Article Figures & Data
Figures
- Figure 1.
Three pathways of complement activation. The classical pathway is triggered by IgG– and/or IgM–containing immune complexes. The alternative pathway is constantly initiated by spontaneous hydrolysis of C3 [C3b(H2O)] that is efficiently powered by the covalent attachment of C3b on an activating surface. The lectin pathway requires a particular sugar moiety pattern (N-acetylglucosamine [GlcNAc]) to be recognized and bound by MBL, leading to a classical pathway–like activation cascade. Each pathway leads to formation of a C3 convertase. The addition of C3b to the C3 convertase creates a C5 convertase that, in turn, triggers the assembly of the membrane attack complex (C5b-9), which is also known as the terminal pathway complete complex. Regulatory factors are in red. CR1, complement receptor 1; FD, factor D; MAC, membrane attack complex; MCP, membrane cofactor protein; P, properdin.
- Figure 2.
C3 proteolytic cascade. The hydrolysis of C3 leads to the release of activation products C3a, a potent anaphylatoxin, and C3b, which contains a highly reactive thioester bond that can covalently bind activating surfaces, such as a bacterial wall. This attachment of C3b initiates a powerful amplification system from the formation of the C3 convertase to the subsequent proteolysis of new molecules of C3, allowing more C3b to bind to the surface. This amplification is controlled by regulator molecules, such as FI, FH, and complement receptor 1 (CR1), that degrade C3b into products that cannot contribute to the formation of the C5 convertase. Detection of these inactive breakdown products (iC3b, C3c, C3dg, and C3d) is considered evidence of activation of C3. The numbers, in kilodaltons, represent the molecular masses of the corresponding polypeptides. MCP, membrane cofactor protein.
- Figure 3.
Comparison of the structures of FH, CFHR1, and CFHR3. The structure of FH contains 20 SCRs. SCR1–SCR4 possess the regulatory activity (FI cofactor activity and decay acceleration of the C3 convertase) as well as a weak C3b-binding capacity. SCR19 and SCR20 contain the most powerful C3b-binding zone that is critical for binding to cell surfaces. This latter area is the hotspot of aHUS-associated mutations, likely explained by the loss of ability of an abnormal FH to bind to endothelial cells. CFHR1 and CFHR3 resemble FH by the presence of structurally similar SCRs. These molecules possess the corresponding C3b/cell surface–binding zone (SCR4 and SCR5 corresponding to SCR19 and SCR20, respectively, of FH) but lack the regulatory portion (having no region equivalent to SCR1–SCR4). In contrast to FH and CFHR3, CFHR1 contains a unique pair of highly conserved SCR1 and SCR2 (also shared with CFHR2 and CFHR5). These domains enable formation of homo- and heterodimers involving CFHR1, CFHR2, and CFHR5.
- Figure 4.
Proposed mechanism to explain the protective effect of CFHR1,3 deletion on the development of IgAN. CFHR1 and CFHR3 proteins can bind to C3b in competition with FH. The regulatory activities of CFHR1 and CFHR3 are less efficient than those of FH. CFHR1,3 deletion, thus, allows FH to bind C3b effectively and thereby to strongly inhibit the initiation and amplification of the alternative pathway cascade.
- Figure 5.
Integrative view of the role of complement activation in the four-hit model of the pathogenesis of IgAN. C3 can be activated directly by IgA1–containing immune complexes formed from Gd-IgA1 and antiglycan antibodies7 and increase the pathogenic potential of these complexes. Other proteins can bind Gd-IgA1, such as the soluble form of Fcα receptor (sCD89), to generate complexes with Gd-IgA1. An association between the levels of sCD89-IgA complexes in serum and the severity of IgAN has been observed.104 Specifically, patients with IgAN without disease progression had high levels of sCD89 in contrast to low levels of sCD89 in the disease progression group, suggesting that sCD89-IgA complexes may be protective. In contrast, an animal model suggested that interaction between four entities—Gd-IgA1, sCD89, transferrin receptor, and transglutaminase 2 in mesangial cells—is needed for disease development.105 The lectin and alternative pathways can each contribute to the glomerular damage induced by immune complexes in the mesangium. Mesangial cells can also play an active role, arising from their capacity to be stimulated by C3a as well as produce C3 in response to an inflammatory stimulus.
In this issue
Jump to section
- Article
- Abstract
- Complement Pathways in IgAN
- Terminal Pathway Complement Complex
- Inherited Partial Deficiencies of Alternative Pathway Proteins
- Complement Factor H–Related Genes 1 and 3 Gene Deletion: A Role of Complement Factor H–Related Genes 1 and 3 Proteins in Regulation of Complement Activation
- Where Complement Is Activated: From Soluble Circulating Immune Complexes to Glomeruli
- Complement as a Biomarker
- Conclusion
- Disclosures
- Acknowledgments
- Footnotes
- References
- Figures & Data Supps
- Info & Metrics
- View PDF
More in this TOC Section
Up Front Matters
Cited By...
- GWAS-Based Discoveries in IgA Nephropathy, Membranous Nephropathy, and Steroid Sensitive Nephrotic Syndrome
- Plasma Galactose-Deficient IgA1 and C3 and CKD Progression in IgA Nephropathy
- Mesangial Deposition Can Strongly Involve Innate-Like IgA Molecules Lacking Affinity Maturation
- Sublytic C5b-9 Induces IL-23 and IL-36a Production by Glomerular Mesangial Cells via PCAF-Mediated KLF4 Acetylation in Rat Thy-1 Nephritis
- Deletion Variants of CFHR1 and CFHR3 Associate with Mesangial Immune Deposits but Not with Progression of IgA Nephropathy
- IgA Nephropathy
- All Things Complement
- Fine Mapping Implicates a Deletion of CFHR1 and CFHR3 in Protection from IgA Nephropathy in Han Chinese