BACKGROUND Complement overactivation is a major driver of lupus nephritis(LN).Impaired interactions of C-reactive protein(CRP)with complement factor H(CFH)have been shown as a pathogenic mechanism that contributes to ...BACKGROUND Complement overactivation is a major driver of lupus nephritis(LN).Impaired interactions of C-reactive protein(CRP)with complement factor H(CFH)have been shown as a pathogenic mechanism that contributes to the overactivation of complement in LN.However,genetic variations of neither CRP nor CFH show consistent influences on the risk of LN.AIM To examine whether genetic variations of CRP and CFH in combination can improve the risk stratification in Chinese population.METHODS We genotyped six CRP single nucleotide polymorphisms(SNPs)(rs1205,rs3093062,rs2794521,rs1800947,rs3093077,and rs1130864)and three CFH SNPs(rs482934,rs1061170,and rs1061147)in 270 LN patients and 303 healthy subjects.RESULTS No linkage was found among CRP and CFH SNPs,indicating lack of genetic interactions between the two genes.Moreover,CRP and CFH SNPs,neither individually nor in combination,are associated with the risk or clinical manifestations of LN.Given the unambiguous pathogenic roles of the two genes.CONCLUSION These findings suggest that the biological effects of most genetic variations of CRP and CFH on their expressions or activities are not sufficient to influence the disease course of LN.展开更多
Angiogenesis,the process of formation of new capillaries from existing blood vessels,is required for multiple physiological and pathological processes.Complement factorH(CFH)is a plasma protein that inhibits the alter...Angiogenesis,the process of formation of new capillaries from existing blood vessels,is required for multiple physiological and pathological processes.Complement factorH(CFH)is a plasma protein that inhibits the alternative pathway of the complement system.Loss of CFH enhances the alternative pathway and increases complement activation fragments with pro-angiogenic capacity,including complement 3a,complement 5a,and membrane attack complex.CFH protein contains binding sites for C-reactive protein,malondialdehyde,and endothelial heparan sulfates.Dysfunction of CFH prevents its interaction with these molecules and initiates pro-angiogenic events.Mutations in the CFH gene have been found in patients with age-related macular degeneration characterized by choroidal neovascularization.The Cfh-deficient mice show an increase in angiogenesis,which is decreased by administration of recombinant CFH protein.In this review,we summarize the molecular mechanisms of the anti-angiogenic effects of CFH and the regulatory mechanisms of CFH expression.The therapeutic potential of recombinant CFH protein in angiogenesisrelated diseases has also been discussed.展开更多
AIM: Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world and complement factor H (CFH) polymorphism has been found to associate with the AMD. To investigate whether the Y402...AIM: Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world and complement factor H (CFH) polymorphism has been found to associate with the AMD. To investigate whether the Y402H variant in CFH is associated with AMD in Chinese populations, a systematic review and meta-analysis were performed to estimate the magnitude of the gene effect and the possible mode of action. METHODS: A meta-analysis was performed using data available from ten case-control studies assessing association between the CFH Y402H polymorphism and AMD in Chinese populations involving 1538 AMD. Data extraction and study quality assessment were performed in duplicate. Summary odds ratios (ORs) and 95% confidence intervals (CIs) an allele contrast and genotype contrast were estimated usingfixed- effects models. The Q-statistic test was used to assess heterogeneity, and Funnel plot was used to evaluate publication bias. RESULTS: Seven of ten case-control studies were neovascular AMD, and few studies came from west and north of China. There was strong evidence for association between CFH and AMD in Chinese population, with those having risk allele C 2.35 times more likely to have AMD than subjects with T allele. Evidence of publication bias was not observed in our meta-analysis. CONCLUSION: This meta-analysis summarizes the strong evidence for an association between CFH and AMD in Chinese and indicates each C allele increasing the odds of AMD by 2.33-fold. But more evidences about the relation between CFH polymorphism and different type of Chinese AMD from various district were needed.展开更多
