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

Yen-Ling Chiu,Kai-Hsiang Shu,Wei-Chou Lin,Wen-Chih Chiang,Ching-Fang Wu,Yung-Ming Chen,Yi-Wen Fang,Ming-Shiou Wu,Fan-Chi Chang,Shuei-Liong Lin,Yu-Hsiang Chou

doi:10.3389/fimmu.2021.638309

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.

Highlights

IgA nephropathy (IgAN) is the most frequent primary glomerulonephritis worldwide [1] with highest incidence in eastern Asia [2] and is an important cause of end-stage renal disease [3]
We investigated the blood levels of alternative/ terminal complement factor B/C5a and tissue levels of factor Bb in IgAN patients
C5 is the key mediator that regulates the final common complement pathway, generating C5a, the end product of complement activation that can be detected in circulation

Summary

Introduction

IgA nephropathy (IgAN) is the most frequent primary glomerulonephritis worldwide [1] with highest incidence in eastern Asia [2] and is an important cause of end-stage renal disease [3]. The formation of immune complexes could activate the complement system which is composed of classic, alternative and lectin pathways. Researchers started to explore which complement pathway mediates the Gd-IgA1/anti-glycan immune complex induced glomerular damage in IgAN patients. Classical pathway is not considered to participate in this process, as C1q, a key indicator of classical pathway activation, was not usually found in glomerular specimens in IgAN patients [11]. There is only one study demonstrating properdin glomerular deposition in 30~90% IgAN patients which could indicate the activation of alternative pathway [14]. Galactose-deficient IgA1 (Gd-IgA1) and alternative complement pathway activation are considered to be involved in the pathogenesis of IgA nephropathy (IgAN). The relationships between alternative pathway activation and disease activity or Gd-IgA1 level remains unclear

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