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Mark J. Daly - One of the best experts on this subject based on the ideXlab platform.
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variation near Complement Factor i is associated with risk of advanced amd
European Journal of Human Genetics, 2009Co-Authors: Jesen Fagerness, Benjamin M. Neale, Robyn Reynolds, Mark J. Daly, Julian MallerAbstract:A case–control association study for advanced age-related macular degeneration was conducted to explore several regions of interest identified by linkage. This analysis identified a single nucleotide polymorphism just 3′ of Complement Factor I on chromosome 4 showing significant association (P<10−7). Sequencing was performed on coding exons in linkage disequilibrium with the detected association. No obvious functional variation was discovered that could be the proximate cause of the association, suggesting a noncoding regulatory mechanism.
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variation in Complement Factor 3 is associated with risk of age related macular degeneration
Nature Genetics, 2007Co-Authors: Jesen Fagerness, Benjamin M. Neale, Robyn Reynolds, Mark J. Daly, Julian MallerAbstract:The association of variants in Complement Factors H and B with age-related macular degeneration has led to more intense genetic and functional analysis of the Complement pathway. We identify a nonsynonymous coding change in Complement Factor 3 that is strongly associated with risk of age-related macular degeneration in a large case-control sample.
Pilvi Riihilä - One of the best experts on this subject based on the ideXlab platform.
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Complement component c3 and Complement Factor b promote growth of cutaneous squamous cell carcinoma
American Journal of Pathology, 2017Co-Authors: Mehdi Farshchian, Markku Kallajoki, Atte Kivisaari, Liisa Nissinen, Pilvi Riihilä, Seppo MeriAbstract:Cutaneous squamous cell carcinoma (cSCC) is one of the most common metastatic skin cancers with increasing incidence. We examined the roles of Complement component C3 and Complement Factor B (CFB) in the growth of cSCC. Analysis of cSCC cell lines ( n = 8) and normal human epidermal keratinocytes ( n = 11) with real-time quantitative PCR and Western blotting revealed up-regulation of C3 and CFB expression in cSCC cells. Immunohistochemical staining revealed stronger tumor cell–specific labeling for C3 and CFB in invasive cSCCs ( n = 71) and recessive dystrophic epidermolysis bullosa–associated cSCCs ( n = 11) than in cSCC in situ ( n = 69), actinic keratoses ( n = 63), and normal skin ( n = 5). Significant up-regulation of C3 and CFB mRNA expression was noted in chemically induced mouse cSCCs, compared to benign papillomas. Knockdown of C3 and CFB expression inhibited migration and proliferation of cSCC cells and resulted in potent inhibition of extracellular signal–regulated kinase 1/2 activation. Knockdown of C3 and CFB markedly inhibited growth of human cSCC xenograft tumors in vivo . These results provide evidence for the roles of C3 and CFB in the development of cSCC and identify them as biomarkers and potential therapeutic targets in this metastatic skin cancer.
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abstract 3201 Complement component c3 and Complement Factor b regulate growth of cutaneous squamous cell carcinoma
Cancer Research, 2015Co-Authors: Pilvi Riihilä, Mehdi Farshchian, Markku Kallajoki, Atte Kivisaari, Juha Peltonen, Seppo Meri, Taina Pihlajaniemi, Ritva Heljasvaara, Reidar Grenman, Sirkku PeltonenAbstract:Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer and its incidence is increasing globally. We have examined the role of Complement component C3 and Complement Factor B (CFB) in the progression of cSCC. Significantly elevated mRNA levels for C3 and CFB were detected din cSCC cell lines (n = 8) compared to normal human epidermal keratinocytes (n = 11) by quantitative real-time reverse transcriptase-PCR. Increased production of C3 and CFB by cSCC cell lines was detected by western blotting. The mRNA levels for C3 and CFB were also markedly higher in cSCC tumors (n = 6) than in normal skin (n = 10). Tumor cell specific staining for C3 and CFB was detected in cSCC tumors in vivo by immunohistochemistry and the staining intensity was stronger in invasive cSCCs (n = 71) than in cSCC in situ (n = 69), premalignant epidermal lesions (actinic keratoses, n = 65) and normal skin (n = 5). Significant upregulation of C3 and CFB mRNA expression was also noted in chemically induced mouse skin cSCCs (n = 27) compared to benign papillomas (n = 17). The expression of C3 and CFB at mRNA and protein level was markedly higher in invasive tumorigenic Ha-ras-transformed HaCaT cell line than in benign tumorigenic ras-transformed HaCaT cells and parental non-tumorigenic HaCaT cells. The expression of both C3 and CFB was significantly upregulated by IFN-γ and TNF-α in cSCC cells. Knockdown of CFB and C3 by specific siRNAs inhibited migration of cSCC cells. Knockdown of CFB inhibited proliferation of cSCC cells and this was associated with potent inhibition of ERK1/2 activation. Knockdown of C3 and CFB also significantly inhibited growth of human cSCC xenograft tumors in vivo in SCID mice. These results provide evidence for the role of C3 and CFB in progression of cSCC and identify them as specific biomarkers and putative therapeutic targets for invasive cSCC. Citation Format: Pilvi Riihila, Mehdi Farshchian, Markku Kallajoki, Atte Kivisaari, Seppo Meri, Reidar Grenman, Ritva Heljasvaara, Taina Pihlajaniemi, Juha Peltonen, Sirkku Peltonen, Veli-Matti Kahari. Complement component C3 and Complement Factor B regulate growth of cutaneous squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3201. doi:10.1158/1538-7445.AM2015-3201
Wim A Buurman - One of the best experts on this subject based on the ideXlab platform.