目的探讨血清半乳糖缺陷型IgA1(galactose-deficient IgA1,Gd-IgA1)、补体C4、补体因子H(complement factor H,CFH)和补体因子H相关蛋白(complement factor H related proteins,CFHRP)1、3、5在IgA肾病(IgA nephropathy,IgAN)中的诊断...目的探讨血清半乳糖缺陷型IgA1(galactose-deficient IgA1,Gd-IgA1)、补体C4、补体因子H(complement factor H,CFH)和补体因子H相关蛋白(complement factor H related proteins,CFHRP)1、3、5在IgA肾病(IgA nephropathy,IgAN)中的诊断价值。方法本研究为回顾性研究,收集2021年11月1日至2023年12月31日在雅安市人民医院行肾穿刺活检诊断为原发性IgAN的患者58例,同期其他肾小球疾病患者48例和健康志愿者20名作为对照,采用酶联免疫吸附分析法检测上述对象血清IgA、补体C4、Gd-IgA1、CFH、CFHRP1、3、5浓度并行组间比较,绘制受试者工作特征曲线评估血清Gd-IgA1、Gd-IgA1/CFH、CFHRP1/CFH、CFHRP5/CFH在IgAN中的诊断价值,筛选出受试者工作特征曲线的曲线下面积较大的指标Gd-IgA1、CFHRP1/CFH、CFHRP5/CFH,重点研究Gd-IgA1分别联合检测CFHRP1/CFH、CFHRP5/CFH对IgAN的诊断价值。结果原发性IgAN组患者血清IgA[1.568(1.344,1.705)g/L比1.177(0.618,1.893)g/L、0.538(0.433,0.732)g/L]、补体C4[0.547(0.494,0.643)g/L比0.396(0.312,0.515)g/L、0.289(0.186,0.356)g/L]、Gd-IgA1[0.003(0.002,0.004)g/L比0.002(0.001,0.003)g/L、0.0017(0.0010,0.0020)g/L]、CFHRP1[0.013(0.011,0.015)g/L比0.010(0.009,0.013)g/L、0.011(0.009,0.012)g/L]水平及Gd-IgA1/CFH[0.023(0.017,0.030)比0.012(0.009,0.021)mmol/L、0.005(0.004,0.007)mmol/L]、CFHRP1/CFH[0.115(0.091,0.161)比0.093(0.061,0.108)、0.038(0.028,0.043)]比值明显高于其他肾小球疾病组和健康组(P<0.05),血清CFH[0.000109(0.000089,0.000110)g/L比0.000285(0.000259,0.000347)g/L]浓度低于健康组(P<0.05);血清Gd-IgA1联合CFHRP1/CFH、CFHRP5/CFH诊断原发性IgAN的曲线下面积分别为0.946(95%CI:0.908~0.985)、0.926(95%CI:0.874~0.978),灵敏度分别为80%、90%,特异度分别为93.9%、86.3%。结论Gd-IgA1联合检测CFHRP1/CFH、CFHRP5/CFH对于诊断原发性IgAN具有较好价值,或可作为诊断IgAN的潜在无创性生物标志物。展开更多
Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD includes soft drusen and pigmentary changes in the retinal pigment epithelium (RPE). ...Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD includes soft drusen and pigmentary changes in the retinal pigment epithelium (RPE). As people age, such soft confluent drusen can progress into two forms of advanced AMD, geographic atrophy (GA, or dry AMD) or choroidal neovascularization (CNV, or wet AMD) and result in the loss of central vision. The exact mechanism for developing early AMD and progressing to advanced stage of disease is still largely unknown. However, significant evidence exists demonstrating a complex interplay of genetic and environmental factors as the cause of AMD progression. Together, complement factor H (CFH) and HTRA1/ARMS polymorphisms contribute to more than 50% of the genetic risk for AMD. Environmentally, oxidative stress from activities such as smoking has also demonstrated a powerful contribution to AMD progression. To extend our previous finding that genetic polymorphisms in CFH results in OxPLs and the risk-form of CFH (CFH Y402H) has reduced affinity for oxidized phospholipids, and subsequent diminished capacity which subsequently diminishes the capability to attenuate the inflammatory effects of these molecules, we compared the binding properties of CFH and CFH related protein 1 (CFHR1), which is also associated with disease risk, to OxPLs and their effects on modulating inflammation and lipids uptake. As both CFH-402H and CFHR1 are associated with increased risk to AMD, we hypothesized that like CFH-402H, CFHR1 contribution to AMD risk may also be due to its diminished affinity for OxPLs. Interestingly, we found that association of CFHR1 with OxPLs was not statistically different than CFH. However, binding of CFHR1 did not elicit the same protective benefits as CFH in that both inflammation and lipid uptake are unaffected by CFHR1 association with OxPLs. These findings demonstrate a novel and interesting complexity to the potential interplay between the complement system and oxidative stress byproducts, such as OxPLs, in the mechanistic contribution to AMD. Future work will aim to identify the molecular distinctions between CFH and CFHR1 which confer protection by the former, but not latter molecules. Understanding the molecular domains necessary for protection could provide interventional insights in the generation of novel therapeutics for AMD and other diseases associated with oxidative stress.展开更多
