Relationship between immunoglobulin A1 lectin-binding specificities, mesangial C4d deposits and clinical phenotypes in immunoglobulin A nephropathy

Abstract

Background and objectives The reason why mesangial C4d deposits are detected in only certain biopsies of IgA nephropathy remains unclear. We analyse the association between IgA glycosylation patterns, mesangial C4 deposition and clinical phenotypes in IgA nephropathy. Design, setting, participants and measurements: This cross-sectional study included 145 patients with idiopathic IgA nephropathy. We measured the serum levels of three different IgA1 lectin-binding specificities, using enzyme-linked-immunosorbent assays with and without treatment with neuraminidase, and we analysed the relationship between these glycoforms, C4d mesangial deposits and clinical phenotypes. Results C4d-positive vs Cd4-negative patients had higher proteinuria (median: 3.1 g/g [0.9-4.2] vs. 1.8 g/g [1-2.2]; p = 0.000), hematuria (223 cel/µL [32-278] vs 99 cel/µL [25-186], p = 0.000), and higher levels of IgA binding to neuraminidase untreated Helix Aspersa (HA IgA1 neu-) (150.6 ± 52 U vs 96.2 ± 64.1 U, p = 0.000), neuraminidase untreated Helix Pomatia (HPA IgA1 neu-) (0.34 ± 0.15 vs 0.27 ± 0.13p = 0.04), Triticum vulgaris (TV IgA1) (85.1 ± 31.7 vs42.2 ± 26.9p = 0.000), and Canavalia ensiformis (ConA IgA1) (32.5 ± 18 U vs 16.7 ± 9.38 U, p = 0.000). The levels of HA IgA1 neu-, HPA IgA1 neu-, TV IgA1 and ConA IgA1 were all associated with the mesangial deposition of C4d, extracapillary proliferation and acute kidney injury. In ROC curves, HA IgA1 neu-, HPA IgA1 neu-, TV IgA1 and ConA IgA1 significantly discriminated between C4d positive ad C4d-negative biopsies. In logistic models, TVIgA1 and ConAIgA1 were the only independent predictors of mesangial C4d deposits. Conclusions In IgA nephropathy, the severity of the disease is associated with the level of IgA exposing N-Acetyl-D-Galactosamine, N-Acetyl-D-Glucosamine or mannose whereas C4d deposits are only associated with elevated levels of IgA1 glycoforms exhibiting glycan residues with specificity for mannose and N-Acetyl-D-Glucosamine binding lectins.

Systematic Review of the Link Between Oxford MEST-C Classification and Complement Activation in IgA Nephropathy

“…, 29 2023 C4d China Pediatric 65 IF NA NA NA NA Medrano et al. , 30 2022 C4d Spain Adult 34 IHC 34 46 85 (72–101) 2.9 (0.9–3.7) Wang et al. , 11 2022 C4d China Adult 34 urine, ELISA 34 56 33.4 (16.2–61.7) 3.5 (1.7–5.1) Itami et al.…”

“…, 29 2023 Associated with T1-2 and C1-2 classes a Medrano et al. , 30 2022 Lectin pathway Higher levels in patients with M1, E1, T1-2, C1-2 classes c Wang et al. , 11 2022 No relationship with MEST-C classes a Itami et al.…”

Phosphatase control of cytokine-mediated overproduction of galactose-deficient IgA1, the main autoantigen in IgA nephropathy

“…However, the origins and mechanisms that mediate the overproduction of Gd-IgA1 during states of disease activity are poorly understood. The correlation between autoantigen production and inflammation can be seen in IgAN patients who present with synpharyngitic hematuria with concurrent elevated levels of Gd-IgA1 and its circulating immune complexes [ 22 , 27 ]. Furthermore, GWAS have supported this connection with inflammation, based on discovery of IgAN-risk-associated genetic alleles, i.e., SNPs, such as those in HORMAD2 locus with genes encoding also LIF and OSM (oncostatin M) [ 28 ].…”

“…It is well accepted that IgA1-secreting cells in vivo are exposed to cytokine mixtures and, usually, not to a single cytokine. The in vivo conditions that lead to elevated serum levels of Gd-IgA1 are unknown, but can be associated with mucosal infections, as IgAN patients often present with synpharyngitic hematuria [ 11 , 22 ]. This suggests that a cytokine milieu may promote Gd-IgA1 production, leading to formation of new immune complexes that may deposit in the glomeruli and further enhance kidney injury.…”

Advances in IgA glycosylation and its correlation with diseases

“…In IgAN patients, Gd-IgA1 mainly exists in the polymeric or immune complex status. This kind of IgA1 can recognize MBL and activate the complement system, resulting in the deposition of component C4 in the mesangial membrane ( Medrano et al, 2022 ). Meanwhile, the anti-Gd-IgA1 IgG in the immune complex will further activate the C3 component in the complement system ( Chen et al, 2019 ).…”