Background/Purpose: We have previously shown that autoantibodies targeting malondialdehyde-acetaldehyde protein adducts (anti-MAA) in rheumatoid arthritis (RA) patients boosted osteoclast differentiation and induced bone erosion in mice (1). Anti-MAA IgG levels are increased in certain autoimmune diseases suggesting a link between inflammation and MAA autoimmunity (2), however, the cause and consequence in this relationship have not been investigated. IgG anti-MAA responses could be triggered by the oxidative stress in an inflammatory milieu, but these antibodies might also be pathogenic mediators driving certain inflammatory processes. Here we studied the effects of IgG anti-MAA on inflammation and, more specifically, on macrophage functions.   

Methods: We measured serum anti-MAA IgG levels in individuals at risk of RA using ELISA, and analyzed a potential link to disease progression and to circulating inflammatory mediators, monitored by Olink Proximity Extension Assay. We tested the effects of patient-derived anti-MAA antibodies on macrophage gene expression and cytokine profile and on joint inflammation in mice.

Results: A set of circulating immune mediators, CCL19, sIL-15Rα, CD5, CXCL10 and TNFRSF9 correlated with anti-MAA levels in a period immediately preceding arthritis onset (6 month in median), whereas 15 (out of the detected 78) immune mediators correlated with anti-MAA at disease onset. A low number of transient associations have been observed in individuals not yet progressing to RA. In mechanistic experiments, we detected a profound reprogramming of gene expressions and the production of chemokines, such as CCL22 and CCL24 in anti-MAA exposed macrophages. Moreover, anti-MAA pretreatment promoted a more inflammatory cytokine profile upon TLR activation. Although anti-MAA are multi-reactive towards different MAA-modified proteins, we observed a prominent clonal diversity in inducing macrophage activation. Anti-MAA antibodies had no arthritogenic effect in mice but altered gene expressions in the joints following LPS stimulation, affecting a set of genes encoding cytokines and growth factors.

Conclusion: Certain IgG anti-MAA clones may thus contribute to an inflammatory priming of the joint, and potentially other tissues, prior to the onset of systemic inflammation. FcγR-mediated macrophage pre-activation could play an important role in this effect, by setting the stage for augmented responses to subsequent inflammatory stimuli. The clonal diversity in macrophage modulation suggests on the other hand a high level of patient-to-patient variability in the overall effects of the carried anti-MAA repertoire.

1. Sakuraba et al. J Autoimmun 2022
2. Grönwall et al. J Autoimmun 2017

« Back to ACR Convergence 2024

ACR Meeting Abstracts - https://acrabstracts.org/abstract/inflammatory-priming-by-anti-maa-antibodies-in-rheumatoid-arthritis/