目的筛选家系早发冠心病血瘀证的特异性蛋白,为今后临床早期诊断和预防疾病提供潜在生物标志物。方法通过同位素相对标记与绝对定量技术(isobaric tags for relative and absolute quantification,i TRAQ)分析家系早发冠心病血瘀证患者...目的筛选家系早发冠心病血瘀证的特异性蛋白,为今后临床早期诊断和预防疾病提供潜在生物标志物。方法通过同位素相对标记与绝对定量技术(isobaric tags for relative and absolute quantification,i TRAQ)分析家系早发冠心病血瘀证患者、家系早发冠心病非血瘀证患者及健康人的血浆蛋白表达,数据分析后得到各组间的差异蛋白表达情况,再经差异蛋白筛选标准初步得到疾病的预测蛋白,并使用Western blot验证预测蛋白。结果通过i TRAQ技术共得到差异蛋白75个,其中家系早发冠心病血瘀证组与健康对照组之间共得到32个差异蛋白,包括22个上调蛋白与10个下调蛋白,共涉及429个生物学过程,其与角质化、皮肤发展、蛋白质激活级联反应等关系最为密切;在代谢途径金黄色葡萄球菌感染、补体和凝血级联、血小板激活等KEGG通路上富集。与健康对照组相比,家系早发冠心病血瘀证组差异蛋白补体因子H(complement factor H,CFH)表达水平差异有统计学意义(P<0.01)。结论经差异蛋白筛选标准得到的CFH蛋白,可作为家系早发冠心病血瘀证早期诊断的潜在生物标志物。展开更多
Complement (C) activation-related hypersensitivity reactions (HSRs) represent an unsolved adverse immune effect of many i.v. administered “nanomedicines”, such as liposomal doxorubicin (Doxil/Caelyx). Because these ...Complement (C) activation-related hypersensitivity reactions (HSRs) represent an unsolved adverse immune effect of many i.v. administered “nanomedicines”, such as liposomal doxorubicin (Doxil/Caelyx). Because these pseudoallergic reactions can be severe or even lethal, it is an important clinical objective to find biomarkers for proneness for C activation by reactogenic nanoparticles that will allow the prediction of in vivo reactions by in vitro assays. With this goal in mind we identified a normal human blood donor who consistently showed high sensitivity to Caelyx-induced C activation in vitro, whose plasma (Caelyx sensitive plasma, CSP) was subjected to proteome profiling with a library of human plasma proteome specific mAbs. The chip (PlasmaScan-380TM) contained 380 non redundant (with respect to epitopes) mAbs. The analysis revealed 8 proteins that were differentially represented in CSP in comparison with Caelyx-insensitive control plasma. These proteins were identified by mass spectrometry and Western blot analyses to represent factor H (decreased in CSP), factor H related protein, serum amyloid P component, fibronectin, complement component C4, Apo B100, prothrombin and alpha-2-HS glycoprotein (all increased in CSP). Some of these protein changes are consistent with proneness for increased C activation, suggesting the potential use of this method in the search for biomarkers for liposome-induced or other types of nanomedicine-induced HSRs.展开更多
文摘BACKGROUND Complement overactivation is a major driver of lupus nephritis(LN).Impaired interactions of C-reactive protein(CRP)with complement factor H(CFH)have been shown as a pathogenic mechanism that contributes to the overactivation of complement in LN.However,genetic variations of neither CRP nor CFH show consistent influences on the risk of LN.AIM To examine whether genetic variations of CRP and CFH in combination can improve the risk stratification in Chinese population.METHODS We genotyped six CRP single nucleotide polymorphisms(SNPs)(rs1205,rs3093062,rs2794521,rs1800947,rs3093077,and rs1130864)and three CFH SNPs(rs482934,rs1061170,and rs1061147)in 270 LN patients and 303 healthy subjects.RESULTS No linkage was found among CRP and CFH SNPs,indicating lack of genetic interactions between the two genes.Moreover,CRP and CFH SNPs,neither individually nor in combination,are associated with the risk or clinical manifestations of LN.Given the unambiguous pathogenic roles of the two genes.CONCLUSION These findings suggest that the biological effects of most genetic variations of CRP and CFH on their expressions or activities are not sufficient to influence the disease course of LN.
