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    • Sialylated IgG has been reported to

    2018-11-14

    Sialylated IgG has been reported to have anti-inflammatory properties likely mediated through interaction with the murine C-type lectin receptor SIGN-R1 (a homologue of the human DC-SIGN) and FcyRIIb (Kaneko et al., 2006; Collin and Ehlers, 2013). In our study, we found that total IgG preserved an anti-inflammatory glycosylation profile in patients who remained in remission, but changed to an inflammation-associated phenotype in relapsing patients. It remains unclear whether this change merely represent a bystander acute-phase reaction or whether the loss of anti-inflammatory ketotifen fumarate function of total IgG enabled PR3-ANCA to induce disease reactivation. Notably, low galactosylation and sialylation at the ANCA rise predicts disease reactivation, suggesting that the change of total IgG towards an inflammation-associated phenotype precedes the onset of disease reactivation. We hypothesize that these anti-inflammatory mechanisms of total IgG are involved in the suppression of active disease in our AAV patients who remain in remission. One may wonder what causes the change of the glycosylation profile of total IgG from an anti-inflammatory towards a pro-inflammatory phenotype. One study observed an average reduction of total IgG sialylation by 40% upon antigenic challenge in a mouse model (Kaneko et al., 2006). Based on our findings, we speculate that a second hit that is not related to the presence of PR3-ANCA nor the glycosylation profile of PR3-ANCA is required for a relapse after an ANCA rise (the “first hit”). Several candidates for such a second hit have been postulated, such as microorganisms (Popa et al., 2002), environmental factors (Gatenby et al., 2009; de Lind van Wijngaarden et al., 2008), and/or other auto-antibodies (Kain et al., 2012). No functional data are currently available regarding the role of the glycosylation profile of total IgG and/or antigen-specific IgG in the capacity of PR3-ANCA to induce inflammation and this should be further studied. A recent study reported a novel correlation between bisection of PR3-ANCA and disease state (Wuhrer et al., 2015b). In our study we find a correlation between bisection and relapse/remission. The level of bisection of total IgG decreases significantly in relapsing patients, while it stays stable in non-relapsing patients. In PR3-ANCA the level of bisection remains stable in relapsing patients, while it increases in non-relapsing patients. While the effect of a bisecting GlcNAc on IgG effector functions is minor compared to that of the other glycosylation features, it has been reported that bisection can enhance antibody-dependent cellular cytotoxicity (ADCC) through increased FcγRIIIa affinity (Davies et al., 2001; Shinkawa et al., 2003). Since a reduction in bisection is seen during AAV relapse, it is likely that the minor anti-inflammatory effect of decreased bisection is overshadowed by effects of other changes in glycosylation and that ADCC may only play a minor role in the pathogenesis of AAV (Mayet et al., 1994). A decrease in IgG bisection has not been reported for any other autoimmune disorders, while an increase in bisection has been observed for Lambert-Eaton Myasthenic Syndrome (LEMS) (Selman et al., 2011). A slight increase in fucosylation over time was seen in total IgG of relapsing patients. In contrast, PR3-ANCA showed a minor decrease in fucosylation for both relapsing and non-relapsing patients. While the absence of a core fucose can greatly enhance the inflammatory properties of IgG through increased FcγRIIIa affinity, the differences in fucosylation in our study cohort are likely too small to be of much influence. Our findings regarding the glycosylation profile of total IgG compared to antigen-specific PR3 markedly differ from those of a previous study, which reported a reduction of galactosylation, sialylation and bisection of PR3-ANCA as compared to total IgG, while we observe that bisection, but not galactosylation and sialylation is reduced in PR3-ANCA. These differences may be largely caused by the pronounced differences in study design (Wuhrer et al., 2015b). First, we included patients with severe AAV as well as patients with more limited forms of AAV, while the previous report only included patients with severe AAV (Wuhrer et al., 2015b). Second, our patients were in remission at the time of sampling, while the patients of Wuhrer et al. were sampled at the time of active disease (Wuhrer et al., 2015b). Interestingly, both studies observe a lower degree of bisection in PR3-ANCA compared to total IgG.