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Complement Factor c5a mediates renal ischemia reperfusion injury independent from neutrophils
Journal of Immunology, 2003Co-Authors: Bart De Vries, Jorg Kohl, Tim G A M Wolfs, Annemarie A Van Bijnen, Peter Heeringa, Wouter K G Leclercq, Wim A BuurmanAbstract:The Complement system has been shown to mediate renal ischemia-reperfusion (I/R) injury. However, the contribution of Complement Factor C5a to I/R injury, in particular in the kidney, remains to be established. In this study, we investigated the impact of blocking the C5aR pathway on the inflammatory response and on the renal function in a murine model of I/R injury. First, we analyzed C5aR expression in kidneys of healthy mice. Intriguingly, we found expression on mesangial, as well as on tubular epithelial, cells. After I/R injury, C5aR expression was up-regulated in tubular epithelial cells. In addition, mRNA levels of CXC chemokines and TNF-alpha increased significantly and kidneys were heavily infiltrated by neutrophils. Blocking the C5aR pathway by a specific C5a receptor antagonist (C5aRA) abrogated up-regulation of CXC chemokines but not of TNF-alpha and reduced neutrophil infiltration by >50%. Moreover, application of the C5aRA significantly reduced loss of renal function. This improvement of function was independent of the presence of neutrophils because neutrophil depletion by mAb NIMP-R14 did not affect the protective effect of C5aRA treatment. Furthermore, blocking of the C5aR pathway had no influence on renal apoptosis. These data provide evidence that C5a is crucially involved in the pathogenesis of renal I/R injury by modulation of neutrophil-dependent as well as neutrophil-independent pathways, which include the regulation of CXC chemokines but not TNF-alpha or apoptotic pathways.
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inhibition of Complement Factor c5 protects against renal ischemia reperfusion injury inhibition of late apoptosis and inflammation
Transplantation, 2003Co-Authors: Bart De Vries, Robert A Matthijsen, Tim G A M Wolfs, Annemarie A Van Bijnen, Peter Heeringa, Wim A BuurmanAbstract:Background Complement has been implicated in the pathophysiology of renal ischemia-reperfusion (I/R) injury. However, the mechanism underlying Complement-mediated renal I/R injury is thus far unknown. To investigate the involvement of Complement in I/R injury, we studied the activation and deposition of Complement in a murine model of renal I/R injury. Furthermore, we examined the effect of inhibition of Complement-Factor C5 on renal I/R injury. Methods. Mice were subjected to 45 min of unilateral ischemia and subsequent contralateral nephrectomy and reperfusion for 2, 12, or 24 hr. Mice were control treated or treated with BB5.1, a monoclonal antibody that prevents cleavage of Complement Factor C5, thereby preventing C5a generation and formation of the membrane attack complex (MAC). Results. Renal I/R induced extensive deposition of C3 early after reperfusion, whereas C6 and C9 deposition (MAC formation) occurred relatively late. I/R-induced Complement deposition was mainly localized to tubular epithelium. Treatment with BB5.1 totally prevented MAC formation but also reduced C3 deposition. Inhibition of C5 strongly inhibited late inflammation, as measured by neutrophil influx and induction of the murine CXC chemokines macrophage inflammatory protein-2, KC, and lipopolysaccharide-induced CXC chemokine. Anti-C5 treatment furthermore abrogated late I/R; induced apoptosis, whereas early apoptosis was not affected. Moreover, BB5.1 treatment significantly protected against I/R-induced renal dysfunction. Conclusions. Renal LIR is followed by activation of the Complement system and intrarenal deposition of C3 and MAC. Complement activation plays a crucial role in the regulation of inflammation and late apoptosis. Complement inhibition, by preventing C5 activation, abrogates late apoptosis and inflammation, being strongly protective against renal function loss.
Matthew C Pickering - One of the best experts on this subject based on the ideXlab platform.
