic disorders has been demonstrated in cohort studies (Benn et al., 2004; Matheson et al., 2009; Cullinan et al., 2003). A similar effect was reported in case of T1D (Cardwell et al., 2008a) and IBD (Koloski et al., 2008). From the viewpoint of the hygiene hypothesis, the decrease of the disease risk can be explained by the increased exposure to pathogens from elder siblings. Regarding atopic disorders, a meta-analysis of atopic dermatitis (AD) has shown inverse relationships with exposure to endotoxins, early day care, and contact with animals (Flohr et al., 2005). The risk of the early onset of allergic rhinitis (AR) was inversely correlated with viral infections during childhood, in addition to cumulative exposure to siblings before the age of 2 years (Matheson et al., 2009). Not only

cytokines). These products have outstanding therapeutic effects on autoimmune diseases (Nixon et al., 2007; Jones & Ding, 2010) compared to traditional immunomodulatory agents such as disease modifying anti-rheumatic drugs (DMARDs). However, they can cause severe adverse effects such as opportunistic infections. Helminths or their excretory/secretary products might solve the problems of monoclonal antibody therapy (Puneet et al, 2011). Therefore, at the end of this chapter, clinical trials of viable parasitic

As described in Introduction, the prevalence of asthma, T1D, MS, and inflammatory bowel diseases (IBD) has been increasing in developed countries in an inverse relation to the declining prevalence of infectious diseases (Bach, 2002). In addition to the chronological trend, the geographical distribution of some autoimmune diseases seems to support the hygiene hypothesis. MS and T1D have a similar geographical distribution pattern known as a "North-south gradient", with a high prevalence in northern European (Scandinavian) countries (= relatively hygienic) and low prevalence in southern European countries (= relatively non-hygienic) (Bach, 2002; Shapira et al., 2010a). This pattern could be explained by the hygiene hypothesis, but also attributable to differences in genetic background. For example, the single nucleotide polymorphism (SNP) PTPN22 is associated with high risk of T1D and distributed more in the northern regions than southern regions of Europe (Shapira et al., 2010a). Another factor that might explain the "North-south gradient" of MS and T1D is the amount of sun exposure. Vitamin D, production of which is dependent on exposure to UV, has been reported to have immunomodulatory effects, and insufficient production of vitamin D might be responsible for the higher incidence of autoimmune disorders in

There is epidemiological evidence of the importance of non-hygienic conditions in the prevention of autoimmune or atopic disorders. For instance, a significant difference in allergen-specific IgE level was reported between people of neighboring regions sharing the same ethnic background; Finland (relatively hygienic) and Russian Karelia (relatively nonhygienic) (Seiskari et al., 2007). Enteroviral infections were found to protect the children in Karelia from atopy. Moreover, there are reports that offspring of immigrants from developing countries acquire a higher incidence of autoimmune diseases, such as T1D and MS, than the population of their parents' motherland countries (Bach, 2002; Bodansky, 1992). These findings clearly indicate the importance of environmental factors (including hygienic standards) rather

The "sibling effect", that children with more siblings have a lower risk of developing atopic disorders (Strachan, 1989), is the basic finding that the hygiene hypothesis comes from. The sibling effect on atopic disorders has been demonstrated in cohort studies (Benn et al., 2004; Matheson et al., 2009; Cullinan et al., 2003). A similar effect was reported in case of T1D (Cardwell et al., 2008a) and IBD (Koloski et al., 2008). From the viewpoint of the hygiene hypothesis, the decrease of the disease risk can be explained by the increased exposure to pathogens from elder siblings. Regarding atopic disorders, a meta-analysis of atopic dermatitis (AD) has shown inverse relationships with exposure to endotoxins, early day care, and contact with animals (Flohr et al., 2005). The risk of the early onset of allergic rhinitis (AR) was inversely correlated with viral infections during childhood, in addition to cumulative exposure to siblings before the age of 2 years (Matheson et al., 2009). Not only

helminths for the treatment of immunological disorders are briefly introduced.

northern European countries (Shoenfeld et al., 2009; Ponsonby et al., 2002).

than genetic background in the pathogenesis of autoimmune disorders.

**2. Evidence of the hygiene hypothesis** 

overt infections but also non-invasive exposure to pathogen-derived products, such as endotoxins (Gereda et al., 2000), are considered responsible for prevention of atopy (von Mutius, 2007). In the case of autoimmune diseases, the risk of T1D is reduced in children living with siblings, sharing a bedroom and of households that often move (Cardwell et al., 2008b). A population-based study in Canada demonstrated correlations between IBD and high socioeconomic status and low rates of enteric infections (Green et al., 2006). The report also revealed a positive correlation between IBD and MS.
