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ObjectiveAutoantibodies are detected in most patients with rheumatoid arthritis (RA) and can be of the IgM, IgG or IgA subclass. Correlations between IgA autoantibodies and more severe disease activity have been previously reported, but the functional role of IgA autoantibodies in the pathogenesis of RA is ill understood. In this study, we explored the effect of IgA immune complexes on osteoclast mediated bone resorption.MethodsAnti-citrullinated peptide antibody (ACPA) and anti-carbamylated protein (anti-CarP) antibody levels of the IgA and IgG isotype and rheumatoid factor (RF) IgA were determined in synovial fluid (SF) of RA patients. Monocytes, neutrophils, and osteoclasts were stimulated with precipitated immune complexes from SF of RA patients or IgA- and IgG-coated beads. Activation was determined by neutrophil extracellular trap (NET) release, cytokine secretion, and bone resorption.ResultsNET formation by neutrophils was enhanced by SF immune complexes compared to immune complexes from healthy or RA serum. Monocytes stimulated with isolated SF immune complexes released IL-6 and IL-8, which correlated with the levels of ACPA IgA levels in SF. Osteoclasts cultured in the presence of supernatant of IgA-activated monocytes resorbed significantly more bone compared to osteoclasts that were cultured in supernatant of IgG-activated monocytes (p=0.0233). Osteoclasts expressed the Fc receptor for IgA (FcαRI; CD89) and Fc gamma receptors. IgA-activated osteoclasts however produced significantly increased levels of IL-6 (p<0.0001) and IL-8 (p=0.0007) compared to IgG-activated osteoclasts. Both IL-6 (p=0.03) and IL-8 (p=0.0054) significantly enhanced bone resorption by osteoclasts.ConclusionIgA autoantibodies induce release of IL-6 and IL-8 by immune cells as well as osteoclasts, which enhances bone resorption by osteoclasts. We anticipate that this will result in more severe disease activity in RA patients. Targeting IgA-FcαRI interactions therefore represents a promising novel therapeutic strategy for RA patients with IgA autoantibodies.

In humans, IgA is expressed in three different forms: monomeric IgA, dimeric IgA (dIgA), and secretory IgA (SIgA). On the mucosal sites, mainly dIgA is produced by local plasma cells, which is composed of two IgA molecules that are connected tail-to-tail by a so-called J chain. Binding of dIgA to the polymeric Ig receptor (pIgR), present on epithelial cells on mucosal membranes, causes dIgA to be secreted in secretions such as mucus and breast milk. A portion of the pIgR, referred to as the secretory component (SC), remains attached to dIgA to form SIgA. In contrast to the mucosal sites, the blood circulation mainly contains monomeric IgA produced by plasma cells in the bone marrow, spleen and lymph nodes. In the circulation, IgA is the second most abundant antibody after IgG. Based on the characteristics of IgA on mucosal sites, IgA in circulation is thought to play mainly a passive and anti-inflammatory role in systemic immunity. However, elevated blood IgA levels or the presence of IgA autoantibodies have been detected in multiple diseases, including rheumatoid arthritis, IgA nephropathy, IgA vasculitis, dermatitis herpetiformis, celiac disease, inflammatory bowel disease, Sjögren's syndrome, ankylosing spondylitis, and alcoholic liver syndrome acquired immune cirrhosis. The exact contribution of IgA in the pathology of these diseases is insufficiently known to date. In this thesis, I investigated the development of IgA and its inflammatory potential after vaccination, during persistent infection and during autoimmunity or chronic inflammation in order to gain a better understanding of the role of IgA in health and disease. With this thesis, I refute the current belief that IgA is a redundant antibody in circulation. It is important to emphasize that the role of IgA in circulation has mainly been studied using different mouse models. Due to the lack of the IgA receptor, FcαRI, in mice, the inflammatory potential of IgA may have been overlooked and the results of these studies should be interpreted carefully. Using a human FcαRI/IgA transgenic mouse model, we demonstrated that FcαRI-mediated neutrophil activation by IgA exacerbates the pathology of DSS-induced intestinal inflammation. FcαRI-mediated cell activation may play an important role in defense against pathogens, however, the flip side of the coin is that abnormal or excessive IgA inflammatory responses can result in tissue damage and thereby contribute to the pathology of inflammatory diseases. On the one hand, increasing antigen-specific IgA levels in the circulation through vaccination may protect against infectious diseases. On the other hand, blocking the interaction between IgA and FcαRI through monoclonal antibodies or peptides can dampen inflammation and disease. It is therefore of great importance that future serological research on vaccination, infectious and inflammatory diseases also includes IgA- and FcαRI-mediated cell activation.