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Yi Wang - One of the best experts on this subject based on the ideXlab platform.
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Specific Inhibition of Complement Activation Significantly Ameliorates Autoimmune Blistering Disease in Mice.
Frontiers in immunology, 2018Co-Authors: Sidonia Mihai, Yi Wang, Joshua M Thurman, Misa Hirose, V. Michael Holers, B. Paul Morgan, Jörg Köhl, Detlef Zillikens, Ralf Ludwig, Falk NimmerjahnAbstract:Epidermolysis bullosa acquisita (EBA) is an antibody-mediated blistering skin disease associated with tissue-bound and circulating autoantibodies to type VII collagen (COL7). Transfer of antibodies against COL7 into mice results in a subepidermal blistering phenotype, strictly depending on the Complement Component C5. Further, activation predominantly by the alternative pathway is required to induce experimental EBA, as blistering was delayed and significantly ameliorated only in factor B-/- mice. However, C5 deficiency not only blocked the activation of terminal Complement Components and assembly of the membrane attack complex (MAC) but also eliminated the formation of C5a. Therefore, in the present study, we first aimed to elucidate which molecules downstream of C5 are relevant for blister formation in this EBA model and could be subsequently pharmaceutically targeted. For this purpose, we injected mice deficient in C5a receptor 1 (C5aR1) or C6 with antibodies to murine COL7. Importantly, C5ar1-/- mice were significantly protected from experimental EBA, demonstrating that C5a-C5aR1 interactions are critical intermediates linking pathogenic antibodies to tissue damage in this experimental model of EBA. By contrast, C6-/- mice developed widespread blistering disease, suggesting that MAC is dispensable for blister formation in this model. In further experiments, we tested the therapeutic potential of inhibitors of Complement Components which were identified to play a key role in this experimental model. Complement Components C5, factor B (fB), and C5aR1 were specifically targeted using Complement inhibitors both prophylactically and in mice that had already developed disease. All Complement inhibitors led to a significant improvement of the blistering phenotype when injected shortly before anti-COL7 antibodies. To simulate a therapeutic intervention, anti-fB treatment was first administered in full-blown EBA (day 5) and induced significant amelioration only in the final phase of disease evolution, suggesting that early intervention in disease development may be necessary to achieve higher efficacy. Anti-C5 treatment in incipient EBA (day 2) significantly ameliorated disease during the whole experiment. This finding is therapeutically relevant, since the humanized anti-C5 antibody eculizumab is already successfully used in patients. In conclusion, in this study, we have identified promising candidate molecules for Complement-directed therapeutic intervention in EBA and similar autoantibody-mediated diseases.
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role of Complement Component C5 in cerebral ischemia reperfusion injury
Brain Research, 2006Co-Authors: Cristina Costa, Limin Zhao, Yamin Shen, Liming Hao, Sean P. Colgan, Gregory L. Stahl, Tong Zhou, Yi WangAbstract:We evaluated the role of Complement Component C5 during the course of cerebral ischemic reperfusion injury in a rat model of middle cerebral artery occlusion (MCAO). Systemic C5 inhibition was achieved with an anti-C5 monoclonal antibody, which significantly prevented the deterioration of the motor functions by reducing cerebral lesion and edema. Our results show that activated C5 Complement Components played an important role in cerebral tissue inflammation resulting from ischemia/reperfusion injury.
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Role of Complement Component C5 in cerebral ischemia/reperfusion injury.
Brain research, 2006Co-Authors: Cristina Costa, Limin Zhao, Yamin Shen, Liming Hao, Sean P. Colgan, Gregory L. Stahl, Tong Zhou, Yi WangAbstract:We evaluated the role of Complement Component C5 during the course of cerebral ischemic reperfusion injury in a rat model of middle cerebral artery occlusion (MCAO). Systemic C5 inhibition was achieved with an anti-C5 monoclonal antibody, which significantly prevented the deterioration of the motor functions by reducing cerebral lesion and edema. Our results show that activated C5 Complement Components played an important role in cerebral tissue inflammation resulting from ischemia/reperfusion injury.
