IgG3 donor-specific antibodies with a proinflammatory glycosylation profile may be associated with the risk of antibody-mediated rejection after kidney transplantation.

The pathogenicity of de novo donor-specific antibodies (dnDSA) varies according to their characteristics. While their MFI, complement-fixing ability, and IgG3 subclass are associated with ABMR occurrence and graft loss, they are not fully predictive of outcomes. We investigated the role of the Fc glycosylation of IgG3 dnDSA in ABMR occurrence using mass spectrometry after isolation by single HLA antigen beads. Between 2014 and 2018, we enrolled 54 patients who developed dnDSA (ABMR- n = 24; ABMR+ n = 30) in two French transplant centers. Fucosylation, galactosylation, GlcNAc bisection, and sialylation of IgG3 dnDSA were compared between ABMR+ and ABMR- patients. IgG3 dnDSA from ABMR+ patients exhibited significantly lower sialylation (7.5% vs. 10.5%, p < .001) and higher GlcNAc bisection (20.6% vs. 17.4%, p = .008). Fucosylation and galactosylation were similar in both groups. DSA glycosylation was not correlated with DSA MFI. In a multivariate analysis, low IgG3 sialylation, high IgG3%, time from transplantation to kidney biopsy, and tacrolimus-free regimen were independent predictive factors of ABMR. We conclude that a proinflammatory glycosylation profile of IgG3 dnDSA is associated with a risk of ABMR occurrence. Further studies are needed to confirm the clinical interest of DSA glycosylation and to clarify its role in determining the risk of ABMR and graft survival.

Contactin-1 is a novel target antigen in membranous nephropathy associated with chronic inflammatory demyelinating polyneuropathy.

Primary membranous nephropathy (MN) is an autoimmune glomerular disease in which autoantibodies are directed against podocyte proteins. In about 80% of cases the main targeted antigen is the phospholipase A2 receptor 1 (PLA2R1). Anti-PLA2R1 antibodies are mainly immunoglobulin G type 4 (IgG4). However, the antigenic target remains to be defined in 20% of cases. MN can be associated with chronic inflammatory demyelinating polyneuropathy, an autoimmune disease of the peripheral nervous system where a common antigenic target has yet to be identified. To ascertain a possible novel target antigen, we analyzed kidney biopsies from five patients positive for anti-contactin 1 antibodies and presenting with MN combined with chronic inflammatory demyelinating polyneuropathy. Eluted IgG from biopsy sections against contactin 1 and nerve tissue were screened. Western blot revealed contactin 1 expression in normal kidney glomeruli. Confocal microscopic analysis showed the presence and colocalization of contactin 1 and IgG4 on the glomerular basement membrane of these patients. Glomerular contactin 1 was absent in patients with anti-PLA2R1-associated MN or membranous lupus nephritis or a healthy control. The eluted IgG from contactin 1-positive biopsy sections but not the IgG eluted from patients with PLA2R1 MN bound contactin 1 with the main eluted subclass IgG4. Eluted IgG could bind paranodal tissue (myelinated axon) and colocalized with commercial anti-contactin 1 antibody. Thus, contactin 1 is a novel common antigenic target in MN associated with chronic inflammatory demyelinating polyneuropathy. However, the precise pathophysiology remains to be elucidated.