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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
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
2009 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 23, no 8, 2450-2458 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2009. Vol. 23, no 8, 2450-2458 p.
Keyword [en]
complement receptor, B cells, knockout mice, autoimmunity
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-107312DOI: 10.1096/fj.08-125849ISI: 000268836700013PubMedID: 19351702OAI: oai:DiVA.org:uu-107312DiVA: diva2:228728
Available from: 2009-08-05 Created: 2009-08-05 Last updated: 2017-12-13Bibliographically approved
In thesis
1. B cells in Autoimmunity: Studies of Complement Receptor 1 & 2 and FcγRIIb in Autoimmune Arthritis
Open this publication in new window or tab >>B cells in Autoimmunity: Studies of Complement Receptor 1 & 2 and FcγRIIb in Autoimmune Arthritis
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

B cells are normally regulated to prevent activation against self-proteins through tolerance mechanisms.  However, occasionally there is a break in tolerance and B cells can become self-reactive, which might lead to the development of autoimmune disease. The activation of self-reactive B cells is regulated by receptors on the B cell surface, such as Fc gamma receptor IIb (FcγRIIb), complement receptor type 1 (CR1), and CR type 2 (CR2).

In this thesis I have studied the role of FcγRIIb, CR1 and CR2 on B cells in autoimmune arthritis. By using a model for rheumatoid arthritis, I discovered that the initial self-reactive B cell response in arthritis was associated with the splenic marginal zone B cell population. Marginal zone B cells express high levels of CR1/CR2 and FcγRIIb, suggesting that they normally require high regulation. Further, female mice deficient in CR1/CR2 displayed increased susceptibility to arthritis compared to CR1/CR2-sufficient female mice. When investigating whether sex hormones affected arthritis susceptibility, we found that ovariectomy, of the otherwise fairly resistant CR1/CR2-sufficient mice, reduced the expression of CR1 on B cells and rendered the mice more susceptible to arthritis.

In humans, a significantly reduced CR1 and FcγRIIb expression was found on B cells in aging women, but not in men. This may contribute to the increased risk for women to develop autoimmune disease as reduced receptor expression may lead to the activation of self-reactive B cells. In agreement, lower CR1, CR2 and FcγRIIb expression was seen in patients with rheumatoid arthritis.

 

Finally, a soluble form of FcγRIIb was used to investigate FcγRIIb’s ability to bind self-reactive IgG in an attempt to treat autoimmune arthritis. Treatment of mice with established arthritis was associated with less self-reactive IgG antibodies and consequently less disease, suggesting that soluble FcγRIIb may be used as a novel treatment in arthritis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 67 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 680
Keyword
B cells, complement receptors, fc gamma receptor IIb, autoimmune arthritis, rheumatoid arthritis
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-109428 (URN)978-91-554-7629-8 (ISBN)
Public defence
2009-11-27, C8:301, Uppsala Biomedical Center, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-11-06 Created: 2009-10-15 Last updated: 2009-11-06Bibliographically approved

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