Background/Purpose: We have previously shown that certain malondialdehyde/acetaldehyde modified protein binding autoantibodies (anti-MAA), obtained from the inflamed joints of rheumatoid arthritis (RA) patients, induced osteoclast differentiation in vitro and bone loss in vivo via an FcγR-mediated mechanism (1). In the present work we studied the effect of these antibodies on joint inflammation and, more specifically, on the function of macrophages.

Methods: We analysed global gene expression, by RNAseq, in the ankle joints of mice injected with patient-derived anti-MAA monoclonal antibodies, in the presence or absence of intraperitoneally injected LPS, which mimicked systemic inflammation. We have also analysed gene expression changes and cytokine production in anti-MAA treated macrophage cultures.

Results: Intravenous injection of anti-MAA antibodies led to subtle changes in the gene expression of the joints, with altered expression of several genes involved in immune responses and cell signalling. Intraperitoneally injected LPS induced robust gene expression changes in the ankles, with several cytokine and other immune mediators expressed at slightly higher level in the anti-MAA pretreated group. Anti-MAA pretreatment could also induce a more inflammatory macrophage phenotype in vitro, in response to a subsequent LPS activation. Similarly to the previously described osteoclast stimulatory effect, the inflammatory priming of macrophages was induced by several but not all of the tested anti-MAA monoclonal antibodies, and the effect was mediated via FcγR-transmitted signals.

Conclusion: Class-switched anti-MAA autoantibodies are typically associated with high disease activity in RA, but such antibodies have also been detected in some of the healthy donors and in individuals at risk of RA (2 and our unpublished data). Our results indicated that certain anti-MAA IgG autoantibody clones may contribute to an inflammatory priming of the joint tissues prior to the onset of systemic inflammation. FcγR-mediated pre-activation of macrophages could play an important role in this effect, by setting the stage for augmented responses to subsequent inflammatory stimuli.

1. Sakuraba et al. J Autoimmun 2022
2. Grönwall et al. Front Immunol 2021

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inflammatory-priming-of-the-joints-via-pre-activation-of-macrophages-by-anti-maa-antibodies-in-rheumatoid-arthritis/