Complement activation in IgA nephropathy

Abstract

IgA nephropathy pathogenesis is incompletely understood, and this limits the development of disease-specific biomarkers and effective therapies. Evidence of complement activity in IgA nephropathy is well established. However, a growing body of research indicates complement activity is an important contributor to IgA nephropathy pathology. In particular, multiple associations have been identified between complement alternative, lectin and terminal pathway proteins and IgA nephropathy severity. Recently, we have also gained insight into possible mechanisms that could link glomerular IgA deposition, complement activity, glomerular inflammation and disease severity. Ongoing clinical trials of therapeutic complement inhibitors will provide insight into the importance of complement activity to IgA nephropathy pathogenesis. Further research into mechanisms of complement activity is essential to improving our understanding and management of patients with IgA nephropathy.

Keywords: Complement; IgA nephropathy; Immunology; Pathology.

Fig. 1

Complement system. The complement system is activated through the classical, lectin or alternative pathway. The classical and lectin pathways are initiated by the recognition of non-host or damaged cell surfaces. The alternative pathway is constitutively and spontaneously activated by the hydrolysis of the C3 to expose the thioester domain and form C3(H₂O). After factor B (FB) has been activated to Bb by factor D (FD), Bb interacts with C3(H₂O) to form a C3 convertase (C3(H₂O)Bb). C3 convertases cleave C3 into the anaphylatoxin C3a and C3b. Through activation of C4 and C2 by the C1 complex or lectin pathway PRM-MASP complex, the classical and lectin pathways form the C3 convertase C4b2a. C3b deposited on surfaces can form additional C3 convertases, C3bBb, after binding activated FB, and this drives the C3 amplification loop. Binding of additional C3b molecules to existing C3 convertases leads to the formation of C5 convertases (C4b2aC3b, C3bBbC3b) that cleave C5 into C5a, a potent anaphylatoxin, and C5b. C5b binds to C6, C7, C8 and C9 and forms the membrane attack complex (C5b9), which causes target cell damage. Complement activation is tightly controlled by fluid-phase and membrane-bound regulators. Factor H (FH) is the major negative regulator of the alternative pathway and controls C3 activation. Other soluble regulatory proteins include C1-INH, C4-BP and factor I (FI). Nearly all cells express membrane-bound regulators including DAF (CD55), MCP (CD46, not present on erythrocytes), CR1 (CD35) and CD59. Properdin (P) stabilises the AP C3 convertase and is a positive regulator of the complement system. The factor H–related proteins 1 (FHR1) and 5 (FHR5) may impair complement activation by competing for C3b binding with FH

Fig. 2

Associations between complement proteins and polymorphisms and IgA nephropathy severity. Schematic summary of associations identified between complement proteins and polymorphisms and the severity of IgA nephropathy. Glomerular changes refer to associations identified from immunostaining analyses of pathology series, plasma changes refer to serology evidence of complement protein levels and genetic associations refer to the association between polymorphism alleles and IgAN disease severity. See main text for further details and references

Fig. 3

Representative images of kidney biopsy immunohistochemistry staining for complement pathway proteins in IgA nephropathy. Representative images from the diagnostic biopsy of one patient with progressive IgA nephropathy (IgAN) and one patient with stable IgAN. Progressive IgAN was defined as the occurrence of 40% loss of estimated glomerular filtration rate or end-stage kidney disease over 5 years from diagnosis. Images show immunohistochemistry staining using antibodies to complement (C)3b/iC3b/C3c, C3dg, C4d, C5b9 (the membrane attack complex), factor H (FH), factor H–related protein (FHR)1 and FHR5. All images are at 400 × magnification. Patients were enrolled in the Causes and Predictors of Outcome in IgA Nephropathy study (UK National Research Ethics Service Committee number 14/LO/0155), and the images are taken from research reported in [34]