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an engineered Complement Factor h construct for treatment of c3 glomerulopathy
Journal of The American Society of Nephrology, 2018Co-Authors: Yi Yang, Matthew C Pickering, Andrew P Herbert, Paul N Barlow, Kate Smithjackson, Harriet Denton, Owen R Davies, Heather Kerr, Kevin J MarchbankAbstract:Background C3 glomerulopathy (C3G) is associated with dysregulation of the alternative pathway of Complement activation, and treatment options for C3G remain limited. Complement Factor H (FH) is a potent regulator of the alternative pathway and might offer a solution, but the mass and complexity of FH makes generation of full-length FH far from trivial. We previously generated a mini-FH construct, with FH short consensus repeats 1–5 linked to repeats 18–20 (FH 1–5^18–20 ), that was effective in experimental C3G. However, the serum t 1/2 of FH 1–5^18–20 was significantly shorter than that of serum-purified FH. Methods We introduced the oligomerization domain of human FH-related protein 1 (denoted by R1–2) at the carboxy or amino terminus of human FH 1–5^18–20 to generate two homodimeric mini-FH constructs (FH R1–2^1–5^18–20 and FH 1–5^18–20^R1–2 , respectively) in Chinese hamster ovary cells and tested these constructs using binding, fluid-phase, and erythrocyte lysis assays, followed by experiments in FH-deficient Cfh−/− mice. Results FH R1–2^1–5^18–20 and FH 1–5^18–20^R1–2 homodimerized in solution and displayed avid binding profiles on clustered C3b surfaces, particularly FH R1–2^1–5^18–20 . Each construct was >10-fold more effective than FH at inhibiting cell surface Complement activity in vitro and restricted glomerular basement membrane C3 deposition in vivo significantly better than FH or FH 1–5^18–20 . FH 1–5^18–20^R1–2 had a C3 breakdown fragment binding profile similar to that of FH, a >5-fold increase in serum t 1/2 compared with that of FH 1–5^18–20 , and significantly better retention in the kidney than FH or FH 1–5^18–20 . Conclusions FH 1–5^18–20^R1–2 may have utility as a treatment option for C3G or other Complement-mediated diseases.
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circulating Complement Factor h related proteins 1 and 5 correlate with disease activity in iga nephropathy
Kidney International, 2017Co-Authors: Nicholas R Medjeralthomas, Terence H Cook, Hannah J Lomaxbrowne, Hannah Beckwith, Michelle Willicombe, Adam Mclean, P Brookes, Charles D Pusey, Mario Falchi, Matthew C PickeringAbstract:IgA nephropathy (IgAN) is a common cause of chronic kidney disease and end-stage renal failure, especially in young people. Due to a wide range of clinical outcomes and difficulty in predicting response to immunosuppression, we need to understand why and identify which patients with IgAN will develop progressive renal impairment. A deletion polymorphism affecting the genes encoding the Complement Factor H-related protein (FHR)-1 and FHR-3 is robustly associated with protection against IgAN. Some FHR proteins, including FHR-1 and FHR-5, antagonize the ability of Complement Factor H (fH), the major negative regulator of the Complement alternative pathway, to inhibit Complement activation on surfaces, a process termed fH deregulation. From a large cohort of patients, we demonstrated that plasma FHR-1 and the FHR-1/fH ratio were elevated in IgAN and associated with progressive disease. Plasma FHR-1 negatively correlated with eGFR but remained elevated in patients with IgAN with normal eGFR. Serum FHR5 was slightly elevated in IgAN but did not correlate with eGFR. Neither FHR5 levels nor the FHR-5/fH ratio was associated with progressive disease. However, higher serum FHR-5 levels were associated with a lack of response to immunosuppression, the presence of endocapillary hypercellularity, and histology scores of disease severity (the Oxford Classification MEST score). Thus, FHR-1 and FHR-5 have a role in IgAN disease progression.
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partial Complement Factor h deficiency associates with c3 glomerulopathy and thrombotic microangiopathy
Journal of The American Society of Nephrology, 2016Co-Authors: Katherine A Vernon, Terence H Cook, Marina Botto, Marieta M. Ruseva, Talat H Malik, Matthew C PickeringAbstract:The Complement-mediated renal diseases C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS) strongly associate with inherited and acquired abnormalities in the regulation of the Complement alternative pathway (AP). The major negative regulator of the AP is the plasma protein Complement Factor H (FH). Abnormalities in FH result in uncontrolled activation of C3 through the AP and associate with susceptibility to both C3G and aHUS. Although previously developed FH-deficient animal models have provided important insights into the mechanisms underlying susceptibility to these unique phenotypes, these models do not entirely reproduce the clinical observations. FH is predominantly synthesized in the liver. We generated mice with hepatocyte-specific FH deficiency and showed that these animals have reduced plasma FH levels with secondary reduction in plasma C3. Unlike mice with complete FH deficiency, hepatocyte-specific FH-deficient animals developed neither plasma C5 depletion nor accumulation of C3 along the glomerular basement membrane. In contrast, subtotal FH deficiency associated with mesangial C3 accumulation consistent with C3G. Although there was no evidence of spontaneous thrombotic microangiopathy, the hepatocyte-specific FH-deficient animals developed severe C5-dependent thrombotic microangiopathy after induction of Complement activation within the kidney by accelerated serum nephrotoxic nephritis. Taken together, our data indicate that subtotal FH deficiency can give rise to either spontaneous C3G or aHUS after a Complement-activating trigger within the kidney and that the latter is C5 dependent.
