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Ile50Val variant of IL4Rα upregulates IgE synthesis and associates with atopic asthma

Nature Genetics volume 19, pages 119–120 (1998)Cite this article

Atopy is an immune disorder characterized by heightened immunoglobulin E (IgE) production and leads to the clinical disorders of asthma, eczema and rhinitis1. Interleukin 4 (IL4) is a pleiotropic cytokine which plays a crucial role in IgE-dependent atopic disorders2; it is central to B cells switching to IgE antibody production and to the maturation of T-helper cells to the Th2 phenotype (type-2 T-helper lymphocyte). Human IL4 operates through the IL4 receptor (IL4R) and thereby Stat6 (signal transducer and activator of transcription 6) activation3. Mice deficient in Stat6 (Refs 4,5) or the IL4Rα chain6 lack IgE production and Th2 inflammatory reactions. IL4Rα is therefore a crucial component required for IL4 binding and signal transduction. A cytoplasmic variant of IL4Rα, an Arg576Gln substitution (numbering from the first ATG), has been recently identified and is found in excess in a study of a group of individuals with hyper-IgE syndrome and severe eczema7; functional assays showed impaired binding of the negative regulatory molecule, protein tyrosine phosphatase, SHP-1, and increased expression of CD23 was found on peripheral blood mononuclear cells after being challenged with IL4. Stat6 activation, however, was not upregulated and no information was provided on cellular IgE synthesis.

An extracellular variant, Thr49Ile, in IL4Rα of BALB/c mice alters the ligand-binding affinity of IL4Rα (ref. 8). An Ile50Val (numbering for mature peptide) variant of human IL4Rα has also been identified9,10 and it is, to date, the only known extracellular variant of human IL4Rα (ref. 11). To test whether the Ile50Val variant promotes dysregulation of IgE synthesis, we first conducted a genetic association study for serum IgE levels in a Japanese population. There was a significant difference in Ile/Val 50 genotype frequencies between control and atopic subjects (Table 1); Ile50 associated with atopic asthma but not with non-atopic asthma; Ile50 specifically and significantly associated with raised total serum IgE levels and mite-specific IgE. The association with atopy was especially strong in children. The high frequency of Ile50 homozygotes (approximately 60%) in the childhood atopic asthma group described here, and the significant skewing from Hardy-Weinberg equilibrium (P<0.0001), suggest a largely recessive genetic effect for Ile50 on atopy; the previously reported effect of the Arg576Gln variant of IL4Rα appeared mainly dominant7.

Table 1 Association between Ile50Val substitution of IL4Rα and atopy and atopic asthma
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Figure 1: Upregulated cellular responses to human IL4 after transfection with the Ile50 variant of IL4Rα compared with the Val50 variant a, Cell proliferation by MTT dye assay.

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Acknowledgements

We thank D. Kang for his kind discussion, and the Japanese government, Astra Japan, and Mitsubishi Chemical Co. for support.

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Authors and Affiliations

  1. Department of Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan

    Hiromichi Mitsuyasu, Kenji Izuhara, Yojiro Arinobu & Naotaka Hamasaki

  2. Osler Chest Unit, Churchill Hospital, Oxford , UK

    Xiao-Quan Mao, Pei-Song Gao, Taro Shirakawa & Julian M. Hopkin

  3. Department of Otolaryngology, Japanese Red Cross Society, Wakayama Medical Center, Wakayama, Japan

    Tadao Enomoto & Yasuhiro Dake

  4. Kyoto Preventive Medical Center, Kyoto, Japan

    Mitsuru Kawai

  5. Department of Pediatrics, Osaka College of Medicine, Takatsuki, Japan

    Sei Sasaki

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Correspondence to Taro Shirakawa.

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Mitsuyasu, H., Izuhara, K., Mao, XQ. et al. Ile50Val variant of IL4Rα upregulates IgE synthesis and associates with atopic asthma. Nat Genet 19, 119–120 (1998). https://doi.org/10.1038/472

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