IL-4Ralpha polymorphism in regulation of IL-4 synthesis by T cells: implication in susceptibility to a subset of murine lupus.
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-4Ralpha gene on chromosome 7. Sequence analysis of IL-4Ralpha 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-4Ralpha 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.
Shiroiwa
Wakana
W
Department of Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Tsukamoto
Kazuyuki
K
Ohtsuji
Mareki
M
Lin
Qingshun
Q
Ida
Akinori
A
Kodera
Sanki
S
Ohtsuji
Naomi
N
Nakamura
Kazuhiro
K
Tsurui
Hiromichi
H
Kinoshita
Katsuyuki
K
Nishimura
Hiroyuki
H
Shirai
Toshikazu
T
Hirose
Sachiko
S
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020022:Genetic Predisposition to Disease; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D008814:Mice, Inbred NZB; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D040641:Quantitative Trait Loci; D011956:Receptors, Cell Surface / Q000235:genetics*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology; D053662:Interleukin-4 Receptor alpha Subunit
D007371:Interferon-gamma; D015847:Interleukin-4; D011956:Receptors, Cell Surface; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit