Aberrant genetic control of invariant TCR-bearing NKT cell function in New Zealand mouse strains: possible involvement in systemic lupus erythematosus pathogenesis.
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-gamma in response to alpha-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)F(1) 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)F(1) 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, alpha-galactosylceramide-stimulated NKT cells from NZW and (NZB x NZW)F(1) 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)F(1) 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)F(1) disease.
Tsukamoto
Kazuyuki
K
Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan.
Ohtsuji
Mareki
M
Shiroiwa
Wakana
W
Lin
Qingshun
Q
Nakamura
Kazuhiro
K
Tsurui
Hiromichi
H
Jiang
Yi
Y
Sudo
Katsuko
K
Nishimura
Hiroyuki
H
Shirai
Toshikazu
T
Hirose
Sachiko
S
D000818:Animals; D018791:CD4 Lymphocyte Count; D002875:Chromosomes / Q000235:genetics; D005838:Genotype; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D009520:New Zealand; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
D011948:Receptors, Antigen, T-Cell; D015847:Interleukin-4; D007371:Interferon-gamma