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Complement system for diseases

发布时间:2017-04-07
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How is complement activated in the glomerulus during glomerulonephritis, and to what extent does this activation account for progression of this group of disease? The complement system is a biochemical cascade that plays a central role in anti-microbial defence, and the clearance of immune complexes and apoptotic cells. The complement system consists of a number of plasma- and membrane-bound proteins, which protects against immune-mediated tissue damage in a number of settings. The role of complement is not exclusive to the innate immune system but includes important functions in the regulation of the adaptive immune system. However, complement undoubtedly contributes to tissue damage in many forms of glomerulonephritis (Berger and Daha, 2007). Antigen-associated antibody deposits in the glomerulus either at sub-endothelial and mesangial sites, or at sub-epithelial sites induces complement activation cascade. Sub-epithelial antibody-induced complement deposition plays an important role in the pathogenesis of membranous nephropathy (MN), whereas antibody-induced complement deposits at sub-endothelial and mesangial sites mediate mesangial proliferative glomerulonephritis such as IgA nephropathy (Couser, 1998).

The complement activation cascade consists of three different pathways: the classical pathway, the lectin pathway and the alternative pathway. The three pathways all converge in the activation of the central complement molecule C3 (Fig. 1).

Berger, S.P. & Daha, M.R. (2007) Complement in glomerular injury. Semin Immunopathol 29: 375-384.

The classical pathway of complement activation is triggered by activation of the C1 complex (C1q, two molecules of C1r and two molecules of C1s), which occurs at least when two binding sites of C1q molecule binds to Fc fragments of IgG or IgM complexed with membrane bound antigen. Acute phase proteins such C-reactive protein (CRP) or dead cells leads to conformational changes in C1q, which leads to the activation of the associated serine proteases C1r and C1s. Activated C1s cleave C4 into C4a and C4b, and C4b covalently binds to C1qC1r2C1s2 structure. The C1 complex-bound C4b then cleaves C2 into C2a and C2b, resulting in the formation of the C4bC2a complex, which is also known as the classical pathway C3 convertase.

The mannose-binding lectin pathway is homologous to the classical pathway and uses the same C3 convertase (C4bC2a). The lectin pathway initiator molecules mannose-binding lectin (MBL) and ficolins recognise carbohydrate moieties present on a wide range of pathogens. The binding of MBL to its ligand leads to the activation of the MBL-associated serine proteases (MASP-1, MASP-2 and MASP-3). MASP-2 then cleaves C4 and subsequently C2 resulting in the formation of the C3 convertase, C4bC2a as in the classical pathway (Fig. 1).

The alternative pathway of complement is triggered by spontaneous hydrolysis of the internal thioester bond of the C3 molecule, resulting in the formation of the C3b-like molecule C3(H20). C3(H20) then binds to factor B, and makes factor B susceptible to cleavage by factor D leading to the release of the Ba fragment and the formation of the C3 convertase C3(H20)Bb. C3(H20)Bb constantly cleaves C3 at low rate yielding C3b, and this constant low rate production of C3b is referred to as the 'tick over' of the alternative complement pathway. The generated C3b then interacts with factor B to form the more active C3 convertase C3bBb, which is the alternative pathway C3 convertase (Berger and Daha, 2007). An important positive regulator of the alternative pathway called properdin interacts with the unstable C3 convertase, to stabilise and promote the assembly of a complement-activating lattice by further binding factor B and C3b molecules (Hourcade, 2006).

All three pathways of complement activation converge in a common terminal pathway starting with the generation of the C3 convertase. This C3 convertase promotes the cleavage of C3 into C3a and C3b. After hydrolysis of C3, C3b molecule interacts with the C3 convertase complex to form C4bC2aC3b in the case of both the classical and lectin pathways, and to the formation of C3bBbC3b in the case of the alternative pathway. Both C4bC2aC3b and C3bBbC3b complexes are also known as C5 convertase (Fig. 1). These C5 convertases then cleaves C5 into C5a and C5b molecules. The generated C5a can then function as a potent anaphylatoxin. C5b then initiate the assembly of the membrane attack complex also known as MAC, by binding C6 and C7. After insertion of C5bC6C7 complex (an amphiphilic molecule) into the cell membrane, this complex binds C8 and polymeric C9 molecules, resulting in the formation of the pore-forming membrane attack complex (C5b-9), a macromolecular complex. This MAC complex can initiate cell lysis, and in sublytic quantities can lead to cell (glomerular cell) activation (Berger and Daha, 2007).

