The complement system and glomerular kidney diseases: Etiopathogenesis, diagnostics and treatment
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The human immune system consists of the innate and the acquired immunity. The complement system is part of the innate immune response and it can be activated through one of the three pathways: the classical pathway, the alternative pathway and the lectin pathway. Complement activation forms the C3-convertase complex. The C3-convertase proteolytically cleaves the C3 component into C3a and C3b fragments. The C3b fragment binds to the C3-convertase to form the C5-convertase. The C5-convertase is an enzyme complex that cleaves the C5 component into C5a and C5b fragments. The C5b component binds to C6, C7, C8, C9 thus forming the terminal complex of the complement activation - the membrane attack complex (MAC) which is responsible for effector functions of the complement system. The serum complement is a mediator of C3 glomerulopathy (C3G), a group of diseases that includes membranoproliferative glomerulonephritis type II (MPGN II) or dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). These diseases are caused by a dysregulation of the alternative pathway of the complement activation system. The C3 nephritic factor (C3NeF) is an autoantibody to the alternative pathway C3-convertase, which can cause dysregulation of the pathway. Newly acquired knowledge has enabled therapeutic applications of a specific antibody to the C5 complement component (eculizumab). Eculizumab is a recombinant monoclonal antibody that exhibits high affinity for the complement component C5, with the aim to inhibit its cleavage and activation of the terminal complement pathway.Keywords:
C3-convertase
Complement component 2
Membranoproliferative glomerulonephritis
Complement factor B
Complement component 5
Complement component 3
Properdin
Lectin pathway
Complement C1q
Eculizumab
Anaphylatoxin
C3-convertase
Decay-accelerating factor
Complement component 2
Complement control protein
Complement
Complement factor B
Complement component 3
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Citations (313)
C3-convertase
Lectin pathway
Complement component 2
Zymogen
Complement control protein
Complement C1q
Complement factor B
Complement
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Citations (26)
Complement component 2
Paroxysmal nocturnal hemoglobinuria
Complement component 5
C3-convertase
Complement
Complement control protein
Complement component 3
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Citations (18)
The complement system is a tightly controlled proteolytic cascade in the innate immune system, which tags intruding pathogens and dying host cells for clearance. An essential protein in this process is complement component C3. Uncontrolled complement activation has been implicated in several human diseases and disorders and has spurred the development of therapeutic approaches that modulate the complement system. Here, using purified proteins and several biochemical assays and surface plasmon resonance, we report that our nanobody, hC3Nb2, inhibits C3 deposition by all complement pathways. We observe that the hC3Nb2 nanobody binds human native C3 and its degradation products with low nanomolar affinity and does not interfere with the endogenous regulation of C3b deposition mediated by Factors H and I. Using negative stain EM analysis and functional assays, we demonstrate that hC3Nb2 inhibits the substrate-convertase interaction by binding to the MG3 and MG4 domains of C3 and C3b. Furthermore, we notice that hC3Nb2 is cross-reactive and inhibits the lectin and alternative pathway in murine serum. We conclude that hC3Nb2 is a potent, general, and versatile inhibitor of the human and murine complement cascades. Its cross-reactivity suggests that this nanobody may be valuable for analysis of complement activation within animal models of both acute and chronic diseases.
C3-convertase
Complement control protein
Complement component 2
Complement component 3
Complement C1q
Complement factor B
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The cleavage of human complement component C5 to fragment C5b by the alternative pathway C5 convertase was studied. The alternative-pathway C5 convertase on zymosan can be represented by the empirical formula zymosan--C3b2BbP. Both properdin-stabilized C3 and C5 convertase activities decay with a half life of 34 min correlating with the loss of the Bb subunit. The C5 convertase functions in a stepwise fashion: first, C5 binds to C3b and this is followed by cleavage of C5 to C5b. The capacity to bind C3b is a stable feature of component C5, as C5b also has this binding capacity. Component C5, unlike component C3, does not form covalent bonds with zymosan after activation, and C5 is not inhibited by amines. Therefore C5, although similar in structure to C3, does not appear to contain the internal thioester group reported for C3 and C4.