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amelioration of lupus like autoimmune disease in nzb wf1 mice after treatment with a blocking monoclonal antibody specific for Complement Component C5
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Yi Wang, Joseph A Madri, Scott Rollins, Amy J Chodera, Louis A MatisAbstract:New Zealand black x New Zealand white (NZB/W) F1 mice spontaneously develop an autoimmune syndrome with notable similarities to human systemic lupus erythematosus. Female NZB/WF1 mice produce high titers of antinuclear antibodies and invariably succumb to severe glomerulonephritis by 12 months of age. Although the development of the immune-complex nephritis is accompanied by abundant local and systemic Complement activation, the role of proinflammatory Complement Components in disease progression has not been established. In this study we have examined the contribution of activated terminal Complement proteins to the pathogenesis of the lupus-like autoimmune disease. Female NZB/W F1 mice were treated with a monoclonal antibody (mAb) specific for the C5 Component of Complement that blocks the cleavage of C5 and thus prevents the generation of the potent proinflammatory factors C5a and C5b-9. Continuous therapy with anti-C5 mAb for 6 months resulted in significant amelioration of the course of glomerulonephritis and in markedly increased survival. These findings demonstrate an important role for the terminal Complement cascade in the progression of renal disease in NZB/W F1 mice, and suggest that mAb-mediated C5 inhibition may be a useful approach to the therapy of immune-complex glomerulonephritis in humans.
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Amelioration of lupus-like autoimmune disease in NZB/WF1 mice after treatment with a blocking monoclonal antibody specific for Complement Component C5
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Yi Wang, Joseph A Madri, Scott Rollins, Amy J Chodera, Louis A MatisAbstract:New Zealand black x New Zealand white (NZB/W) F1 mice spontaneously develop an autoimmune syndrome with notable similarities to human systemic lupus erythematosus. Female NZB/WF1 mice produce high titers of antinuclear antibodies and invariably succumb to severe glomerulonephritis by 12 months of age. Although the development of the immune-complex nephritis is accompanied by abundant local and systemic Complement activation, the role of proinflammatory Complement Components in disease progression has not been established. In this study we have examined the contribution of activated terminal Complement proteins to the pathogenesis of the lupus-like autoimmune disease. Female NZB/W F1 mice were treated with a monoclonal antibody (mAb) specific for the C5 Component of Complement that blocks the cleavage of C5 and thus prevents the generation of the potent proinflammatory factors C5a and C5b-9. Continuous therapy with anti-C5 mAb for 6 months resulted in significant amelioration of the course of glomerulonephritis and in markedly increased survival. These findings demonstrate an important role for the terminal Complement cascade in the progression of renal disease in NZB/W F1 mice, and suggest that mAb-mediated C5 inhibition may be a useful approach to the therapy of immune-complex glomerulonephritis in humans.
Cristina Costa - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of Complement Component C5 protects porcine chondrocytes from xenogeneic rejection
Osteoarthritis and cartilage, 2013Co-Authors: Roberta Sommaggio, Magdiel Pérez-cruz, J.l. Brokaw, Rafael Mañez, Cristina CostaAbstract:Summary Objective Tissue-based xenografts such as cartilage are rejected within weeks by humoral and cellular mechanisms that preclude its clinical application in regenerative medicine. The problem could be overcome by identifying key molecules triggering rejection and the development of genetic-engineering strategies to counteract them. Accordingly, high expression of α1,2-fucosyltransferase (HT) in xenogeneic cartilage reduces the galactose α1,3-galactose (Gal) antigen and delays rejection. Yet, the role of Complement activation in this setting is unknown. Design To determine its contribution, we assessed the effect of inhibiting C5 Complement Component in α1,3-galactosyltransferase-knockout (Gal KO) mice transplanted with porcine cartilage and studied the effect of human Complement on porcine articular chondrocytes (PAC). Results Treatment with an anti-mouse C5 blocking antibody for 5 weeks enhanced graft survival by reducing cellular rejection. Moreover, PAC were highly resistant to Complement-mediated lysis and primarily responded to human Complement by releasing IL-6 and IL-8. This occurred even in the absence of anti-Gal antibody and was mediated by both C5a and C5b-9. Indeed, C5a directly triggered IL-6 and IL-8 secretion and up-regulated expression of swine leukocyte antigen I (SLA-I) and adhesion molecules on chondrocytes, all processes that enhance cellular rejection. Finally, the use of anti-human C5/C5a antibodies and/or recombinant expression of human Complement regulatory molecule CD59 (hCD59) conferred protection in correspondence with their specific functions. Conclusions Our study demonstrates that Complement activation contributes to rejection of xenogeneic cartilage and provides valuable information for selecting approaches for Complement inhibition.