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treatment with human Complement Factor h rapidly reverses renal Complement deposition in Factor h deficient mice
Kidney International, 2010Co-Authors: Fadi Fakhouri, Terence H Cook, Elena Goicoechea De Jorge, Frederique Brune, Philippe Azam, Matthew C PickeringAbstract:Total deficiency of Complement Factor H (CFH) is associated with dense deposit disease and atypical hemolytic uremic syndrome. CFH is the major regulator of the alternative pathway of Complement activation and its complete deficiency results in uncontrolled C3 activation through this pathway and secondary C3 deficiency. Plasma infusion, as a source of CFH, has been used with variable success to treat renal disease associated with its deficiency. However, the risks of volume and protein overload limit this therapeutic approach. In this study, we investigated the efficacy of a purified human CFH (hCFH) preparation in Cfh-gene knockout mice. These mice spontaneously develop both secondary plasma C3 deficiency and a renal abnormality characterized by massive accumulation of C3 along the glomerular basement membrane. The renal lesion is analogous to human dense deposit disease. Treatment of knockout mice with hCFH resulted in rapid normalization of plasma C3 levels and resolution of the glomerular basement membrane C3 deposition. Long-term treatment of mice with hCFH was not possible because of the development of an immune response against hCFH. Hence, we suggest that hCFH can be an effective alternative therapy to plasma infusions in patients with renal disease associated with CFH deficiency.
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mesangial immune complex glomerulonephritis due to Complement Factor d deficiency
Kidney International, 2007Co-Authors: Maria Asuncion Abreraabeleda, Matthew C Pickering, Y. Xu, Richard J.h. Smith, Sanjeev M SethiAbstract:Complement Factor D is a serine protease essential for the activation of the alternative pathway and is expressed in the kidney, adipocytes, and macrophages. Factor D is found at relatively high levels in glomeruli suggesting that this component of the Complement cascade could influence renal pathophysiology. In this study, we utilize mice with a targeted deletion of the activating Complement Factor D gene and compare these results to mice with targeted deletion of the inhibitory Complement Factor H gene. Eight-month-old mice with a deleted Factor D gene spontaneously develop albuminuria and have reduced creatinine clearance due to mesangial immune complex glomerulonephritis. These mesangial deposits contain C3 and IgM. In contrast to the mesangial location of the immune deposits in the Factor D-deficient mice, age-matched Factor H-deficient mice develop immune deposits along the glomerular capillary wall. Our observations suggest that Complement Factor D or alternative pathway activation is needed to prevent spontaneous accumulation of C3 and IgM deposits within the mesangium. Our studies show that the Complement Factor D gene knockout mice are a novel model of spontaneous mesangial immune complex glomerulonephritis.
Benjamin M. Neale - One of the best experts on this subject based on the ideXlab platform.
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variation near Complement Factor i is associated with risk of advanced amd
European Journal of Human Genetics, 2009Co-Authors: Jesen Fagerness, Benjamin M. Neale, Robyn Reynolds, Mark J. Daly, Julian MallerAbstract:A case–control association study for advanced age-related macular degeneration was conducted to explore several regions of interest identified by linkage. This analysis identified a single nucleotide polymorphism just 3′ of Complement Factor I on chromosome 4 showing significant association (P<10−7). Sequencing was performed on coding exons in linkage disequilibrium with the detected association. No obvious functional variation was discovered that could be the proximate cause of the association, suggesting a noncoding regulatory mechanism.
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variation in Complement Factor 3 is associated with risk of age related macular degeneration
Nature Genetics, 2007Co-Authors: Jesen Fagerness, Benjamin M. Neale, Robyn Reynolds, Mark J. Daly, Julian MallerAbstract:The association of variants in Complement Factors H and B with age-related macular degeneration has led to more intense genetic and functional analysis of the Complement pathway. We identify a nonsynonymous coding change in Complement Factor 3 that is strongly associated with risk of age-related macular degeneration in a large case-control sample.