C3-convertase
Properdin
Zymosan
Complement component 5
Cleavage (geology)
Complement component 2
Complement factor B
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Citations (40)
Complement C5 is a 189 kDa protein synthesized in liver as a single-chain precursor molecule. The precursor molecule is then cleaved to a disulfide linked two-chain glycoprotein consisting of a 115 kDa (C5α) and a 75 kDa N-terminal (C5β) chain. C5 is present in all the three known complement activation pathways: classical, alternative and lectin. C5α chain is cleaved by C5 convertases, which are formed during the complement activation process, to form C5a (74 a.a long) and C5α' chain (925 a.a long). C5α' chain and C5β chain (655 a.a. long) together form C5b. C5a is a major anaphylotoxin involved in chemotaxis of neutrophils and release of pro-inflammatory cytokines. These functions of C5a require binding to its receptor, C5aR. C5b sequentially recruits C6, C7, C8 and C9 in a non-enzymatic manner to form the terminal complement complex (TCC, also called membrane attack complex or MAC). TCC forms a lytic pore in the target membrane and kills the pathogen. While the functions of C5a and C5b aid in killing the pathogen, they can also be responsible for generating an excess inflammatory response, which can damage host cells. Therefore, C5 functions are tightly regulated by interaction with other proteins in host. The regulatory proteins can either be host generated or pathogenic factors. Unregulated C5 function can result in disease phenotypes. Therapeutic antibodies against C5 are being developed with a view to treat these conditions.
Complement component 5
Complement control protein
Complement component 2
C5a receptor
Complement C1q
Lectin pathway
Complement
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Complement factor H-related protein 1 (CFHR1) is a complement regulator which has been reported to regulate complement by blocking C5 convertase activity and interfering with C5b surface association. CFHR1 also competes with complement factor H (CFH) for binding to C3b, and may act as an antagonist of CFH-directed regulation on cell surfaces. We have employed site-directed mutagenesis in conjunction with ELISA-based and functional assays to isolate the binding interaction that CFHR1 undertakes with complement components C3b and C3d to a single shared interface. The C3b/C3d:CFHR1 interface is identical to that which occurs between the two C-terminal domains (SCR19-20) of CFH and C3b. Moreover, we have been able to corroborate that dimerization of CFHR1 is necessary for this molecule to bind effectively to C3b and C3d, or compete with CFH. Finally, we have established that CFHR1 competes with complement factor H-like protein 1 (CFHL-1) for binding to C3b. CFHL-1 is a CFH gene splice variant, which is almost identical to the N-terminal 7 domains of CFH (SCR1-7). CFHR1, therefore, not only competes with the C-terminus of CFH for binding to C3b, but also sterically blocks the interaction that the N-terminus of CFH undertakes with C3b, and which is required for CFH-regulation.
C3-convertase
Complement control protein
Complement component 2
Complement factor B
Decay-accelerating factor
Complement component 5
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Citations (25)
The human immune system consists of the innate and the acquired immunity. The complement system is part of the innate immune response and it can be activated through one of the three pathways: the classical pathway, the alternative pathway and the lectin pathway. Complement activation forms the C3-convertase complex. The C3-convertase proteolytically cleaves the C3 component into C3a and C3b fragments. The C3b fragment binds to the C3-convertase to form the C5-convertase. The C5-convertase is an enzyme complex that cleaves the C5 component into C5a and C5b fragments. The C5b component binds to C6, C7, C8, C9 thus forming the terminal complex of the complement activation - the membrane attack complex (MAC) which is responsible for effector functions of the complement system. The serum complement is a mediator of C3 glomerulopathy (C3G), a group of diseases that includes membranoproliferative glomerulonephritis type II (MPGN II) or dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). These diseases are caused by a dysregulation of the alternative pathway of the complement activation system. The C3 nephritic factor (C3NeF) is an autoantibody to the alternative pathway C3-convertase, which can cause dysregulation of the pathway. Newly acquired knowledge has enabled therapeutic applications of a specific antibody to the C5 complement component (eculizumab). Eculizumab is a recombinant monoclonal antibody that exhibits high affinity for the complement component C5, with the aim to inhibit its cleavage and activation of the terminal complement pathway.
C3-convertase
Complement component 2
Membranoproliferative glomerulonephritis
Complement factor B
Complement component 5
Complement component 3
Properdin
Lectin pathway
Complement C1q
Eculizumab
Anaphylatoxin
Cite
Citations (0)
Complement
Complement component 2
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Citations (69)
Complement
C3-convertase
Component (thermodynamics)
Complement component 2
Complement component 5
Complement component 3
Fragment (logic)
Complement control protein
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