The Contribution of Complement to the Pathogenesis of IgA Nephropathy: Are Complement-Targeted Therapies Moving from Rare Disorders to More Common Diseases?

Abstract

Primary IgA nephropathy (IgAN) is a leading cause of chronic kidney disease and kidney failure for which there is no disease-specific treatment. However, this could change, since novel therapeutic approaches are currently being assessed in clinical trials, including complement-targeting therapies. An improved understanding of the role of the lectin and the alternative pathway of complement in the pathophysiology of IgAN has led to the development of these treatment strategies. Recently, in a phase 2 trial, treatment with a blocking antibody against mannose-binding protein-associated serine protease 2 (MASP-2, a crucial enzyme of the lectin pathway) was suggested to have a potential benefit for IgAN. Now in a phase 3 study, this MASP-2 inhibitor for the treatment of IgAN could mark the start of a new era of complement therapeutics where common diseases can be treated with these drugs. The clinical development of complement inhibitors requires a better understanding by physicians of the biology of complement, the pathogenic role of complement in IgAN, and complement-targeted therapies. The purpose of this review is to provide an overview of the role of complement in IgAN, including the recent discovery of new mechanisms of complement activation and opportunities for complement inhibitors as the treatment of IgAN.

Keywords: complement; kidney; nephrology.

Figure 1

Overview of the complement system. Complement activation can be initiated via three different pathways: the classical pathway, the lectin pathway, and the alternative pathway. The classical pathway begins with the activation of C1, a complex composed of one C1q molecule (the pattern recognition molecule—dark green) as well as two C1r molecules and two C1s molecules (the serine proteases—light green). The lectin pathway begins via any of its pattern recognition molecules (dark green); that is, mannose-binding lectin (MBL), ficolins, or certain collectins, which work together with MBL-associated serine protease 1 (MASP-1) and 2 (MASP-2). Activation of either the classical or the lectin pathway leads to the cleavage of C4 and C2 and the formation of the C4bC2a complex, also known as the C3-convertase (gold). In the alternative pathway, activation occurs via the spontaneously thioester-hydrolyzed form of C3 (C3(H₂O)) or via surface interactions of properdin (the pattern recognition molecules—dark green), which acts with Factor B and Factor D (the serine proteases—light green) to form the C3-convertase C3bBb (gold). Overall, all three pathways lead to the formation of their respective C3-convertases (gold), which in turn cleave C3 into C3a (an anaphylatoxin—blue) and the opsonin C3b (yellow). MASP-2 has also been shown to directly cleave native C3, thereby bypassing C2 and C4 in the activation of the lectin pathway; this is also known as the C4/C2 bypass mechanism (grey). Recently, MASP-3 was revealed to cleave pro-Factor D into Factor D, establishing a novel link between the lectin and alternative pathway. Although MASP-3 is responsible for the main activation of pro-Factor D, there is also an unknown alternative pro-Factor D activator. Increasing densities of C3b through activation of C3 by the C3-convertases favors the formation of the C5-convertases (gold). In the classical and lectin pathways, C5-convertase is formed by a complex of C3b with C4b and C2a known as C4b2b3b. In the alternative pathway, an additional C3b binds to the C3 convertase (C3bBb) to form the C5-convertase C3bBb3b. Properdin is a key positive regulator of complement activity which acts by stabilizing alternative pathway C3- and C5-convertases. The C5-convertases (C4b2b3b and/or C3bBb3b, respectively) cleave C5 to generate the potent chemoattractant C5a (an anaphylatoxin—blue) and C5b (yellow), the initial component of the membrane attack complex. Next, C6, C7, C8, and C9 bind serially to surface-bound C5b to form the final complex, C5b-9 (yellow). Further interactions with additional C9 molecules, up to 17 molecules, widens the inner pore of the membrane attack complex. In addition, the anaphylatoxins C3a and C5a bind to their respective receptor (blue), C3a-receptor (C3aR), C5a receptor 1 (C5aR1), and C5a receptor 2 (C5aR2) on target cells to mediate a variety of inflammatory responses. In parallel to these activation pathways, complement regulation is established through membrane-bound and soluble complement inhibitors. In the classical and lectin pathway, C1-inhibitor (C1-INH) regulates the activity of the pattern recognition molecules and associated serine proteases, whereas C4b-binding protein (C4BP) inhibits activation at the C4 level. Factor I and Factor H act on C3- and C5-convertases. In addition, the membrane-bound inhibitors complement receptor 1 (CR1/CD35) and membrane cofactor protein (MCP/CD46) act as co-factors for Factor I, whereas decay-accelerating factor (DAF/CD55) accelerates the decay of C3-convertases. The membrane-bound regulator CD59, as well as soluble regulators clusterin and vitronectin, impair the formation of C5b-9. The Factor H protein family consists of Factor H, Factor H-like protein 1 (FHL-1), and five Factor H-related proteins (FHR). Factor H consists of 20 domains. The first four domains (white) provide the inhibitory function of the protein, while the internal region (black) and the last two units (black) are needed for binding to cells and tissue sites. FHL-1 is composed of the first 7 domains of Factor H, whereas the FHRs have structural homology to binding domains (black) of Factor H. The current belief is therefore that FHRs compete with Factor H (and FHL-1) for binding to certain surfaces. The binding of Factor H (and FHL-1) will lead to complement inhibition, whereas binding of the FHRs will further enhance complement activation.

Figure 2

The role of complement activation in IgA nephropathy. (A) In a healthy glomerulus, filtration of blood occurs, and intact podocytes prevent the loss of proteins. In IgA nephropathy (IgAN), deposition occurs of immune complexes containing polymeric galactose-deficient IgA1 in the glomerular mesangium. (B) This leads to immune activation and induces proliferation of mesangial cells, increases the synthesis of extracellular matrix, and causes glomerular basement membrane (GBM) thickening, podocyte injury and protein loss. (C) Polymeric IgA1 and IgA1-containing immune complexes can activate both the alternative and lectin pathway, leading to the cleavage of intact C3, thereby forming C3a and C3b. (D) Factor H is a key regulator of the complement system, and together with Factor I, Factor H cleaves C3b to iC3b. Lastly, the Factor H-related proteins can compete with the regulatory functions of Factor H, thereby promoting complement activation.