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role of Complement Component C5 in cerebral ischemia reperfusion injury
Brain Research, 2006Co-Authors: Cristina Costa, Limin Zhao, Yamin Shen, Liming Hao, Sean P. Colgan, Gregory L. Stahl, Tong Zhou, Yi WangAbstract:We evaluated the role of Complement Component C5 during the course of cerebral ischemic reperfusion injury in a rat model of middle cerebral artery occlusion (MCAO). Systemic C5 inhibition was achieved with an anti-C5 monoclonal antibody, which significantly prevented the deterioration of the motor functions by reducing cerebral lesion and edema. Our results show that activated C5 Complement Components played an important role in cerebral tissue inflammation resulting from ischemia/reperfusion injury.
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Role of Complement Component C5 in cerebral ischemia/reperfusion injury.
Brain research, 2006Co-Authors: Cristina Costa, Limin Zhao, Yamin Shen, Liming Hao, Sean P. Colgan, Gregory L. Stahl, Tong Zhou, Yi WangAbstract:We evaluated the role of Complement Component C5 during the course of cerebral ischemic reperfusion injury in a rat model of middle cerebral artery occlusion (MCAO). Systemic C5 inhibition was achieved with an anti-C5 monoclonal antibody, which significantly prevented the deterioration of the motor functions by reducing cerebral lesion and edema. Our results show that activated C5 Complement Components played an important role in cerebral tissue inflammation resulting from ischemia/reperfusion injury.
Rick A. Wetsel - One of the best experts on this subject based on the ideXlab platform.
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The receptor for Complement anaphylatoxin C5a protects against the development of airway hyperresponsiveness in allergic asthma by inhibiting cysteinyl leukotriene pathway
The FASEB Journal, 2008Co-Authors: Meenal Sinha, Scott M. Drouin, Rick A. WetselAbstract:We have reported that Complement Component C5 is protective against airway inflammation in a rodent model of Aspergillus fumigatus induced allergic airway disease. Using mice deficient in the C5a receptor (C5aR) and an antagonist specific for the C5aR, we tested if these responses could be mediated by C5a, an activation-induced cleavage fragment of C5. Consistent with previous results, C5aR−/− mice and wild-type (WT) mice treated with a specific C5aR antagonist exhibited exacerbated airway hyperresponsiveness (AHR) compared to the WT mice. We also examined if Th2 responses, that are known to regulate many aspects of allergic airway inflammation including AHR, were elevated in the lungs of C5aR−/− mice as C5a and its receptor are thought to promote Th1 responses. Surprisingly, Th2-type cytokines IL-5 and IL-13 were significantly reduced in the lungs and bronchoalveolar lavage fluid of C5aR−/− mice. However, pretreatment with a specific cysteinyl leukotriene (cysLT) receptor 1 antagonist could abolish AHR i...
