Targeted inhibition of the complement alternative pathway with complement receptor 2 and factor H attenuates collagen
Nirmal K Banda1, Brandt Levitt, Magdalena J Glogowska
1Division of Rheumatology, University of Colorado Denver, School of Medicine, Aurora, CO 80045, USA.
Abstract:
The alternative pathway (AP) of complement is required for the induction of collagen Ab-induced arthritis (CAIA) in mice. The objective of this study was to examine the effect of a recombinant AP inhibitor containing complement receptor 2 and factor H (CR2-fH) on CAIA in mice. CR2 binds to tissue-fixed activation fragments of C3, and the linked fH is a potent local inhibitor of the AP. CAIA was induced in C57BL/6 mice by i.p. injections of 4 mAb to type II collagen (CII) on day 0 and LPS on day 3. PBS or CR2-fH (250 or 500 microg) were injected i.p. 15 min after the mAb to CII on day 0 and 15 min after LPS on day 3; the mice were sacrificed on day 10. The disease activity score (DAS) was decreased significantly (p < 0.001) in both groups receiving CR2-fH compared with the PBS. Histology scores for inflammation, pannus, bone damage, and cartilage damage decreased in parallel with the DAS. C3 deposition in the synovium and cartilage was significantly reduced (p < 0.0001) in the mice treated with CR2-fH. In vitro studies with immune complexes containing type II collagen and mAb to CII showed that CR2-fH specifically inhibited the AP with minimal effect on the classical pathway (CP) and no effect on the lectin pathway (LP). The relative potency of CR2-fH in vitro was superior to mAbs to factor B and C5. Thus, CR2-fH specifically targets and inhibits the AP of complement in vitro and is effective in CAIA in vivo.
Insights
A novel recombinant inhibitor, CR2-fH, effectively reduced collagen-induced arthritis (CAIA) in mice by specifically targeting the alternative pathway (AP) of complement. This treatment significantly decreased disease activity and joint damage.
Area of Science:
- Immunology
- Rheumatology
- Complement System
Background:
- The alternative pathway (AP) of the complement system is crucial for initiating collagen antibody-induced arthritis (CAIA).
- Targeting the AP offers a potential therapeutic strategy for autoimmune diseases like CAIA.
Purpose of the Study:
- To evaluate the efficacy of a recombinant inhibitor, CR2-fH, which targets the AP, in a mouse model of CAIA.
- To investigate the specific inhibitory effects of CR2-fH on complement pathways in vitro and in vivo.
Main Methods:
- CAIA was induced in C57BL/6 mice using antibodies to type II collagen (CII) and lipopolysaccharide (LPS).
- Mice were treated with either PBS or CR2-fH (250 or 500 μg) after induction.
- Disease activity scores, histological damage (inflammation, pannus, bone, and cartilage), and C3 deposition were assessed.
Main Results:
- CR2-fH treatment significantly reduced disease activity scores (p < 0.001) and histological damage in arthritic mice.
- Significant reductions in C3 deposition within the synovium and cartilage were observed in CR2-fH treated mice (p < 0.0001).
- In vitro studies confirmed CR2-fH specifically inhibited the AP with minimal impact on the classical (CP) and lectin (LP) pathways, outperforming other AP inhibitors.
Conclusions:
- CR2-fH is a potent and specific inhibitor of the complement alternative pathway.
- CR2-fH demonstrates significant therapeutic efficacy in mitigating collagen antibody-induced arthritis in vivo.
- This study highlights CR2-fH as a promising therapeutic agent for complement-mediated autoimmune diseases.
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