Abstract
Antibody-mediated rejection (ABMR) is now recognized as the leading cause of graft loss beyond the first year. De novo donor-specific anti-HLA antibodies (DSAdn) are the main risk factor for ABMR after kidney transplantation. However, the clinical course after the detection of a DSAdn is extremely heterogeneous, suggesting that not all DSA have the same pathogenicity. Several characteristics of DSAdn have been identified as being associated with a higher risk of ABMR or graft loss such as the “strength” of the antibodies (evaluated by the MFI in the Luminex Single Beads Antigen test), their ability to activate the classical complement pathway and the detection of IgG3 subclass. In this work, we studied the role of the DSA subclasses distribution and the DSA glycosylation profile in ABMR occurrence and graft outcomes. For this, we developed an innovative method for DSA characterization based on mass-spectrometry.In the first part of this work, we highlighted that the DSAs were always composed of the four IgG subclasses but with a variable distribution. The distribution of subclasses was specific to DSA with more IgG1, more IgG3, more IgG4 but less IgG2 compared to total IgG. A high proportion of IgG3 (> 6.4%) was significantly associated with ABMR occurrence and with ABMR severity (more complement deposition and more microvascular inflammation) and with the decline of the glomerular filtration rate, independently to other DSA characteristics, in particular the MFI value.In the second part of this work, we showed for the first time an association between the glycosylation profile of DSA and the risk of ABMR. DSA from ABMR+ patients exhibited a pro-inflammatory glycosylation profile, associating a lower galactosylation of IgG1, a lower sialylation of IgG3 and a higher proportion of bisecting GlcNAc. Hyposialylation of IgG3 appears to be a promising factor in the ABMR risk prediction. These results also potentially pave the way to new therapeutic strategies which are particularly expected, the effectiveness of current therapies often being disappointing.