Contribution of NZB autoimmunity 2 to Y-linked autoimmune acceleration-induced monocytosis in association with murine systemic lupus

被引:28
作者
Kikuchi, Shuichi
Santiago-Raber, Marie-Laure
Amano, Hirofumi
Amano, Eri
Fossati-Jimack, Liliane
Moll, Thomas
Kotzin, Brian L.
Izui, Shozo [1 ]
机构
[1] Univ Geneva, Med Ctr, Dept Pathol & Immunol, Fac Med, CH-1211 Geneva 4, Switzerland
[2] Imperial Coll Sch Med, Rheumatol Sect, London, England
[3] Univ Colorado, Hlth Sci Ctr, Div Immunol, Denver, CO 80206 USA
[4] Natl Jewish Med & Res Ctr, Denver, CO 80206 USA
关键词
D O I
10.4049/jimmunol.176.5.3240
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The accelerated development of systemic lupus erythematosus (SLE) in BXSB male mice is associated with the presence of the Y-linked autoimmune acceleration (Yaa) mutation, which induces an age-dependent monocytosis. Using a cohort of C5713L/6 (136) x (NZB x B6)F-1 backcross male mice bearing the Yaa mutation, we defined the pathogenic role and genetic basis for Yaa-associated monocytosis. We observed a remarkable correlation of monocytos 'is' with autoantibody production and subsequent development of lethal lupus nephritis, indicating that monocytosis is an additional useful indicator for severe SLE. In addition, we identified an NZB-derived locus on chromosome I predisposing to the development of monocytosis, which peaked at Fcgr2b encoding Fc gamma RIIB and directly overlapped with the previously identified NZB autoimmunity 2 (Nba2) locus. The contribution of Nba2 to monocytosis was confirmed by the analysis of Yaa-bearing B6 mice congenic for the NZB-Nba2 locus. Finally, we observed a very low-level expression of Fc gamma RIIB on macrophages bearing the NZB-type Fcgr2b allele, compared with those bearing the B6-type allele, and the development of monocytosis in Fc gamma RIIB haploinsufficient B6 mice carrying the Yaa mutation. These data suggest that the Nba2 locus may play a supplementary role in the pathogenesis of SLE by promoting the development of monocytosis and the activation of effector cells bearing stimulatory Fc gamma R, in addition to its implication in the dysregulated activation of autoreactive B cells.
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页码:3240 / 3247
页数:8
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