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Aberrant Genetic Control of Invariant TCR-Bearing NKT Cell Function in New Zealand Mouse Strains: Possible Involvement in Systemic Lupus Erythematosus Pathogenesis¹

Kazuyuki Tsukamoto^*, Mareki Ohtsuji^*, Wakana Shiroiwa^*,, Qingshun Lin^*,, Kazuhiro Nakamura^*, Hiromichi Tsurui^*, Yi Jiang^¶, Katsuko Sudo, Hiroyuki Nishimura, Toshikazu Shirai^* and Sachiko Hirose^2,*

^* Department of Pathology and Department of Obstetrics and Gynecology, Juntendo University School of Medicine; Animal Research Center, Tokyo Medical University, Tokyo; Toin Human Science and Technology Center, Department of Biomedical Engineering, Toin University of Yokohama, Yokohama, Japan; and ^¶ Central Laboratory of First Clinical College, China Medical University, Shenyang, China

Both suppressive and promoting roles of NKT cells have been reported in the pathogenesis of systemic lupus erythematosus (SLE). Herein, we found that although New Zealand mice have normal frequencies of NKT cells, their in vitro potential to produce IL-4 and IFN- in response to -galactosylceramide was remarkably impaired in New Zealand Black (NZB) mice prone to mild SLE, while production was highly up-regulated in nonautoimmune New Zealand White (NZW) mice and at intermediate levels in (NZB x NZW)F₁ mice, which are prone to severe SLE. Because this aberration is evident in young mice before disease onset, genetic mechanisms are thought to be involved. Genome-wide quantitative trait locus analysis and association studies revealed that a locus linked to D11Mit14 on chromosome 11 may be involved in the difference in cytokine-producing potential between NZB and NZW NKT cells. Additionally, (NZB x NZW)F₁ x NZB backcross progeny with the NZW genotype for D11Mit14 showed significantly increased frequencies of age-associated SLE phenotypes, such as high serum levels of IgG, IgG anti-DNA Abs, and lupus nephritis. In coculture studies, -galactosylceramide-stimulated NKT cells from NZW and (NZB x NZW)F₁ mice, but not from NZB mice, showed significantly enhanced Ig synthesis by B cells. These findings suggest that the D11Mit14-linked NZW locus may contribute to the development of SLE in (NZB x NZW)F₁ mice through a mechanism that up-regulates NKT cell function. Thus, this NZW allele may be a candidate of the NZW modifiers that act to promote (NZB x NZW)F₁ disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by Grants-in-Aid for Scientific Research on Priority Areas and for Center of Excellence Research from the Ministry of Education, Science, Technology, Sports and Culture, Japan; a grant from the Organization for Pharmaceutical Safety and Research, Japan; and a Health and Labor Sciences Research Grant from the Ministry of Health, Labor and Welfare, Japan.

² Address correspondence and reprint requests to Dr. Sachiko Hirose, Department of Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. E-mail address: sacchi{at}med.juntendo.ac.jp

³ Abbreviations used in this paper: -GalCer, -galactosylceramide; SLE, systemic lupus erythematosus; B6, C57BL/6; NZB, New Zealand Black; NZW, New Zealand White; CIA, collagen-induced arthritis; QTL, quantitative trait loci; LOD, logarithm of odds; Ntm1, NKT cell modifier 1; Tim, T cell Ig mucine.