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International Immunology Advance Access originally published online on December 22, 2006
International Immunology 2007 19(2):175-183; doi:10.1093/intimm/dxl134
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© The Japanese Society for Immunology. 2006. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

IL-4R{alpha} polymorphism in regulation of IL-4 synthesis by T cells: implication in susceptibility to a subset of murine lupus

Wakana Shiroiwa1,2, Kazuyuki Tsukamoto1, Mareki Ohtsuji1, Qingshun Lin1,2, Akinori Ida1, Sanki Kodera1, Naomi Ohtsuji1, Kazuhiro Nakamura1, Hiromichi Tsurui1, Katsuyuki Kinoshita2, Hiroyuki Nishimura3, Toshikazu Shirai1 and Sachiko Hirose1

1 Department of Pathology
2 Department of Obstetrics and Gynecology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
3 Toin Human Science and Technology Center, Department of Biomedical Engineering, Toin University of Yokohama, Yokohama, Japan

Correspondence to: S. Hirose; E-mail: sacchi{at}med.juntendo.ac.jp

To thoroughly understand the role of IL-4 in the pathogenesis of systemic lupus erythematosus (SLE), a prototypic antibody-mediated systemic autoimmune disease, we examined the potential of in vitro IL-4 production by anti-CD3 mAb-stimulated splenic T cells in SLE model of NZB, BXSB and related mouse strains. Unexpectedly, both SLE-prone NZB and BXSB mice had a limited potential to produce IL-4, while disease-free NZW mice had a high potential. Levels in (NZB x NZW) F1 and (NZW x BXSB) F1 were in between. Genome-wide search for quantitative trait loci (QTL) controlling this variation identified a single significant QTL in the vicinity of IL-4R{alpha} gene on chromosome 7. Sequence analysis of IL-4R{alpha} cDNA revealed that there are 17 nucleotide substitutions resulting in eight amino acid changes between NZB and NZW strains. BXSB showed the identical sequence, as did NZB. Thus, it was suggested that the NZW-type polymorphism controls a high potential and the NZB/BXSB-type polymorphism controls a low potential for IL-4 production by T cells. Linkage studies using NZW x (NZW x BXSB) F1 male and (NZB x NZW) F1 x NZW female back-cross mice revealed that the BXSB/NZB-type IL-4R{alpha} polymorphism significantly linked to BXSB, but not to (NZB x NZW) F1 lupus. Thus, the low IL-4-producing phenotype appears to predispose to SLE in BXSB, but not NZB-related strains, suggesting that the role of IL-4 in the pathogenesis may differ between certain subsets of SLE, even if they show similar disease phenotypes.

Keywords: CD4+ T cells, quantitative trait loci, systemic lupus erythematosus, Yaa gene

Transmitting editor: K. Yamamoto


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