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A protective role for the fifth Complement Component (C5) in allergic airway disease
American journal of respiratory and critical care medicine, 2006Co-Authors: Scott M. Drouin, John D. Lambris, Meenal Sinha, Georgia Sfyroera, Rick A. WetselAbstract:Rationale: Reports from our laboratory, as well as those from others, have documented the importance of Complement activation, the C3a anaphylatoxin, and its receptor, C3aR, in promoting Th2 effector functions in a mouse model of bronchopulmonary allergy. Although deficiency in the fifth Complement Component (C5) has been linked to enhanced airway hyperresponsiveness in mice, the contribution of C5 to other major biological hallmarks of asthma has not been evaluated. Objective: Accordingly, congenic C5-sufficient and C5-deficient mice were subjected to a mouse model of bronchopulmonary allergy to assess the impact of C5 on pulmonary inflammation and Th2 effector functions in experimental asthma. Methods and Main Results: In contrast to observations reported for C3- and C3aR-deficient animals, C5-deficient mice exhibited significantly increased airway hyperresponsiveness relative to wild-type congenic control mice after antigen challenge. Moreover, challenged C5-deficient mice had a 3.4-fold and 2.7-fold increase in the levels of airway eosinophils and lung interleukin (IL)-4–producing cells, respectively, compared with challenged wild-type mice. Consistent with the numbers of IL-4–producing cells, C5-deficient mice also had increased bronchoalveolar lavage levels of the Th2 cytokines IL-5 and IL-13 and elevated serum levels of total and antigenspecific IgE. Conclusions: These data indicate that C5 plays an important protective role in allergic lung disease by suppressing inflammatory responses and Th2 effector functions observed in this experimental model. The protection provided by the presence of C5 is likely mediated by C5a, suggesting that C5a may play a significant role in tempering inflammation in Th2-driven diseases such as asthma.
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Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome
Journal of Clinical Investigation, 2003Co-Authors: Guillermina Girardi, Jessica R Berman, Patricia Redecha, Lynn A Spruce, Joshua M Thurman, Damian M Kraus, Travis J Hollmann, Paolo Casali, Michael C Caroll, Rick A. WetselAbstract:Antiphospholipid syndrome (APS) is defined by recurrent pregnancy loss and thrombosis in the presence of antiphospholipid (aPL) Ab’s. Currently, therapy for pregnant women with APS is focused on preventing thrombosis, but anticoagulation is only partially successful in averting miscarriage. We hypothesized that Complement activation is a central mechanism of pregnancy loss in APS and tested this in a model in which pregnant mice receive human IgG containing aPL Ab’s. Here we identify Complement Component C5 (and particularly its cleavage product C5a) and neutrophils as key mediators of fetal injury, and we show that Ab’s or peptides that block C5a–C5a receptor interactions prevent pregnancy complications. The fact that F(ab)′2 fragments of aPL Ab’s do not mediate fetal injury and that C4-deficient mice are protected from fetal injury suggests that activation of the Complement cascade is initiated via the classical pathway. Studies in factor B–deficient mice, however, indicate that alternative pathway activation is required and amplifies Complement activation. In contrast, activating FcγRs do not play an important role in mediating aPL Ab–induced fetal injury. Our findings identify the key innate immune effectors engaged by pathogenic autoantibodies that mediate poor pregnancy outcomes in APS and provide novel and important targets for prevention of pregnancy loss in APS.
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Hypersusceptibility of A/J Mice to Tuberculosis is in Part Due to a Deficiency of the Fifth Complement Component (C5)
Scandinavian journal of immunology, 2000Co-Authors: Chinnaswamy Jagannath, Rick A. Wetsel, H. Hoffmann, E. Sepulveda, J. K. Actor, Robert L. HunterAbstract:Mycobacterium tuberculosis (MTB) causes tuberculosis in man, which occurs as an acute, chronic or dormant disease reactivating over several years. The mechanisms of persistence and reactivation are not well understood and there is a need for animal models. Moderate-dose, aerosol infection killed A/J mice earlier than partially resistant C57Bl/6 mice, whereas a low-dose, aerosol-induced chronic infection exacerbated earlier in A/J mice. A/J mice lethally infected with MTB but drug cured of disease underwent reactivation of tuberculosis at least 100 days before similarly infected C57Bl/6 mice. Because A/J mice were C5 deficient, congenic B10 mice sufficient and deficient for C5 were infected intravenously with MTB to define the role of C5. C5-deficient mice again showed enhanced growth of MTB in the lungs. MTB-infected macrophages from C5-deficient mice showed enhanced growth of MTB coinciding with a reduced secretion of both cytokines (TNF-α, IL-1β, IL-6, IL-12) and chemokines (KC, MIP-2 and MIP-1α) in A/J and TNF-α and chemokines in C5-deficient mice. Because C5-deficient macrophages could be activated from extraneous C5 and TNF-α we suggest that both play a role in the macrophage-mediated killing as well as containment mechanisms in tuberculosis.
