Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose
The complement system is a major effector mechanism of innate and adaptive immunity. It is activated in rheumatoid arthritis (RA) patients but the pathway involved remains unclear. RA is associated with the production of autoantibodies with some of them, anti-citrullinated protein antibodies, representing a diagnosis and even a prognosis marker. Antibodies are known to activate the complement system via the classical pathway in a C1q-dependent manner. But some models suggest C1q-independent pathways in arthritis. Therefore, we have investigated whether C1q is necessary for disease development in a mouse model of RA based on (auto)immunization and we have analyzed C1q receptor expression in patients.
Methods
Disease development was studied in the collagen-induced arthritis (CIA) mouse model. The impact of C1q was evaluated by comparing wild-type (WT) mice and C1q-knockout (KO) true littermates. Arthritis was followed by clinical score evaluation. Inflammation and bone destruction were estimated by histology. Anti-collagen antibody, C3a and blood cytokine levels were measured by ELISA and Luminex. B/T lymphocytes and neutrophils were analyzed by flow cytometry. Osteoclastogenesis was analyzed by culturing bone marrow cells with M-CSF/RANKL and then counting TRAP-positive multinucleated cells by microscopy. In addition, whole blood cells from healthy donors and RA patients were used to estimate their C1q binding capacity ex vivo by flow cytometry.
Results
C1q is absolutely required for arthritis development as C1q-KO mice did not develop clinical signs of arthritis in contrast to WT mice. Both WT and KO mice developed anti-collagen antibodies and particularly similar levels of pathogenic IgG2a anti-collagen antibodies. Moreover, neither inflammation nor joint destruction was observed in C1q-KO mice. Importantly, the level of complement activation, estimated by C3a production, was similar in WT and C1q-KO mice. Surprisingly, no statistical difference was observed between WT and KO mice regarding the percentage or the activation of lymphocytes and neutrophils in the blood, spleen and lymph nodes. As a recent study suggested that C1q might influence osteoclastogenesis in vitro, we have shown that C1q deficiency does not alter development of osteoclasts from CIA mice. The impact of C1q on cytokine secretion in vivo is currently being analyzed. In RA patients, we have shown that the percentage of neutrophils able to bind C1q is significantly and positively correlated with the disease activity estimated by the DAS28.
Conclusion
C1q-KO mice are protected from arthritis development and thus C1q plays a key role in the CIA model. Although the complement system is activated, the classical pathway cannot be compensated by the alternative/lectin pathways in this model. Our results strongly differ from those reported in the serum-transfer model where C1q is not necessary for disease development, suggesting that C1q might be involved at different steps, maybe before antibodies are produced, for example in the response to DAMPs. In patients, the expression of total C1q receptors by neutrophils reflects disease activity, supporting the potential role of C1q in RA.
Disclosure:
M. Ribon,
None;
J. Mussard,
None;
R. Herve,
None;
M. Botto,
None;
M. C. Boissier,
None;
P. Decker,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/c1q-is-mandatory-for-disease-development-in-experimental-arthritis-and-expression-of-its-receptors-correlates-with-disease-activity-in-patients/