**5. References**

14 Atopic Dermatitis – Disease Etiology and Clinical Management

Histological examination of H&E-stained sections of involved *Flgft* skin after 16 applications showed acanthosis, elongation of rete ridges, and dense lymphocyte and neutrophil infiltration in the dermis, accompanied by an increased number of mast cells in the dermis. Consistently, scratching behavior, TEWL, and Dp-specific IgE levels were significantly higher in *Flgft* mice than in B6 mice (Fig.8) (Moniaga, et al., 2010). Thus the treatment of *Flgft* mice with Dp ointment, even without prior barrier disruption, remarkably enhanced both the clinical manifestations and the laboratory findings that

Fig. 8. TEWL and mite-specific serum IgE levels of *Flgft* mice and control mice after the last

We have summarized the findings on *Flgft* mice revealed by four different groups (Table 1). While most of these findings were consistent with each other, there still remain several issues to be solved, for example, the influence of the genetic background and other gene

**Spontaneous AD** - + n.r. +

**state** slightly n.r. + (old age) +

**skin lesion in steady state** + + n.r. +

**state** n.r. + + +

**antigen ingress** + (OVA) + (OVA) + (low dose

Table 1. Summary of the phenotypes of flaky tail mice

**Oyoshi et al. (Oyoshi, et al., 2009)**

**Scharschmidt** 

oxaxolone)


**Moniaga et al. (Moniaga, et al.,** 

> + (mite, D.p.)

**2010)**

**et al. (Scharschmidt, et al., 2009)**

**Fallon et al. (Fallon, et al., 2009)**

correspond to indicators of human AD.

**4. Summary and future direction** 

mutations in these mice.

**Increased TEWL in steady** 

**Histopathology AD like** 

**Enhanced cutaneous** 

**response**

**Increase total IgE in steady** 

**Enhanced non cutaneous antigen (OVA-i.p)** 

application.


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**2** 

*Japan* 

**Mouse Models for Atopic Dermatitis** 

Hiromichi Yonekawa1, Toyoyuki Takada2, Hiroshi Shitara1, Choji Taya1, Yoshibumi Matsushima3, Kunie Matsuoka4 and Yoshiaki Kikkawa4

*4Mammalian Genetics Project, Tokyo Metropolitan Institute of Medical Science, Tokyo* 

The term atopic dermatitis (AD) was first proposed by Wise & Sulzberger (Wise, 1993), who defined the condition as "confusing types of localized and generalized lichenification, generalized neurodermatitis or a manifestation of atopy." AD (or atopic eczema) is recognized as a very common disease that affects at least 15% of children and is strongly associated with cutaneous hyper-reactivity to environmental triggers (Geha, 2003, Leung and Bieber, 2003, Novak et al., 2003). AD is characterized by complex symptoms, including chronic relapsing, extreme pruritus and eczematous skin disease, all of which are frequently associated with IgE hyperresponsiveness to environmental allergens (Hanifin, 1980, Larsen et al., 1986, Schultz Larsen, 1993). The rapid increase in the prevalence of AD over the past three decades has resulted in an intense effort to elucidate the underlying pathogenesis and in the use of radical treatments for this disorder (Taylor et al., 1984, Larsen et al., 1986, Geha, 2003). The causative factors for AD generally fall into two categories: environmental and genetic factors. House dust mites and air pollution are included in the environmental category, and their involvement in the disease has been strongly suggested by epidemiological studies (Hanifin, 1982). Alternatively, genetic factors, including several different candidate regions, have been suggested from linkage studies on atopic and nonatopic phenotypes see Morar et al., (2006) and references therein). The fact that multiple linkage regions have been associated with the disease might be due to: 1) the disease is polygenic and many different genetic factors may be affected with the diseases, 2) the disease is clinically heterogeneous and different subphenotypes are influenced by different risk loci, which is not always followed by one-to-one correspondence, 3) different populations have a different genetic pool and may have different genetic factors for the disease, and consequently genetic studies are still not good enough to correspond to these situations. Additionally, there is a lack of appropriate animal models for human AD except for the flaky tail (*Flgft*) mouse. The *Flgft* mouse carries a loss-of-function (LOF) mutation in the gene encoding filaggrin (FLG), and this LOF mutation causes the barrier abnormality.

**1. Introduction** 

*2Mammalian Genetics Laboratory, National Institute of Genetics, Mishima 3Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama* 

**Developed in Japan** 

*1Center for Basic Technology Research* 

*Tokyo Metropolitan Institute of Medical Science, Tokyo* 

