Innocent until proven guilty: IgA and inflammatory diseases

In chapter 2 literature on the contribution of RA to B lymphocyte differentiation towards the IgA isotype is summarized. We describe that CD103-expressing DCs are essential for metabolizing retinal into RA, upon which they can transfer it to B cells, throughout the GALT, and stimulate their isotype switch towards the IgA-isotype. Studies investigating the role of CD103-expressing DCs in RA metabolism and their role in B cell immunity have been primarily conducted using murine models, because studying the role of RA on human immunology is technically challenging as RA is difficult to visualize or quantify. To overcome this limitation, a chemical tool to study retinoid-derivatives in human immunology was developed and validated in chapter 3. Here, we confirm findings from murine studies and demonstrate that CD103+ DCs metabolize retinal into RA, triggering B lymphocyte differentiation in vitro. In chapter 4 the role of dextran sulfate sodium (DSS)-induced gut inflammation on the production of IgA antibodies in different secondary lymphoid tissues was studied. It was observed that the induction of gut inflammation resulted in elevated levels of IgA-expressing B lymphocytes in PPs and MLNs in a subset of mice. Yet, it remained unclear if IgA itself contributed to gut pathology and overall disease. This was studied in chapter 5 using again the same gut inflammation mouse model but in mice that allowed us to specifically address the role of IgA and its receptor. Mice produce IgA, but do not express a natural homologue of its receptor, FcαRI. Moreover, mouse IgA is unable to bind to human FcαRI. To overcome this limitation, I used a transgenic mouse model co-expressing human IgA (hIgA) and human FcαRI. It was observed that mice with hIgA have more severe gut inflammation in the presence of FcαRI-expressing myeloid cells, which was not observed in mice expressing only hIgA. This suggests that the interaction between IgA and FcαRI promotes myeloid-mediated disease pathogenesis when intestinal inflammation occurs. In chapter 6 it was studied whether FcαRI-stimulated myeloid cells in turn may influence B lymphocyte functionality, which may subsequently further enhance IgA production and disease pathogenesis. It was observed that FcαRI-stimulated monocytes produce chemokine CCL20 and recruit B lymphocytes, which was reflected in colon tissue of IBD patients as interaction between myeloid cells and B lymphocytes was observed. Moreover, FcαRI-stimulated monocytes produced cytokines, including interleukin-6 (IL6), interleukin-10 (IL10), tumour necrosis factor-α (TNF α) and a proliferating-inducing ligand (APRIL), that promote IgA differentiation of human naïve B lymphocytes. It is poorly understood whether IgA-FcαRI interactions can contribute to inflammatory disease pathology. This was further studied in the chapters 7 and 8. In chapter 7 it was studied whether IgAV patient-derived EACA deposits activate neutrophils, triggering pro-inflammatory responses and if this affects endothelial cell viability in vitro, to further elaborate on their possible role in disease pathology. Although levels of EACA were elevated in the IgAV patient cohort, I did not find an effect of these complexes on endothelial cell death, which may suggest that EACA do not induce FcαRI-mediated pathogenesis in IgAV. In chapter 8 the effect of anti-collagen 17 IgA autoantibodies on LABD pathology was investigated. Hereto anti-collagen 17 IgA autoantibodies were injected in the ears of hIgA and FcαRI-expressing transgenic mice, which resulted in neutrophil activation and extravasation from blood vessels into skin tissue at the injection site. Continued exposure to anti-collagen 17 IgA led to massive severe tissue damage and blister formation, which could be resolved when treated with FcαRI blocking antibodies. Thus, IgA contributes to pro- and anti-inflammatory immune functions, which greatly depends on location in the body and immune environment.