Alternative Complement Pathway Is Activated and Associated with Galactose-Deficient IgA1 Antibody in IgA Nephropathy Patients

Abstract

BackgroundGalactose-deficient IgA1 (Gd-IgA1) and alternative complement pathway activation are considered to be involved in the pathogenesis of IgA nephropathy (IgAN). Nevertheless, the relationships between alternative pathway activation and disease activity or Gd-IgA1 level remains unclear.MethodsNinety-eight biopsy-diagnosed IgAN, twenty-five primary focal segmental sclerosis (FSGS) patients and forty-two healthy individuals were recruited in this study. Among them, fifty IgAN patients received immunosuppression. Follow-up blood samples at 1 and 3~6 months after immunosuppression were collected. Plasma levels of complement C5a, factor Ba and Gd-IgA1 were measured and analyzed. Immunostaining for complement was performed in twenty-five IgAN and FSGS patients.ResultsAt baseline, IgAN patients had higher levels of plasma C5a, factor Ba and Gd-IgA1 than control subjects. Gd-IgA1 levels positively correlated with plasma C5a and factor Ba. In addition, levels of factor Ba and Gd-IgA1 were positively associated with proteinuria and negatively associated with renal function. Immunostaining revealed positive staining for factor Bb and C3c in glomeruli in IgAN patients, but not in FSGS patients. At baseline, patients receiving immunosuppression had more severe proteinuria and higher factor Ba. After 6 months, eGFR declined and proteinuria persisted in patients without immunosuppression. In contrast, patients who received immunosuppression exhibited decreased plasma levels of C5a, factor Ba, and Gd-IgA1 as early as 1 month after treatment. Proteinuria decreased and renal function also remained stable 6 months after immunosuppression.ConclusionsOur results indicate a close relationship between alternative complement pathway activation, Gd-IgA1 concentration and clinical severity of IgAN. Level of complement factor B may be a potential marker for disease activity and therapeutic target in IgAN patients.

Associations between Biomarkers of Complement Activation, Galactose-Deficient IgA1 Antibody and the Updated Oxford Pathology Classification of IgA Nephropathy

“…These results suggested that renal function and the UPCR level were associated with the plasma levels of Gd-IgA1 and factor Ba but not with C5a. In summary, these findings were consistent with our prior study [ 17 ].…”

“…The discrepancy in the relationship between the Gd-IgA1 level and disease activity may be related to the baseline disease severity of the enrolled IgAN patients. Gd-IgA1 levels may have a stronger clinical impact in moderate to severe IgAN patients than in patients with mild disease activity [ 17 ]. In this current study, not only was the Gd-IgA1 level positively correlated with disease activity, but the alternative complement of the plasma factor Ba level was also correlated with clinical parameters.…”

“…Patients aged between 20~80 years old with the pathologic diagnosis of IgAN were enrolled in this study at the time of renal biopsy between January 2015 and December 2019, as described previously [ 17 ]. For the purpose of this study, we only selected patients with renal biopsy reports which were scored according to the updated Oxford classification of IgAN.…”

“…Until recently, few studies have examined the complement factor Ba and C5a levels in IgAN patients. Our prior study [ 17 ] disclosed the close relationship between complement pathway activation (based on levels of Ba and C5a), Gd-IgA1 concentration and clinical severity of IgAN.…”

Advances in IgA glycosylation and its correlation with diseases

“…It is generally believed that IgA cannot activate the complement system through the classical pathway, however, in some cases, it can activate the complement system through the alternative pathway or lectin pathway ( Medjeral-Thomas et al, 2021 ). It was reported that the overexpressed galactose-deficient IgA1 (Gd-IgA1) can bind to mannose-binding lectin (MBL) in patients with IgA nephropathy (IgAN) ( Chiu et al, 2021 ). After treatment with galactosidase, the binding abilities of monovalent and multivalent IgA1 and IgA2 to MBL can be improved by more than 10-fold.…”