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Contribution of NZB Autoimmunity 2 to Y-Linked Autoimmune Acceleration-Induced Monocytosis in Association with Murine Systemic Lupus¹

Shuichi Kikuchi^2,*, Marie-Laure Santiago-Raber^2,*, Hirofumi Amano^*, Eri Amano^*, Liliane Fossati-Jimack, Thomas Moll^*, Brian L. Kotzin and Shozo Izui^3,*

^* Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Rheumatology Section, Hammersmith Campus, Imperial College School of Medicine, London, United Kingdom; and Division of Clinical Immunology, University of Colorado Health Sciences Center and National Jewish Medical and Research Center, Denver, Colorado 80206

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 C57BL/6 (B6) x (NZB x B6)F₁ 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 monocytosis 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 1 predisposing to the development of monocytosis, which peaked at Fcgr2b encoding FcRIIB 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 FcRIIB on macrophages bearing the NZB-type Fcgr2b allele, compared with those bearing the B6-type allele, and the development of monocytosis in FcRIIB 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 FcR, in addition to its implication in the dysregulated activation of autoreactive B cells.

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