**1. Introduction**

590 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

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> In developed countries, the prevalence of both allergic disease (asthma) and autoimmune disorders such as Crohn's disease (CD), multiple sclerosis (MS), and type 1 diabetes (T1D) is increasing. This trend seems to be inversely correlated to prominent decreases in infectious diseases such as measles, tuberculosis, and hepatitis A (Bach, 2002). Based on such epidemiological observations, the "hygiene hypothesis", that exposure to infectious agents; i.e. bacteria, viruses, and parasites, especially in childhood, lowers the risk of later onset of immunological disorders, has attracted much attention. According to the hypothesis, a reduced exposure to infectious agents due to improved hygienic conditions in developed countries, urbanized areas, and/or a westernized lifestyle is responsible for the higher incidence of autoimmunity and allergies in modern society. A number of epidemiological and experimental studies have demonstrated the plausibility of this hypothesis. However, there is also considerable evidence that does not support or contradicts the hypothesis. In this chapter, conflicting reports are introduced and discussed.

> Most studies trying to elucidate the mechanisms involved have been conducted using rodent models. In various models of autoimmune or allergic diseases, effects of bacterial, viral or parasitic infections were tested. Consequently, in many cases, preventive or ameliorating effects of infectious agents have been confirmed. In the main part of this chapter, the influence of parasitic helminths on autoimmune disorders will be introduced.

> Although the mechanisms underlying the amelioration and/or prevention of immunological disorders by infectious agents have been studied extensively, they are not yet fully understood. As both Th1-polarizing (bacteria and viruses) and Th2-polarizing (parasitic helminths) infectious agents have anti-autoimmune/anti-allergic activities (Zaccone & Cooke, 2011), the "Th1/Th2 paradigm" is not enough to explain the mechanisms involved. Additionally, some autoimmune diseases have been shown to be dependent on a pathogenic T helper subset (Th17), and not on the Th1 subset. The suppressive mechanisms of infectious agents have been attributed to various regulatory/suppressive cell populations, such as Treg cells, Breg cells, NKT cells and alternatively activated macrophages (AA MΦs). In addition, the involvement of suppressive cytokines (e.g. IL-4, IL-10 or TGF-β) has been studied and demonstrated. Focusing on helminth infections, the possible involvement of regulatory cells and cytokines is discussed.

> Some autoimmune diseases are being treated successfully with recently developed biological products (mainly humanized monoclonal antibodies against pro-inflammatory

Parasitic Helminths as Potential Therapeutic Agents Against Autoimmune Disorders 593

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

In great contrast to T1D and MS, rheumatoid arthritis (RA) has been declining in prevalence in recent decades (Gabriel &Michaud, 2009). Moreover, its geographical distribution is very different from that of T1D or MS. That is, RA is generally evenly distributed in the world and does not have a "North-south gradient". (Shapira et al., 2010b). The geographical distribution of systemic sclerosis (SSc) seems to be contrast to those of T1D and MS. Within Europe, SSc is less frequent in the north than south (Shapira et al., 2010b). In the case of ankylosing spondylitis (AS), a genetic factor (HLA-B27) rather than environmental factors seems to explain the prevalence of the disease (Shapira et al., 2010b). Therefore, the geographical distribution and/or chronological transition of some autoimmune diseases

For atopic disorders, the sibling effect itself has been confirmed (Benn et al, 2004; Matheson et al., 2009; Cullinan et al., 2003). However, some authors suggest that infections in early life do not explain the observed sibling effect (Benn et al., 2004; Cullinan et al., 2003). In a report on the preventive effects of endotoxins against AD (Flohr et al., 2005), apparent infections in early life were shown to increase the risk of AD. In a meta-analysis of relationships between exposure to furry pets and asthma and allergic rhinitis, there were different effects in different species of animals. That is, exposure to dogs increases the risk but exposure to cats decreases it (Takkouche et al., 2008). Moreover, in a meta-analysis of interrelationships between vaccinations with bacterial products (BCG and pertussis vaccine) and the incidence of asthma, no statistical association was found (Balicer et al., 2007). For T1D, there was no association between routinely recorded infections in early life and subsequent risk of the disease (Cardwell et al., 2008a). In addition, T1D had inverse relationships with asthma (Cardwell et al., 2003). These finding do not match the hypothesis that infections and exposure to pathogens protect against both atopy and autoimmunity. A systematic review of mycobacterial infections and atopy (Obihara et al., 2007) found that the negative correlations between them were mainly based on cross-sectional studies. The authors,

therefore, claimed that population-based prospective studies would be needed.

Regarding etiology of MS, two hypotheses have been proposed (Milo & Kahana, 2010). The "prevalence hypothesis" postulates that MS is caused by a pathogen common in highincidence areas. In contrast, according to the more accepted "poliomyelitis-hygiene hypothesis", certain infections in early childhood protect against MS whereas infections with the same infectious agents later in life (e.g. adolescence) cause the disease, as in the cases of poliomyelitis. This concept is different from that of the "original" hygiene hypothesis, in that people living in hygienic conditions (= non-infected people) are protected from the disease. Epstein-Barr virus (EBV) is one of the infectious agents suspected to be causative of MS. Individuals infected with EBV in early childhood have a lower risk of MS than those infected in adolescence and as a consequence, suffer from

also revealed a positive correlation between IBD and MS.

cannot be explained by the hygiene hypothesis.

**3. Evidence that does not match the hygiene hypothesis** 

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 helminths for the treatment of immunological disorders are briefly introduced.
