Immune role of the complement component 6 gene and its associated novel miRNA, miR-727, in half-smooth tongue sole (Cynoglossus semilaevis)
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Complement activation has a role in the pathogenesis of IgA nephropathy, an autoimmune disease mediated by pathogenic immune complexes consisting of galactose-deficient IgA1 bound by antiglycan antibodies. Of three complement-activation pathways, the alternative and lectin pathways are involved in IgA nephropathy. IgA1 can activate both pathways in vitro, and pathway components are present in the mesangial immunodeposits, including properdin and factor H in the alternative pathway and mannan-binding lectin, mannan–binding lectin–associated serine proteases 1 and 2, and C4d in the lectin pathway. Genome–wide association studies identified deletion of complement factor H–related genes 1 and 3 as protective against the disease. Because the corresponding gene products compete with factor H in the regulation of the alternative pathway, it has been hypothesized that the absence of these genes could lead to more potent inhibition of complement by factor H. Complement activation can take place directly on IgA1–containing immune complexes in circulation and/or after their deposition in the mesangium. Notably, complement factors and their fragments may serve as biomarkers of IgA nephropathy in serum, urine, or renal tissue. A better understanding of the role of complement in IgA nephropathy may provide potential targets and rationale for development of complement-targeting therapy of the disease.
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The complement system plays a crucial role in orchestrating the activation and regulation of inflammation within the human immune system. Three distinct activation pathways-classical, lectin, and alternative-converge to form the common lytic pathway, culminating in the formation of the membrane-attacking complex that disrupts the structure of pathogens. Dysregulated complement system activity can lead to tissue damage, autoimmune diseases, or immune deficiencies. In this study, the antimicrobial activity of human serum was investigated by using a bioluminescent microbe probe, Escherichia coli (pEGFPluxABCDEamp). This probe has previously been used to determine the antimicrobial activity of complement system and the polymorphonuclear neutrophils. In this study, blocking antibodies against key serum activators and components, including IgG, complement component 1q, factor B, and properdin, were utilized. The influence of body temperature and acute phase proteins, such as C reactive protein (CRP) and serum amyloid alpha (SAA), on the complement system was also examined. The study reveals the critical factors influencing complement system activity and pathway function. Alongside crucial factors like C1q and IgG, alternative pathway components factor B and properdin played pivotal roles. Results indicated that the alternative pathway accounted for approximately one third of the overall serum antimicrobial activity, and blocking this pathway disrupted the entire complement system. Contrary to expectations, elevated body temperature during inflammation did not enhance the antimicrobial activity of human serum. CRP demonstrated complement activation properties, but at higher physiological concentrations, it exhibited antagonistic tendencies, dampening the response. On the other hand, SAA enhanced the serum's activity. Overall, this study sheds a light on the critical factors affecting both complement system activity and pathway functionality, emphasizing the importance of a balanced immune response.
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The complement system plays a key role in host defense against pneumococcal infection. Three different pathways, the classical, alternative and lectin pathways, mediate complement activation. While there is limited information available on the roles of the classical and the alternative activation pathways of complement in fighting streptococcal infection, little is known about the role of the lectin pathway, mainly due to the lack of appropriate experimental models of lectin pathway deficiency. We have recently established a mouse strain deficient of the lectin pathway effector enzyme mannan-binding lectin associated serine protease-2 (MASP-2) and shown that this mouse strain is unable to form the lectin pathway specific C3 and C5 convertases. Here we report that MASP-2 deficient mice (which can still activate complement via the classical pathway and the alternative pathway) are highly susceptible to pneumococcal infection and fail to opsonize Streptococcus pneumoniae in the none-immune host. This defect in complement opsonisation severely compromises pathogen clearance in the lectin pathway deficient host. Using sera from mice and humans with defined complement deficiencies, we demonstrate that mouse ficolin A, human L-ficolin, and collectin 11 in both species, but not mannan-binding lectin (MBL), are the pattern recognition molecules that drive lectin pathway activation on the surface of S. pneumoniae. We further show that pneumococcal opsonisation via the lectin pathway can proceed in the absence of C4. This study corroborates the essential function of MASP-2 in the lectin pathway and highlights the importance of MBL-independent lectin pathway activation in the host defense against pneumococci.