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hypersusceptibility of a j mice to tuberculosis is in part due to a deficiency of the fifth Complement Component C5
Scandinavian Journal of Immunology, 2000Co-Authors: Chinnaswamy Jagannath, Rick A. Wetsel, H. Hoffmann, E. Sepulveda, J. K. Actor, Robert L. HunterAbstract:Mycobacterium tuberculosis (MTB) causes tuberculosis in man, which occurs as an acute, chronic or dormant disease reactivating over several years. The mechanisms of persistence and reactivation are not well understood and there is a need for animal models. Moderate-dose, aerosol infection killed A/J mice earlier than partially resistant C57Bl/6 mice, whereas a low-dose, aerosol-induced chronic infection exacerbated earlier in A/J mice. A/J mice lethally infected with MTB but drug cured of disease underwent reactivation of tuberculosis at least 100 days before similarly infected C57Bl/6 mice. Because A/J mice were C5 deficient, congenic B10 mice sufficient and deficient for C5 were infected intravenously with MTB to define the role of C5. C5-deficient mice again showed enhanced growth of MTB in the lungs. MTB-infected macrophages from C5-deficient mice showed enhanced growth of MTB coinciding with a reduced secretion of both cytokines (TNF-alpha, IL-1beta, IL-6, IL-12) and chemokines (KC, MIP-2 and MIP-1alpha) in A/J and TNF-alpha and chemokines in C5-deficient mice. Because C5-deficient macrophages could be activated from extraneous C5 and TNF-alpha we suggest that both play a role in the macrophage-mediated killing as well as containment mechanisms in tuberculosis.
Lourdes Isaac - One of the best experts on this subject based on the ideXlab platform.
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Role of Murine Complement Component C5 in Acute in Vivo Infection by Pathogenic Leptospira interrogans.
Frontiers in cellular and infection microbiology, 2018Co-Authors: Íris Arantes De Castro, Lorena Bavia, Tatiana R. Fraga, Mariane T. Amano, Leandro Carvalho Dantas Breda, Adriana P Granados-martinez, Ana Maria Gonçalves Da Silva, Silvio Arruda Vasconcellos, Lourdes IsaacAbstract:Leptospirosis is considered one of the most important zoonosis worldwide. The activation of the Complement System is important to control dissemination of several pathogens in the host. Only a few studies have employed murine models to investigate leptospiral infection and our aim in this work was to investigate the role of murine C5 during in vivo infection, comparing wild type C57BL/6 (B6 C5+/+) and congenic C57BL/6 (B6 C5-/-, C5 deficient) mice during the first days of infection. All animals from both groups survived for at least 8 days post-infection with pathogenic Leptospira interrogans serovar Kennewicki strain Fromm (LPF). At the third day of infection, we observed greater numbers of LPF in the liver of B6 C5-/- mice when compared to B6 C5+/+ mice. Later, on the sixth day of infection, the LPF population fell to undetectable levels in the livers of both groups of mice. On the third day, the inflammatory score was higher in the liver of B6 C5+/+ mice than in B6 C5-/- mice, and returned to normal on the sixth day of infection in both groups. No significant histopathological differences were observed in the lung, kidney and spleen from both infected B6 C5+/+ than B6 C5-/- mice. Likewise, the total number of circulating leukocytes was not affected by the absence of C5. The liver levels of IL-10 on the sixth day of infection was lower in the absence of C5 when compared to wild type mice. No significant differences were observed in the levels of several inflammatory cytokines when B6 C5+/+ and B6 C5-/- were compared. In conclusion, C5 may contribute to the direct killing of LPF in the first days of infection in C57BL/6 mice. On the other hand, other effector immune mechanisms probably compensate Complement impairment since the mice survival was not affected by the absence of C5 and its activated fragments, at least in the early stage of this infection.
