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Down regulation of Fc and complement receptors on B cells in rheumatoid arthritis
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär immunologi. (Sandra Kleinau)
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär immunologi. (Sandra Kleinau)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
Visa övriga samt affilieringar
2010 (Engelska)Ingår i: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 137, nr 3, s. 322-329Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

B cell tolerance is regulated by receptors that modulate B cell receptor signaling, such as Fc gamma receptor IIb (FcγRIIb; CD32b) and complement receptors (CR) 1 and 2. Deficiency in these receptors may contribute to autoimmunity. To address this we have investigated the receptor expression in healthy individuals in comparison with rheumatoid arthritis (RA) patients. In healthy subjects we found that women had overall lower Fcgamma;RIIb expression on B cells than men that significantly decreased with age. RA patients had fewer FcγRIIb, CR1 and CR2 positive B cells and decreased receptor expressions compared to healthy subjects. Further, the RA B cells displayed a significantly increased proliferative response when cultured with interleukin-2 in vitro. In summary, the dysregulated B cells in RA are associated with lower FcγRIIb, CR1 and CR2 levels. The reduced FcγRIIb expression on B cells in women may influence the increased frequency of autoimmunity in women.

Ort, förlag, år, upplaga, sidor
2010. Vol. 137, nr 3, s. 322-329
Nyckelord [en]
B cells, Fc receptor, Complement receptor, Autoimmunity, Rheumatoid arthritis
Nationell ämneskategori
Reumatologi och inflammation
Forskningsämne
Immunologi
Identifikatorer
URN: urn:nbn:se:uu:diva-108924DOI: 10.1016/j.clim.2010.08.006ISI: 000284300600003OAI: oai:DiVA.org:uu-108924DiVA, id: diva2:272205
Tillgänglig från: 2009-10-15 Skapad: 2009-10-05 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
Ingår i avhandling
1. B cells in Autoimmunity: Studies of Complement Receptor 1 & 2 and FcγRIIb in Autoimmune Arthritis
Öppna denna publikation i ny flik eller fönster >>B cells in Autoimmunity: Studies of Complement Receptor 1 & 2 and FcγRIIb in Autoimmune Arthritis
2009 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2009. s. 67
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 680
Nyckelord
B cells, complement receptors, fc gamma receptor IIb, autoimmune arthritis, rheumatoid arthritis
Nationell ämneskategori
Immunologi inom det medicinska området
Identifikatorer
urn:nbn:se:uu:diva-109428 (URN)978-91-554-7629-8 (ISBN)
Disputation
2009-11-27, C8:301, Uppsala Biomedical Center, Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2009-11-06 Skapad: 2009-10-15 Senast uppdaterad: 2018-01-12Bibliografiskt granskad

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