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The complement system provides a fundamental component of the body's immune response to invading microorganisms. This chapter highlights the various roles of the complement system in the orchestration of the immune response towards microbial infections, gives examples of microbial strategies to evade complement-mediated clearance, and discusses how acquired and inherited complement deficiencies may predispose an organism to infectious disease. Complement is activated by three pathways: the classical pathway, the alternative pathway, and the lectin pathway. The lectin pathway is activated by carbohydrate recognition molecules that bind to polysaccharide on the surface of a pathogen. Factor B, factor D, and properdin (factor P) are specific components of the alternative pathway of complement activation. The complement activation is tightly regulated by membrane-bound and fluid-phase regulatory components to avoid runaway activation of the enzymatic cascade that could lead to excess host tissue damage, inflammation, and depletion of complement components. A deficiency in any component of the classical pathway is associated with an increased risk of immunological disease and recurrent bacterial infections. Pneumolysin is a potent virulence factor produced by all serotypes of S. pneumoniae. Pneumolysin is released as a 52 kDa soluble monomer. It binds cholesterol-containing membranes and the monomeric subunits oligomerize to form a pore in the target cell membrane that leads to cell death. Pneumococcal surface protein C (PspC) is a major virulence factor of Streptococcus pneumoniae and contributes to many different biological functions.
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Homozygous complement protein deficiencies are rare. However, the study of inherited deficiencies of complement proteins in vivo offer insights into the physiological activities of the complement system that are not readily available from in vitro analysis. The phenotype of complement deficiency varies according to the position of the missing component within the complement activation pathways. This demonstrates that different parts of the complement system subserve particular functions. For example, terminal complement component deficiency predisposes to recurrent Neisserial infections. Furthermore, individuals with classical pathway component deficiencies develop SLE. These observations have led to the hypothesis that the classical pathway protects against the development of SLE. However, the mechanism underlying this association has not been fully established. Recent findings obtained using animal models of complement deficiencies, suggest that the classical pathway plays an important role in promoting the physiological clearance of apoptotic cells. The discovery that apoptotic cells may be the source of autoantigens in SLE has lead to the hypothesis that complement deficiency may promote autoimmunity by impairing the clearance of apoptotic cells. To prevent host tissue injury and depletion of complement components, the complement system is tightly regulated by a series of proteins circulating in plasma and present on cell membranes. The major inhibitory protein of the alternative pathway is factor H (FH). Deficiency of this protein results in secondary depletion of C3 due to uncontrolled alternative pathway (AP) activation. This occurs commonly in individuals with C3 nephritic factor, an IgG autoantibody that stabilises the alternative pathway C3 convertase. Both individuals deficient in FH and those with C3 nephritic factor develop membranoproliferative glomerulonephritis (MPGN). To explore the mechanisms by which uncontrolled C3 activation predisposes to MPGN, we have developed an in vivo model of factor H deficiency. FH deficient mice have secondary C3 deficiency, show large amounts of C3 deposited preferentially on the glomerular basement membrane and develop MPGN. Both partial and complete FH deficiencies have been associated with haemolytic uraemic syndrome (HUS) and the pathogenesis is poorly understood. This animal model will allow us to investigate the mechanisms by which C3 dysregulation predisposes to glomerulonephritis and HUS. In conclusion, individuals and experimental models of complement deficiency prove to be an invaluable tool to investigate the role of the complement system in health and in disease.
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Pickering MC, Botto M, Taylor PR, Lachmann PJ, Walport MJ. Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv Immunol. 2001;76:227–324Complement factor B
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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.
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Complement component 2
Membranoproliferative glomerulonephritis
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The complement system is an important component of innate immunity. The alternative pathway (AP) amplification loop is considered an essential feed forward mechanism for complement activation. However, the role of the AP in classical pathway (CP) activation has only been studied in ELISA settings. Here, we investigated its contribution on physiologically relevant surfaces of human cells and bacterial pathogens and in antibody-mediated complement activation, including in autoimmune haemolytic anaemia (AIHA) setting with autoantibodies against red blood cells (RBCs).We evaluated the contribution of the AP to complement responses initiated through the CP on human RBCs by serum of AIHA patients and recombinant antibodies. Moreover, we studied complement activation on Neisseria meningitidis and Escherichia coli. The effect of the AP was examined using either AP-depleted sera or antibodies against factor B and factor D.We show that the amplification loop is redundant when efficient CP activation takes place. This is independent of the presence of membrane-bound complement regulators. The role of the AP may become significant when insufficient CP complement activation occurs, but this depends on antibody levels and (sub)class. Our data indicate that therapeutic intervention in the amplification loop will most likely not be effective to treat antibody-mediated diseases.The AP can be bypassed through efficient CP activation. The AP amplification loop has a role in complement activation during conditions of modest activation via the CP, when it can allow for efficient complement-mediated killing.
