**3.3 IL-4Rα gene**

44 Atopic Dermatitis – Disease Etiology and Clinical Management

Fig. 1. The receptor structures and signal pathways of IL-4 and IL-13.

levels (33-35), specific anti-allergen IgE (33, 35), or AD (36).

kinases followed by activation of STAT6.

**3.2 IL-13 gene** 

IL-4 binds to type I IL-4R or type II IL-4R/IL-13R, and IL-13 binds to type II IL-4R/IL-13R. Type I IL-4R and type II IL-4R/IL-13R are composed of IL-4Rα and the IL-2R γ chain

(common γ) or IL-4Rα and IL-13Rα1, respectively. Engagement of the receptors activates Jak

There exist several SNPs on the *IL13* gene. Thus far, two of them (Arg110Gln, also referred to as Arg130Gln or G4257A; and -1055C/T, also referred to as -1111C/T or -1024C/T) are reported to be associated with atopy or AD. We and other groups reported the genetic association of Arg110Gln with bronchial asthma (27), serum IgE levels (28, 29), and AD (29). This SNP causes exchange of arginine at the 110 (130) amino acid for glutamine. Several functional differences between the arginine type and the glutamine type have been demonstrated (30-32): (1) The glutamine type has lower affinity with the IL-13R α2 chain, a decoy receptor for IL-13, than the arginine type. (2) The glutamine type has enhanced stability over the arginine type (3). The glutamine type transduces a stronger signal via IL-13Rα1, a functional receptor for IL-13, than the arginine type. All of these results suggest that the glutamine type acts more potently *in vivo* than the arginine type. It has been reproducibly demonstrated that this SNP is genetically associated with serum total IgE The type II IL-4R or the IL-13R is composed of IL-4Rα and IL-13Rα1. Both IL-4 and IL-13 bind to this receptor on cell surface, transducing their signals intracellularly (5, 6). Several SNPs on the *IL4RA* gene are known to be genetically associated with atopy or allergic diseases. The genetic association of Gln576Arg, also referred as Gln551Arg, was originally found in hyper IgE syndrome patients, some of who had severe AD (41). Position 576 is adjacent to the tyrosine residue at 575, a binding site for SHP-1, a phosphotyrosine phosphatase. Exchange of glutamine for arginine decreases the binding activities for SHP-1, resulting in up-regulation of STAT6 activation. The genetic association of this SNP with AD was confirmed by another group (42).

### **3.4 IL-13α1 gene**

IL-13Rα1 is another component of type II IL-4R/IL-13R, together with IL-4Rα. A SNP in the coding region of the *IL13RA1* gene, 1398A/G, was reported to be genetically associated with serum IgE levels (27). The function of this SNP is unclear because this SNP is a silent one.