基金supported by the National Nature Science Foundation of China (82171318,82241030,82011530024)the State Program of Scientific Research“Natural resources and the Environment” (3.01,2020–2021,Belarus)Academic Promotion Program of Shandong First Medical University (2019QL014)and Shandong Taishan Scholarship (J.L).
文摘Angiogenesis,the process of formation of new capillaries from existing blood vessels,is required for multiple physiological and pathological processes.Complement factorH(CFH)is a plasma protein that inhibits the alternative pathway of the complement system.Loss of CFH enhances the alternative pathway and increases complement activation fragments with pro-angiogenic capacity,including complement 3a,complement 5a,and membrane attack complex.CFH protein contains binding sites for C-reactive protein,malondialdehyde,and endothelial heparan sulfates.Dysfunction of CFH prevents its interaction with these molecules and initiates pro-angiogenic events.Mutations in the CFH gene have been found in patients with age-related macular degeneration characterized by choroidal neovascularization.The Cfh-deficient mice show an increase in angiogenesis,which is decreased by administration of recombinant CFH protein.In this review,we summarize the molecular mechanisms of the anti-angiogenic effects of CFH and the regulatory mechanisms of CFH expression.The therapeutic potential of recombinant CFH protein in angiogenesisrelated diseases has also been discussed.
文摘AIM: Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world and complement factor H (CFH) polymorphism has been found to associate with the AMD. To investigate whether the Y402H variant in CFH is associated with AMD in Chinese populations, a systematic review and meta-analysis were performed to estimate the magnitude of the gene effect and the possible mode of action. METHODS: A meta-analysis was performed using data available from ten case-control studies assessing association between the CFH Y402H polymorphism and AMD in Chinese populations involving 1538 AMD. Data extraction and study quality assessment were performed in duplicate. Summary odds ratios (ORs) and 95% confidence intervals (CIs) an allele contrast and genotype contrast were estimated usingfixed- effects models. The Q-statistic test was used to assess heterogeneity, and Funnel plot was used to evaluate publication bias. RESULTS: Seven of ten case-control studies were neovascular AMD, and few studies came from west and north of China. There was strong evidence for association between CFH and AMD in Chinese population, with those having risk allele C 2.35 times more likely to have AMD than subjects with T allele. Evidence of publication bias was not observed in our meta-analysis. CONCLUSION: This meta-analysis summarizes the strong evidence for an association between CFH and AMD in Chinese and indicates each C allele increasing the odds of AMD by 2.33-fold. But more evidences about the relation between CFH polymorphism and different type of Chinese AMD from various district were needed.
文摘目的探讨血清半乳糖缺陷型IgA1(galactose-deficient IgA1,Gd-IgA1)、补体C4、补体因子H(complement factor H,CFH)和补体因子H相关蛋白(complement factor H related proteins,CFHRP)1、3、5在IgA肾病(IgA nephropathy,IgAN)中的诊断价值。方法本研究为回顾性研究,收集2021年11月1日至2023年12月31日在雅安市人民医院行肾穿刺活检诊断为原发性IgAN的患者58例,同期其他肾小球疾病患者48例和健康志愿者20名作为对照,采用酶联免疫吸附分析法检测上述对象血清IgA、补体C4、Gd-IgA1、CFH、CFHRP1、3、5浓度并行组间比较,绘制受试者工作特征曲线评估血清Gd-IgA1、Gd-IgA1/CFH、CFHRP1/CFH、CFHRP5/CFH在IgAN中的诊断价值,筛选出受试者工作特征曲线的曲线下面积较大的指标Gd-IgA1、CFHRP1/CFH、CFHRP5/CFH,重点研究Gd-IgA1分别联合检测CFHRP1/CFH、CFHRP5/CFH对IgAN的诊断价值。结果原发性IgAN组患者血清IgA[1.568(1.344,1.705)g/L比1.177(0.618,1.893)g/L、0.538(0.433,0.732)g/L]、补体C4[0.547(0.494,0.643)g/L比0.396(0.312,0.515)g/L、0.289(0.186,0.356)g/L]、Gd-IgA1[0.003(0.002,0.004)g/L比0.002(0.001,0.003)g/L、0.0017(0.0010,0.0020)g/L]、CFHRP1[0.013(0.011,0.015)g/L比0.010(0.009,0.013)g/L、0.011(0.009,0.012)g/L]水平及Gd-IgA1/CFH[0.023(0.017,0.030)比0.012(0.009,0.021)mmol/L、0.005(0.004,0.007)mmol/L]、CFHRP1/CFH[0.115(0.091,0.161)比0.093(0.061,0.108)、0.038(0.028,0.043)]比值明显高于其他肾小球疾病组和健康组(P<0.05),血清CFH[0.000109(0.000089,0.000110)g/L比0.000285(0.000259,0.000347)g/L]浓度低于健康组(P<0.05);血清Gd-IgA1联合CFHRP1/CFH、CFHRP5/CFH诊断原发性IgAN的曲线下面积分别为0.946(95%CI:0.908~0.985)、0.926(95%CI:0.874~0.978),灵敏度分别为80%、90%,特异度分别为93.9%、86.3%。结论Gd-IgA1联合检测CFHRP1/CFH、CFHRP5/CFH对于诊断原发性IgAN具有较好价值,或可作为诊断IgAN的潜在无创性生物标志物。