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The complement system is an important pillar of our innate and acquired immune system, and it is essential for host defense against foreign pathogens. Activation of complement has important functions that, in general, are beneficial to the host, but when adverse complement activation occurs by or near our own tissue and cells, the same functions can become detrimental to the host. In general, complement activation is under strict control by a number of fluid phase– and tissue-associated complement regulators. Complement can be activated by three known pathways, namely the classic pathway, the lectin pathway, and the alternative pathway. After initial complement activation by any of these pathways, further amplification is essential for efficient elimination of foreign pathogens, unwanted cell debris, and soluble immune complexes and for triggering of the common effector pathway with activation of C5 and generation of the membrane attack complex (MAC) C5b-9. The degree of amplification of C3 activation in the fluid phase is controlled to an important degree by complement factor H (CFH). CFH is a 155-kD glycoprotein that consists of 20 short consensus repeats. Short consensus repeats 18–20 bind to cell surfaces and recognize C3b. CFH controls complement activation in both the fluid- and tissue-associated phases; because it can bind to cells (for instance, endothelial cells), it conveys extra protection to complement-mediated injury. Uncontrolled C3 activation occurs in C3 glomerulopathy (C3G), and treatment options for C3G are limited. Some progress has been made with the treatment of C3G with eculuzimab, an mAb against C5 that prevents the generation of the phlogistic fragment C5a from C5 and the formation of the MAC; however, the success of treatment is often uncertain. In this issue of the Journal of the American Society of Nephrology, Wang et al.1 explored the potential efficacy of an Fc fusion protein of complement receptor of the Ig superfamily (CRIg-Fc) in the treatment of mice with an experimental form of C3G, namely mice with a common CFH and properdin double deficiency. These mice develop an early onset of C3G with increased C3 catabolism, increased proteinuria, and lethal crescentic GN. Treatment of the double-deficient mice with CRIg-Fc but not the control Fc fusion protein reduced proteinuria, hematuria, BUN, C3 deposition, and GN scores. Additionally, treatment with CRIg-Fc improved complement pathology and survival. Treatment of these mice was started at 4 weeks of age, at which time the mice have a mild form of C3G. The question remains whether CRIg-Fc will prove to be efficient in reversal of a fully active disease. The findings, however, are promising, and combined with the fact that it down modulates the degree of C3 amplification, it adds a potential new approach to the treatment of C3G in patients. Other promising approaches are being explored. Like the approach of using CRIg-Fc as a down modulator of C3 amplification, two other inhibitors have been developed. Both are on the basis of the regulatory domains of CFH itself. Yang et al.2 engineered two CFH miniconstructs consisting of specific domains of CFH, with a higher retention of the drug in the kidneys of mice. These mini-CFH constructs were fully able to regulate complement amplification in mice, and they were shown to be very effective in prevention of glomerular C3 deposition in CFH-deficient mice. The advantage of using these CFH miniconstructs is that they block complement activation in the affected organ directly, whereas the CRIg-Fc mainly down modulates circulating complement activation. Another very promising agent to block the alternative pathway convertase was reported recently by Michelfelder et al.3 They synthesized a fusion protein MFHR1 that contains the regulatory domains of CFH and the C5 convertase/C5b-9 inhibitory fragment of FH-related protein 1. MFHR1 has cofactor and decay accelerating activity and inhibits C5 convertase activation and MAC assembly, which prevent C3b deposition. Administration of MFHR1 to CFH−/− mice resulted in inhibition of C3 activation in vivo and reduced abnormal C3 deposition in the kidneys. The advantage of MFHR1 is that it not only controls alternative pathway C3 activation but that it also affects the C5 convertase and generation of MAC. The idea to down modulate complement activation at the C3 level was introduced quite a number of years ago by the research group of Lambris and colleagues.4 They developed a drug called Compstatin that prevents C3 activation by binding to C3 itself. Continuous development of the Compstatin scaffold for increased target affinity, inhibitory efficacy, and advantageous pharmacokinetic properties has resulted in the analog CP40, which also looks very promising in preclinical models of C3G and other complement-mediated diseases. In summary, several potentially very promising drugs that control the degree of the activity of the alternative pathway are now in the pipeline. Most of these drugs are still in the preclinical stage, and much more work is ahead to bring these drugs to implementation in the clinic. Disclosures None.
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