Background/Purpose:

Collagen Antibody Induced Arthritis (CAIA) is an acute mouse model of rheumatoid arthritis (RA). It is induced by an intravenous injection of a cocktail of monoclonal antibodies (mAb) against collagen type II (CII), producing a transient inflammation that typically starts around day 6-9 and peaks around day 12-15. Interestingly, in our studies aimed at characterizing pain-like behavior in the CAIA model we found that the mice displayed clear signs of nociception prior to the onset of inflammation. Thus, the purpose of this study was to characterize the pre-RA phase from a pain perspective and to investigate what drives anti-CII antibody-induced nociception. 

Methods:

Male B10.RIII, B10.Q, and B10.Q C5^-/-mice were injected i.v. with 4 mg/mouse of anti-CII mAbs cocktail, isotype control IgG, CII Ab Fab fragments, EndoS-treated CII mAbs, or CIIF4 mAbs  and monitored for 5 days. Arthritis was examined by visual scoring of the paws (0-60), histological examination (H&E), and gene expression (qPCR) analysis of the ankle joints. MMP activity in the paws was visualized using MMPsense680. Pain-like behavior was monitored by measuring mechanical hypersensitivity with von Frey filaments day 0-5 and locomotion parameters by Comprehensive Lab Animal Monitoring System the night between days 2-3. Mice were injected subcutaneously (s.c.) with a peptide inhibitor (PMX53, 3 mg/kg/day) of the receptor for complement component 5a (C5aR). 

Results:

Over the 5 days after injection of anti-CII mAb cocktail, only minor visual signs of inflammation (score: <10) in 3 of 14 mice was observed.  Minor cell infiltration and bone erosion (in 2 and 1 mouse, respectively), while no cartilage destruction, change in mRNA expression (of examined cytokines, mast cell proteases, or MMPs), or MMP enzymatic activity was detected day 5. In contrast, all mice injected with CII mAbs, but not control mAbs, displayed a significant reduction in mechanical thresholds day 2, which remained low through day 5 and a significant decrease in ambulation, rearing, and total movement night 3. Mice lacking the C5 protein are resistant to CAIA. However, C5^-/-mice and mice treated with C5aR inhibitor still developed anti-CII mAb-induced mechanical hypersensitivity and reduction in locomotion. The CIIF4 mAb bind cartilage but protects against arthritis, when injected with the CAIA mAbs. Injection of CIIF4 alone induced mechanical hypersensitivity to a similar degree as the anti-CII mAb cocktail. Injection of anti-CII mAbs lacking the Fc-part or the glycan at Asp297 did not induce hypersensitivity or reduce locomotion. 

Conclusion:

No correlation between the arthritis scores, histological changes, gene expression of inflammatory factors, complement activation, and nociception (evoked or ongoing) was found. However, antibody treatment that diminishes the ability of the antibodies to associate with FcγRs prevented nociceptive behavior, indicating that antibody-Fc interaction is necessary for in vivo pain-behavior. Thus, our current work suggests that certain RA-associated antibodies have the capacity to evoke pain through mechanisms that are dependent on their binding to FcγRs but not by inducing inflammation.

« Back to 2015 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/collagen-antibodies-induce-pain-like-behavior-in-mice-independent-of-inflammation-and-complement-activation-but-requires-fci%c2%b3rs/