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The Complement Component C5 promotes liver steatosis and inflammation in murine non-alcoholic liver disease model.
Immunology letters, 2016Co-Authors: Lorena Bavia, Bruno Cogliati, Juliano Bertollo Dettoni, Venancio Avancini Ferreira Alves, Lourdes IsaacAbstract:Non-Alcoholic Fatty Liver Disease (NALD) is considering a hepatic manifestation of metabolic syndrome. Although the pathogenesis of NALD is not completely understood, insulin resistance and inflammatory cytokines are implicated. Considering that Component C5 is a central mediator of inflammation, we investigated the role of C5 in the establishment of NALD. Eight to ten-week old B6 C5(+) and A/J C5(-) male mice were fed a high fat diet containing glucose (HFDG) for 6 and 10 weeks. We observed that B6 C5(+) mice HFDG-fed for 10 weeks developed hepatomegaly, triglycerides (TG) accumulation, steatosis and enhanced liver TNF-α, IL-6, IL-12p70 and IL-17 levels when compared to A/J C5(-) mice. Next, B6 C5(+) mice were compared with congenic B6 C5(-) mice. Again, B6 C5(+) HFDG-fed mice developed more steatosis, liver centro-lobular inflammation and presented higher levels of liver IL-1β, IL-12p70, IL-17 and TFG-β than B6 C5(-) mice under the same conditions. B6 C5(+) mice HFDG-fed also presented lower concentrations of serum albumin, serum cholesterol, blood leukocytes and liver NO production when compared with B6 C5(-) mice. We concluded that murine C5 contributes effectively to liver steatosis and inflammation in NALD pathogenesis. In addition, C5 is also important to control serum cholesterol and albumin levels in the C57BL/6 genetic background.
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A new model of outbred genetically selected mice which present a strong acute inflammatory response in the absence of Complement Component C5
Inflammation research : official journal of the European Histamine Research Society ... [et al.], 2009Co-Authors: M. T. Amano, Lourdes Isaac, A. S. Carneiro, O. G. Ribeiro, M. Franco, O. M. Ibañez, Wafa Hanna Koury Cabrera, N. StarobinasAbstract:Objective: Mice selected for a strong (AIRmax) or weak (AIRmin) acute inflammatory response present different susceptibilities to bacterial infections, autoimmune diseases and carcinogenesis. Variations in these phenotypes have been also detected in AIRmax and AIRmin mice rendered homozygous for Slc11a1 resistant (R) and susceptible (S) alleles. Our aim was to investigate if the phenotypic differences observed in these mice was related to the Complement system.
John D. Lambris - One of the best experts on this subject based on the ideXlab platform.
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Double-blockade of CD14 and Complement Component C5 abolish the inflammatory storm and improve survival in mouse polymicrobial sepsis
Molecular Immunology, 2013Co-Authors: Tom Eirik Mollnes, A. Baratt-due, Søren Erik Pischke, I. Sandanger, Per H. Nilsson, John D. Lambris, Miles A. Nunn, Stephanie Denk, Terje Espevik, Markus Huber-langAbstract:Double-blockade of CD14 and Complement Component C5 abolish the inflammatory storm and improve survival in mouse polymicrobial sepsis
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Complement-targeted therapeutics.
