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Enhanced susceptibility to low-dose collagen-induced arthritis in CR1/2-deficient female mice—possible role of estrogen on CR1 expression

Kajsa E. Nilsson^*, Maria Andrén^*, Teresita Diaz de Ståhl and Sandra Kleinau^*,1

^* Department of Cell and Molecular Biology and

Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden

¹ Correspondence: Department of Cell and Molecular Biology, Uppsala University, Box 596, SE-75 124 Uppsala, Sweden. E-mail: sandra.kleinau{at}icm.uu.se

The influence of complement receptor 1 and 2 (CR1/2) was investigated on the susceptibility to low-dose collagen-induced arthritis (CIA) in wild-type (WT) and CR1/2-deficient DBA/1 mice. Significantly enhanced CIA was observed in female CR1/2-deficient mice compared with WT female mice, while male mutant and WT mice showed similar arthritis development. The enhanced CIA was accompanied with higher complement levels and a prolonged IgM anti-collagen type II response. When investigating whether estrogen contributed to the different arthritis susceptibility, we found that ovariectomy rendered WT females more sensitive to low-dose CIA and to the same extent as CR1/2-deficient females, while CR1/2-deficient mice were unaffected by ovariectomy. Notably, the ovariectomized WT mice displayed reduced CR1⁺ B220⁺ B-cell numbers and CR1 expression compared with sham-operated WT mice, suggesting a stimulatory effect of estrogen on CR1. In accordance, a significant correlation was observed between reduced CR1 expression in B cells and increased age in healthy female blood donors but not in male donors. Our findings demonstrate an important role of CR1/2 in suppressing CIA in female mice under low-antigen conditions. The data suggest that estrogen promote CR1 expression in B cells. These findings provide insight to the increased frequency of rheumatoid arthritis in postmenopausal women.—Nilsson, K. E., Andrén, M., Diaz de Ståhl, T., Kleinau, S. Enhanced susceptibility to low-dose collagen-induced arthritis in CR1/2-deficient female mice—possible role of estrogen on CR1 expression.

Key Words: complement receptor • B cells • knockout mice • autoimmunity