Background/Purpose: Collagen Antibody Induced Arthritis (CAIA) is a mouse model of rheumatoid arthritis (RA). It is induced by injection of a cocktail of monoclonal antibodies (mAb) against collagen type II (CII) and a LPS boosting of the immune response day 5, which produces inflammation and swelling of the joints. Interestingly, in our studies aimed at characterizing pain-like behavior in the CAIA model we found that the mice displayed clear signs of nociception (pain) prior to injection of LPS and 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 if a low-grade inflammation drives CII antibody-induced nociception. 

Methods: Male B10.RIII mice were injected i.v. with either a mix of the four CII mAbs M2139, UL1, CIIC1 and CIIC2 (1 mg each, total 4 mg/mouse) or 4 mg of the respective single CII mAb and monitored for 5 days. Mice injected with M2139 (0.5-4 mg/mouse) were followed for 21 days. LPS was not injected to any of the mice. Joint inflammation and development of arthritis were examined by visual scoring of the paws (0-60), histological examination of the ankles and assessment of mRNA levels of RA and pain-associated genes in ankle joint extracts using quantitative PCR. Pain-like behavior was assessed by measuring evoked mechanical hypersensitivity using von Frey filaments and ongoing pain by the Comprehensive Lab Animal Monitoring System.

Results: No visual signs of inflammation were observed in any of the mice days 1-4 and day 5, 3 of 14 mice showed arthritis scores <10. Histologically no signs of cell infiltration, bone erosion or cartilage destruction were observed day 5, except for the mice with arthritis scores, which had minor cell infiltration and bone erosion in the ankle joints. In contrast, all mice injected with CII mAbs, but not control mAbs, displayed a significant reduction in mechanical thresholds day 2, which remained low throughout the study and a significant decrease in ambulation, rearing and total movement during the night between day 2-3. Even though the different CII mAbs have different pathogenicity, they induced similar decreases in mechanical thresholds. To further investigate the nociceptive properties of the J1 epitope-specific M2139 CII mAb, the dose-response relationship was investigated over 21 days. Even at doses (0.5 and 1 mg) that did not induce arthritis at any time point, significant mechanical pain hypersensitivity was observed from day 5 to 21. While IL-1b, TNF, COX2, and MMP2/9/13 mRNA levels were significantly increased in joint extracts from mice with CAIA-induced joint inflammation day 15, none of these mRNAs were elevated in the CAIA mice on day 5, compared to controls.

Conclusion: As no correlation between pathogenicity of the different CII mAbs, arthritis scores, histological changes or gene expression of inflammatory factors and nociception was found, our data indicate that pre-RA pain-like behavior induced by CII antibodies are not driven by a low-grade inflammation. Thus, the current work suggests that certain RA-associated antibodies have the capacity to evoke pain through mechanisms that are uncoupled from the inflammatory process.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/collagen-antibodies-induce-pain-like-behavior-in-mice-without-signs-of-inflammation/