Prevention of collagen-induced arthritis in mice transgenic for the complement inhibitor complement receptor
Nirmal K Banda1, Damian M Kraus, Michele Muggli
1Division of Rheumatology, University of Colorado Health Sciences Center, Denver, CO 80262. BolderPATH, Boulder, CO 80309, USA.
Abstract:
The objective of these studies was to examine collagen-induced arthritis (CIA) in C57BL/6 mice transgenic for the rodent complement regulatory protein complement receptor 1-related gene/protein y (Crry) (Crry-Tg), a C3 convertase inhibitor. The scores for clinical disease activity and for histological damage in the joints were both significantly decreased in Crry-Tg mice in comparison to wild-type (WT) littermates. The production of both IgG1 and IgG2a anti-collagen Abs was reduced in the Crry-Tg mice, although spleen cell proliferation in response to collagen type II was not altered. The production of IFN-gamma, TNF-alpha, and IL-1beta by LPS-stimulated spleen cells was decreased, and IL-10 was increased, in cells from Crry-Tg mice in comparison to WT. The steady-state mRNA levels for IFN-gamma, TNF-alpha, and IL-1beta were all decreased in the joints of Crry-Tg mice in comparison to WT. The synovium from Crry-Tg mice without CIA contained the mRNA for the Crry transgene, by RT-PCR, and the synovium from transgenic mice with CIA exhibited little deposition of C3 protein by immunohistological analysis. These results suggest that suppression of CIA in Crry-Tg mice may be due to enhanced synthesis of Crry locally in the joint with decreased production of proinflammatory cytokines.
Insights
Transgenic mice expressing complement receptor 1-related gene/protein y (Crry) showed reduced collagen-induced arthritis (CIA) severity. This suggests Crry plays a key role in suppressing CIA by decreasing joint inflammation.
Area of Science:
- Immunology
- Rheumatology
- Molecular Biology
Background:
- Collagen-induced arthritis (CIA) is a model for rheumatoid arthritis.
- The complement system plays a role in inflammatory joint diseases.
- Complement receptor 1-related gene/protein y (Crry) is a complement regulatory protein.
Purpose of the Study:
- To investigate the role of Crry in collagen-induced arthritis (CIA) using transgenic mice.
- To assess the impact of Crry expression on disease activity and joint damage in CIA.
- To explore the molecular mechanisms underlying Crry's effect on CIA.
Main Methods:
- Utilized C57BL/6 mice genetically engineered to express the Crry transgene (Crry-Tg).
- Induced CIA in Crry-Tg and wild-type (WT) littermate mice.
- Assessed clinical disease scores, histological joint damage, anti-collagen antibody production, spleen cell proliferation, cytokine production (IFN-gamma, TNF-alpha, IL-1beta, IL-10), and mRNA levels in joints.
- Analyzed Crry transgene expression and C3 deposition in synovial tissue using RT-PCR and immunohistology.
Main Results:
- Crry-Tg mice exhibited significantly decreased clinical disease activity and histological joint damage compared to WT mice.
- Reduced production of IgG1 and IgG2a anti-collagen antibodies was observed in Crry-Tg mice.
- Spleen cell proliferation to collagen type II was not altered, but LPS-stimulated spleen cells showed decreased IFN-gamma, TNF-alpha, and IL-1beta, with increased IL-10 production.
- Steady-state mRNA levels for IFN-gamma, TNF-alpha, and IL-1beta were lower in the joints of Crry-Tg mice.
- Crry transgene mRNA was detected in the synovium of Crry-Tg mice, and minimal C3 deposition was found in transgenic mice with CIA.
Conclusions:
- Suppression of CIA in Crry-Tg mice is likely due to enhanced local synthesis of Crry within the joint.
- Crry expression leads to decreased production of pro-inflammatory cytokines, contributing to reduced joint inflammation and damage.
- These findings highlight the therapeutic potential of targeting the complement system, specifically via Crry, in treating autoimmune arthritis.