文摘Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD includes soft drusen and pigmentary changes in the retinal pigment epithelium (RPE). As people age, such soft confluent drusen can progress into two forms of advanced AMD, geographic atrophy (GA, or dry AMD) or choroidal neovascularization (CNV, or wet AMD) and result in the loss of central vision. The exact mechanism for developing early AMD and progressing to advanced stage of disease is still largely unknown. However, significant evidence exists demonstrating a complex interplay of genetic and environmental factors as the cause of AMD progression. Together, complement factor H (CFH) and HTRA1/ARMS polymorphisms contribute to more than 50% of the genetic risk for AMD. Environmentally, oxidative stress from activities such as smoking has also demonstrated a powerful contribution to AMD progression. To extend our previous finding that genetic polymorphisms in CFH results in OxPLs and the risk-form of CFH (CFH Y402H) has reduced affinity for oxidized phospholipids, and subsequent diminished capacity which subsequently diminishes the capability to attenuate the inflammatory effects of these molecules, we compared the binding properties of CFH and CFH related protein 1 (CFHR1), which is also associated with disease risk, to OxPLs and their effects on modulating inflammation and lipids uptake. As both CFH-402H and CFHR1 are associated with increased risk to AMD, we hypothesized that like CFH-402H, CFHR1 contribution to AMD risk may also be due to its diminished affinity for OxPLs. Interestingly, we found that association of CFHR1 with OxPLs was not statistically different than CFH. However, binding of CFHR1 did not elicit the same protective benefits as CFH in that both inflammation and lipid uptake are unaffected by CFHR1 association with OxPLs. These findings demonstrate a novel and interesting complexity to the potential interplay between the complement system and oxidative stress byproducts, such as OxPLs, in the mechanistic contribution to AMD. Future work will aim to identify the molecular distinctions between CFH and CFHR1 which confer protection by the former, but not latter molecules. Understanding the molecular domains necessary for protection could provide interventional insights in the generation of novel therapeutics for AMD and other diseases associated with oxidative stress.
文摘Complement (C) activation-related hypersensitivity reactions (HSRs) represent an unsolved adverse immune effect of many i.v. administered “nanomedicines”, such as liposomal doxorubicin (Doxil/Caelyx). Because these pseudoallergic reactions can be severe or even lethal, it is an important clinical objective to find biomarkers for proneness for C activation by reactogenic nanoparticles that will allow the prediction of in vivo reactions by in vitro assays. With this goal in mind we identified a normal human blood donor who consistently showed high sensitivity to Caelyx-induced C activation in vitro, whose plasma (Caelyx sensitive plasma, CSP) was subjected to proteome profiling with a library of human plasma proteome specific mAbs. The chip (PlasmaScan-380TM) contained 380 non redundant (with respect to epitopes) mAbs. The analysis revealed 8 proteins that were differentially represented in CSP in comparison with Caelyx-insensitive control plasma. These proteins were identified by mass spectrometry and Western blot analyses to represent factor H (decreased in CSP), factor H related protein, serum amyloid P component, fibronectin, complement component C4, Apo B100, prothrombin and alpha-2-HS glycoprotein (all increased in CSP). Some of these protein changes are consistent with proneness for increased C activation, suggesting the potential use of this method in the search for biomarkers for liposome-induced or other types of nanomedicine-induced HSRs.