The activation of the complement system: in situ immune complex formation of membrane attack complex (C5b-9), liberation of anaphylatoxins C3a and C5a at sub-endothelial and mesangial sites, or at sub-epithelial sites of the glomerulus, and defective complement regulatory proteins (such as factor I and membrane co-factor protein) have been shown to play important roles in the pathogenesis of glomerular diseases such as membranous nephropathy (Heymann nephritis rat model) and mesangial proliferative glomerulonephritis (IgA nephropathy) (Berger and Daha, 2007; Nangaku et al., 2005). Baker et al. (1989) and Cybulsky et al. (1986) used animals that were selectively depleted of C6 to demonstrate the role of C5b-9 in the development of podocyte injury and proteinuria in the passive Heymann nephritis model of MN. In addition, immunofluorescence studies of MN showed the presence of immunoglobulin and complement components C3 and C5b-9 in the glomerular deposits (Nangaku et al., 2005). Furthermore, Nankagu et al, (1996) demonstrated the functional significance of these regulatory proteins in complement-mediated glomerular disease. The role of complement in these diseases will be discussed in more detail below.

Firstly, sub-epithelial complement fixing antibody and C5b-9 deposition as found in membranous nephropathy (MN) leads to a non-inflammatory complement-induced damage because the anaphylatoxins C3a and C5a generated during the local activation, and immunoglobulin derived chemotactic proteins are not interactive with the circulating inflammatory cells such as leukocytes (Couser, 1998). The sub-epithelial deposited complement components including C3 and C5b-9 mediate glomerular injury in MN by damaging or activating podocytes (glomerular epithelial cells). Podocytes are highly specialised and terminally differentiated cells located on the outside of the glomerular basement membrane (GBM) facing into the Bowman's space. They have a wide range of functions including maintenance of the glomerular barrier to protein filtration, and synthesis and secretion of normal GBM (Nangaku et al., 2005). C5b-9 formation on the membrane of podocytes acts as a potent stimulus to production of reactive oxygen species (oxidants), proteases, prostaglandins and transforming growth factor-b (TGF-b). Several studies including Neale et al. (1993) have shown that production of oxidants by podocytes, which may be mediated by upregulation of NADPH-oxidase derived by release of arachidonic acids, can initiate lipid peroxidation and degradation of GBM collagen IV, leading to development of protein leakage into the Bowman's space (Fig. 2). In vitro studies document that sublytic C5b-9 stimulates podocytes to produce proteases such as metalloproteinase (MMP9), which also leads to GBM disruption (McMillan et al., 1996). In addition to the role of podocyte-derived proteases and oxidants in causing an increase in GBM permeability in MN, it has also been shown that there is a marked increase in expression of the TGF-b2 isoform in podocytes as well as upregulation of TGF-b receptors on the podocytes. This complement-dependent increase mediates overproduction of extracellular matrix components, which leads to characteristic thickening of the basement membranes with spike-like extensions of matrix between interdigitating pedicels. Other TGF-b effects on podocytes with regards to MN include effects on cell cycle regulatory proteins. TGF-b blocks G1/S transition by inhibiting phosphorylation of retinoblastoma protein (pRb) possibly through cyclin-kinase inhibitor- (p27 or p21) dependent route, and this is associated with a decrease in cyclin E-CDK2 activity, eventually leading to glomerular hypertrophy, lack of proliferation and podocyte loss in MN (Shankland et al., 1996; Shankland et al., 1997).

Nangaku, M. Shankland, S.J & Couser, W.G. (2005) Cellular Response to Injury in Membranous Nephropathy. J Am Soc Nephrol 16: 1195-1204.

Furthermore, complement C5b-9 membrane attack complex upregulates cyclooxygenase-2 (COX-2) production and activates phospholipase A2, which induces phospholipid hydrolysis in glomerular epithelial cells (GEC), resulting in increased expression of endoplasmic reticulum stress proteins and subsequently leads to impairment of endoplasmic reticulum membrane integrity and endoplasmic reticulum stress (Cybulsky et al., 2002). In support of the functional significance of these findings, Takano et al. (2003) demonstrated that inhibition of COX-2 reduced complement-mediated podocyte injury and proteinuria in Heymann nephritis rats. Mechanical stress encountered by podocytes also leads to abnormal distribution of slit diaphragm proteins. Nephrin is a key component of the slit diaphragm, with a crucial function in maintaining the glomerular barrier to protein filtration. Nephrin is linked to the actin microfilaments through CD2AP. C5b-9 formation leads to cytoskeletal reorganisation of GEC resulting in the dissociation of nephrin from the actin cytoskeleton and subsequent development of proteinuria (Fig.2) (Saran et al., 2003).

The effects of C5b-9 formation on podocytes trigger the release of oxidants, proteases and chemokines, and various intracellular events such as endoplasmic reticulum stress and cytoskeletal changes (discussed above), which all lead to loss of podocytes through induction of apoptosis, detachment of cells from the underlying GBM and lack of proliferation (Fig. 3) (Nangaku et al., 2005). In support of these findings, Petermann et al. (2003) showed that podocyte number is reduced in experimental MN, and also demonstrated the presence of podocytes in urine of patients and experimental animals with glomerular injury, which is due to detachment of podocytes as a result of GBM degradation by proteases produced by podocytes. In addition, Shankland et al. (1997) demonstrated the involvement of apoptosis and lack of cell proliferation in the failure of podocytes to proliferate in MN. All the cellular events induced after the formation of C5b-9 attack complex on the membrane of podocytes in MN, contribute to both proteinuria and development of glomerulosclerosis.

