All Things Complement

Abstract

The complement (C) cascade is an ancient system of proteins whose primary role is to initiate and modulate immune responses. During C activation, circulating proteins are cleaved and nascent cleavage fragments participate in a broad range of downstream innate and adaptive immune functions. Although the majority of these functions are either homeostatic or protective, a large body of experimental and clinical evidence also highlights a central role for the C system in the pathogenesis of many types of glomerular disease. From classic pathway activation in lupus nephritis to alternative pathway dysregulation in C3 glomerulopathy, our understanding of the spectrum of C involvement in kidney disease has expanded greatly in recent years. However, the characteristics that make the glomerulus so uniquely susceptible to C-mediated injury are not fully understood, and this remains an area of ongoing investigation. Several C inhibitors have been approved for clinical use, and additional C inhibitory drugs are in development. The use of these drugs in patients with kidney disease will expand our understanding of the benefits and limitations of C inhibition.

Keywords: Complement Activation; Complement Inactivating Agents; Complement System Proteins; Humans; Kidney Diseases; Kidney Glomerulus; clinical immunology; complement; glomerular disease; glomerulonephritis; immune complexes; lupus nephritis.

Figure 1.

Overview of the C cascade. The C cascade can be activated through the classic pathway, the alternative pathway, and the mannose binding lectin pathway. Activation through each of these pathways generates C3-convertases (shown in blue font), enzyme complexes that cleave C3 and generate C3b. Further amplification of C activation through the alternative pathway generates additional C3b. C3b combines with the C3-convertases to create C5-convertases (shown in green font), enzyme complexes that cleave C5. Full activation of the C cascade generates several proinflammatory fragments: C3a, C3b, C5a, and C5b-9 (shown in red font). Although the C system is activated in most forms of glomerular disease, the mechanisms of activation and the pathways involved are distinct. Some of the diseases in which each pathway is involved are listed.

Figure 2.

Fate C3 and C4 fragments on cell surfaces. The cleavage of C3 and C4 allows the covalent attachment to cell and tissue surfaces of C3b and C4b, respectively. Deposited C3b composes part of the alternative pathway C3-convertase. This complex is stabilized by properdin and generates additional C3b unless the convertase decays or C3b is inactivated (cleaved) by the plasma protease factor I, generating iC3b. The decay of the convertase is accelerated by some regulatory proteins (not shown in this figure). To inactivate C3b, factor I requires cofactor proteins. Membrane cofactor protein and C receptor-1 (CR1) are cell surface cofactors, and factor H is a soluble cofactor. CR1 also serves as a cofactor for cleavage of iC3b to C3dg. Deposited C4b composes part of the classic pathway C3-convertase and generates C3b unless the convertase decays or C4b is inactivated (cleaved) by factor I. Membrane cofactor protein and CR1 are cell surface cofactors for the cleavage of C4b, and C4 binding protein (C4bp) is a soluble cofactor for this process.

Figure 3.

Conditions within the kidney that are conducive to C activation. The C cascade is activated by distinct mechanisms at various ultrastructural locations within the kidney. Immune-complexes can deposit in the mesangium and at different locations within the glomerular capillary wall. In some diseases, autoantibodies bind to specific renal antigens. Other conditions in the kidney that favor C activation are increased concentrations of C proteins in the efferent vessels, low pH, increased local concentrations of C proteins due to production by tubular epithelial cells, and high concentrations of ammonia which can activate the alternative pathway. The glomerular basement membrane does not express C regulatory proteins, although factor H controls alternative pathway activation on the glomerular basement membrane. The apical surface of tubular epithelial cells also does not express C regulatory proteins, and alternative pathway proteins may be activated at this location in proteinuric conditions. EC, endothelial cell; PO, podocyte; fB, factor B; fD, factor D.

Figure 4.

Molecular defects in C regulation associated with C3 glomerulopathy and atypical hemolytic uremic syndrome. In health, factor H controls C activation in the fluid phase and on the glomerular basement membrane. Factor H and cell surface C regulatory proteins (MCP, membrane cofactor protein; DAF, decay accelerating factor; THBD, thrombomodulin) control C activation on glomerular endothelial cells. In patients with C3 glomerulopathy, congenital or acquired defects probably cause dysregulated C activation in the fluid phase and/or on the glomerular basement membrane. In atypical hemolytic uremic syndrome, congenital or acquired defects probably cause dysregulated C activation on glomerular endothelial cells. Defects in C regulation in the different conditions are indicated with red boxes or red font.