Afucosylation of HLA-specific IgG1 as a potential predictor of antibody pathogenicity in kidney transplantation

Abstract

Antibody-mediated rejection (AMR) is the leading cause of graft failure. While donor-specific antibodies (DSA) are associated with a higher risk of AMR, not all patients with DSA develop rejection suggesting that the characteristics of alloantibodies that determine their pathogenicity remain undefined. Using human leukocyte antigen (HLA)-A2-specific antibodies as a model, we applied systems serology tools to investigate qualitative features of immunoglobulin G (IgG) alloantibodies including Fc-glycosylation patterns and FcγR binding properties. The levels of afucosylation of anti-A2 antibodies were elevated in all seropositive patients and were significantly higher in AMR patients, suggesting potential cytotoxicity via FcγRIII-mediated mechanisms. Afucosylation of both glycoengineered monoclonal and naturally glycovariant polyclonal serum IgG specific to HLA-A2 exhibited potentiated binding to, slower dissociation from, and enhanced signaling through FcγRIII, a receptor widely expressed on innate effector cells. Collectively, these results suggest that afucosylated DSA may be a biomarker of AMR and could contribute to its pathogenesis.

Afucosylated IgG responses in humans – structural clues to the regulation of humoral immunity

“…, 24. ] K ↑↑↑ High Unknown Associated with severe fetal anemia N/A [ 24 , 25 ] Transplantation HLA ↑↑↑ High Unknown Associated with antibody-mediated graft rejection N/A [ 20 ] Enveloped viruses HIV Envelope protein ↑ Low Stable for at least 3 years Feature of HIV elite controllers Unknown [ 26 , 27 ] Dengue virus Envelope protein ↑↑ Intermediate Unknown Associated with disease progression Unknown [ 28 ] Cytomegalovirus Antigen mixture ↑↑↑ High Stable for up to a decade Unknown Unknown [ 27 ] Hepatitis B virus HBsAg ↑ Intermediate Unknown Unknown Soluble HBsAg protein subunit vaccine induces fucosylated HBsAg-specific IgG, unlike natural infection [ 27 ] Measles virus (morbillivirus measles virus) Antigen mixture ↑ Low Stable for multiple decades Unknown Live attenuated viruses induce afucosylated antigen-specific IgG, similarly to natural infection [ 27 ] Mumps virus (mumps orthorubulavirus) Antigen mixture ↑↑ Low Stable for multiple decades Unknown Live attenuated viruses induce afucosylated antigen-specific IgG, similarly to natural infection [ 27 ...…”

“…] ( Figure 3 A, Key figure). Conversely, afucosylated IgG responses share a common feature in that the antigen is localized in the host cell membrane [ 14 , 18 , 20 , 22 , 26. , 27.…”

“…Based on the similarity of IgG-Fc fucosylation in these responses, we recently proposed that antigen recognition by B cells in the context of a host membrane activates a so far unknown receptor–ligand pairs which could be necessary for the induction of afucosylated IgG [ 27 ] ( Figure 3 ). However, although membrane sensing is simple and plausible ( Box 2 and see Figure I in Box 2 ), it is insufficient per se – as illustrated by the large interindividual and interantigen variation of IgG afucosylation, suggesting that more factors are involved [ 14 , 18 , 20 , 22 , 26. , 27.…”

“…(B) For alloantigens on platelets and red blood cells (RBCs) (not shown), and Plasmodium falciparum proteins expressed on infected RBCs, we propose that antigen recognition by the BCR is accompanied by a so far unknown receptor–ligand pair that provides a signal for 'self'. Signaling through these complexes is required for the induction of afucosylated IgG [ 14 , 18 , 20 , 22 ]. (C) Similarly, responses towards enveloped viral infections resemble responses described in (B) for alloantigens and P. falciparum proteins, as these antigens are also self-membrane-bound [ 27 ].…”

“…afucosylated IgGs in human immunity, and limiting the interest to mainly biotechnical and therapeutic exploitation of this phenomenon in cancer [12,13]. However, a growing body of evidence highlights that some antigen-specific IgG responses can be predominantly afucosylated, including responses to alloantigens, enveloped viruses, and Plasmodium falciparum proteins, which can be either beneficial or detrimental depending on the setting [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. In this article we focus on the biological and clinical significance of antibody glycosylation in humans, including fucosylation, that affect FcγR-mediated effector functions; we allude to a possible regulatory mechanism of afucosylated antibody responses by introducing a novel evolutionary hypothesis which might help to explain why self membrane-bound antigens are a necessity for afucosylated IgG responses to occur.…”