Impact of IgA and IgG ACPA on the immune system and disease onset

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Anti-citrullinated protein antibodies (ACPA) are extremely specific for rheumatoid arthritis (RA) and represent a strong indicator for severe disease. Although the majority of ACPA is of the IgG isotype, in many patients, they are present in the form of IgA as well. Humans possess two IgA subclasses: IgA1 and IgA2. In the past funding period, we discovered that these two subclasses act differently on myeloid cells with IgA2 having a stronger capacity to induce neutrophil extracellular trap (NET) formation and proinflammatory cytokine release by neutrophils and macrophages (Steffen et al., Nature Communications 2020). We found that ACPA display a higher IgA2 percentage compared to total serum IgA. The IgA2 percentage in ACPA correlated with disease severity of RA patients with established disease (Steffen et al., Nature Communications 2020) and with the severity of relapse in RA patients in remission (Sokolova et al., submitted). In a model of submaximal collagen induced arthritis (CIA), co-immunization against citrullinated vimentin increased the incidence and disease severity, suggesting that ACPA directly contribute to the outbreak of arthritis. Interestingly, serum ACPA levels of both, IgA and IgG isotypes declined in pre-RA patients of two independent cohorts around disease onset. This may be a sign of increased transmigration of ACPA from the serum to affected tissue, such as the synovium. For the second funding period, we propose to further investigate the impact of IgA and IgG ACPA on the clinical onset of RA. We aim to investigate the effects of (auto)immunity against citrullinated proteins on the adaptive and innate immune system as well as synovitis employing the murine model of submaximal CIA. In addition, we will analyze spatial and temporal changes in the expression of ACPA antigens in the synovial tissue around the onset of arthritis. The results will be translated to patients with different stages of pre-RA and established RA.