Nature biotechnology, 2007Co-Authors: Daniel Ricklin, John D. LambrisAbstract:The Complement system is a central Component of innate immunity and bridges the innate to the adaptive immune response. However, it can also turn its destructive capabilities against host cells and is involved in numerous diseases and pathological conditions. Modulation of the Complement system has been recognized as a promising strategy in drug discovery, and a large number of therapeutic modalities have been developed. However, successful marketing of Complement-targeted drugs has proved to be more difficult than initially expected, and many strategies have been discontinued. The US Food and Drug Administration's approval of the first Complement-specific drug, an antibody against Complement Component C5 (eculizumab; Soliris), in March 2007, was a long-awaited breakthrough in the field. Approval of eculizumab validates the Complement system as therapeutic target and might facilitate clinical development of other promising drug candidates.
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A protective role for the fifth Complement Component (C5) in allergic airway disease
American journal of respiratory and critical care medicine, 2006Co-Authors: Scott M. Drouin, John D. Lambris, Meenal Sinha, Georgia Sfyroera, Rick A. WetselAbstract:Rationale: Reports from our laboratory, as well as those from others, have documented the importance of Complement activation, the C3a anaphylatoxin, and its receptor, C3aR, in promoting Th2 effector functions in a mouse model of bronchopulmonary allergy. Although deficiency in the fifth Complement Component (C5) has been linked to enhanced airway hyperresponsiveness in mice, the contribution of C5 to other major biological hallmarks of asthma has not been evaluated. Objective: Accordingly, congenic C5-sufficient and C5-deficient mice were subjected to a mouse model of bronchopulmonary allergy to assess the impact of C5 on pulmonary inflammation and Th2 effector functions in experimental asthma. Methods and Main Results: In contrast to observations reported for C3- and C3aR-deficient animals, C5-deficient mice exhibited significantly increased airway hyperresponsiveness relative to wild-type congenic control mice after antigen challenge. Moreover, challenged C5-deficient mice had a 3.4-fold and 2.7-fold increase in the levels of airway eosinophils and lung interleukin (IL)-4–producing cells, respectively, compared with challenged wild-type mice. Consistent with the numbers of IL-4–producing cells, C5-deficient mice also had increased bronchoalveolar lavage levels of the Th2 cytokines IL-5 and IL-13 and elevated serum levels of total and antigenspecific IgE. Conclusions: These data indicate that C5 plays an important protective role in allergic lung disease by suppressing inflammatory responses and Th2 effector functions observed in this experimental model. The protection provided by the presence of C5 is likely mediated by C5a, suggesting that C5a may play a significant role in tempering inflammation in Th2-driven diseases such as asthma.
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a novel role of Complement mice deficient in the fifth Component of Complement C5 exhibit impaired liver regeneration
Journal of Immunology, 2001Co-Authors: Dimitrios C Mastellos, John C Papadimitriou, Silvia Franchini, Panagiotis A Tsonis, John D. LambrisAbstract:Components of innate immunity have recently been implicated in the regulation of developmental processes. Most strikingly, Complement factors appear to be involved in limb regeneration in certain urodele species. Prompted by these observations and anticipating a conserved role of Complement in mammalian regeneration, we have now investigated the involvement of Complement Component C5 in liver regeneration, using a murine model of CCl4-induced liver toxicity and mice genetically deficient in C5. C5-deficient mice showed severely defective liver regeneration and persistent parenchymal necrosis after exposure to CCl4. In addition, these mice showed a marked delay in the re-entry of hepatocytes into the cell cycle (S phase) and diminished mitotic activity, as demonstrated, respectively, by the absence of 5-bromo-2′-deoxyuridine incorporation in hepatocytes, and the rare occurrence of mitoses in the liver parenchyma. Reconstitution of C5-deficient mice with murine C5 or C5a significantly restored hepatocyte regeneration after toxic injury. Furthermore, blockade of the C5a receptor (C5aR) abrogated the ability of hepatocytes to proliferate in response to liver injury, providing a mechanism by which C5 exerts its function, and establishing a critical role for C5aR signaling in the early events leading to hepatocyte proliferation. These results support a novel role for C5 in liver regeneration and strongly implicate the Complement system as an important immunoregulatory Component of hepatic homeostasis.