Nangaku, M. Shankland, S.J & Couser, W.G. (2005) Cellular Response to Injury in Membranous Nephropathy. J Am Soc Nephrol 16: 1195-1204.

Lastly, the pathogenesis of mesangial proliferative glomerulosclerosis involves the formation of sub-endothelial or mesangial immune complex deposits that mediate glomerular injury by inflammatory-associated response via complement-dependent processes. Immunoglobulin IgA can activate complement by the alternative pathway (Couser, 1998). A plethora of recent studies have also documented the role of the lectin pathway of complement activation, and co-deposition of IgA and MBL in IgA nephropathy (Matsuda et al., 1998). Complements (C3a and C5a anaphylatoxins) and C5b-9 deposition on sub-endothelial surface of the glomerular capillary wall or mesangial sites easily come into contact with circulating inflammatory cells accounting for the inflammatory nature of the lesion (Couser, 1998). In vitro studies document that C5b-9 is a potent stimulus to mesangial cell production of several metabolites including leukotrienes, extracellular matrix components, oxidants and proteases, and prostaglandins as has been established with podocytes (Hansch et al., 1992). These pro-inflammatory materials mediate capillary wall and mesangial cell injury (mesangiolysis). In addition, the anaphylatoxins C3a and C5a generated during the local activation acts as potent chemoattractants for the infiltration of circulating cells such as neutrophils, monocytes and platelets to sites of glomerular endothelial cell (GEN) and mesangium injury. Neutrophil infiltration occurs early as a consequence of complement-derived factors. Neutrophil infiltration is known to be crucial in this form of renal disease (Couser, 1998).

Neutrophils then localise in glomerular fenestrated endothelium and mesangium through interaction with a variety of leukocyte adhesion molecules (P- or E- or L-selectins, integrins, ICAM 1-3 and VCAM 1), which are displayed on leukocyte and endothelial surfaces (Brady, 1994). More recent studies have shown that neutrophils localised in glomeruli mediate injury by undergoing a respiratory burst resulting in release of hydrogen peroxide (H2O2), which is interacts with neutrophil-derived myeloperoxidase (MPO) causing damage to GBM (Johnson et al., 1987). Infiltrating platelets release platelet-derived growth factor (PDGF), which mediates GEN and mesangial cell proliferation (Johnson et al., 1993). Also, mesangial cell proliferation may be mediated by the release of basic fibroblast growth factor (bFGF) by mesangial cells undergoing lysis (Johnson et al., 1992). Proliferating mesangial cells show increased protein and mRNA expression for PDGF and PDGF receptor, and the functional significance of these observations is highlighted by significant reduction in proliferation by blocking PDGF (Johnson et al., 1992).

The onset of mesangial cell proliferation following mesangial injury is associated with an increase in expression of cyclin A and cyclin dependent kinase 2 (CDK2). Glomerular injury reduces p27 expression, thus allows for increased cyclin A-CDK2 activity. At the peak of mesangial cell proliferation TGF-b is expressed, and this is associated with normalisation of p27 levels and increase in p21 expression. TGF-b causes mesangial cell hypertrophy, inhibition of cell proliferation, and increase in the production of extracellular matrix components including fibronectin and collagen I (Shankland, 1997). Furthermore, resident macrophages in response to cytokines derived from cell-mediated immune reactions produce tissue factor that facilitates fibronectin deposition and release of other cytokines and growth factors including interleukin-1 (IL-1) and TGF-b, which are important mediators of extracellular matrix expansion (Couser, 1998). Subsequently, mesangial cell phenotype switch to myofibroblast phenotype with expression of a-smooth muscle actin and increased production of interstitial collagen (Johnson et al., 1992). In mesangial proliferative glomerulonephritis, glomerular injury is augmented by release of cytokines and chemokines that result in leukocyte infiltration and increased accumulation of extracellular matrix leading to scarring and sclerosis (Couser, 1998).

In conclusion, the early activation steps of the classical, lectin and alternative pathway of complement activation converge in the formation of membrane C5b-9 attack complex. C5B-9 formation and insertion into glomerular cell membranes plays a prominent role in the pathogenesis of renal diseases such as membranous nephropathy and mesangial proliferative glomerulonephritis. In MN, C5b-9 produces glomerular injury by damaging and/or activating glomerular epithelial cells (podocytes) through a non-inflammatory mediated response. These responses lead to disruption of GBM, alterations in slit diaphragm proteins and detachment of podocytes with subsequent development of proteinuria and end-stage renal failure. Complement components in proteinuric urine also mediate tubular epithelial cell injury and leads to progressive interstitial disease. In addition to C5b-9 formation in the pathogenesis of mesangial proliferative glomerulonephritis, leukocyte (neutrophils) infiltration due to release of anaphylatoxins and inflammatory cytokines (TGF-b) at sites of capillary wall and mesangial injury, mediates mesangial cell proliferation and increased accumulation of extracellular matrix, leading to sclerosis and massive proteinuria.

References

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