Activation of complement generates C5a which leads to signaling through C5aR 1. This is tightly controlled, including by the plasma proteins factor H （FH） and carboxypeptidase N. Here we studied a chronic serum sick...Activation of complement generates C5a which leads to signaling through C5aR 1. This is tightly controlled, including by the plasma proteins factor H （FH） and carboxypeptidase N. Here we studied a chronic serum sickness （CSS） model of glomerulonephritis （GN） in which there is an active humoral immune response, formation of glomerular immune complexes （ICs）, and resulting glomerular inflammation. The antibody response, glomerular IC deposition, the degree of GN, and consequent renal functional insufficiency in CSS were all worse in FH-/- mice compared to wild-type FH＋/＋ animals. This was ameliorated in the former by giving a C5aR1 antagonist for the final 3 weeks of the 5-week protocol. In contrast, blocking CP-mediated inactivation of C5a increased these disease measures. Thus, complement regulation by both plasma FH and CP to limit the quantity of active C5a is important in conditions where the humoral immune response is directed to a continuously present foreign antigen. Signaling through C5aR1 enhances the humoral immune response as well as the inflammatory response to ICs that have formed in glomeruli. Both effects are relevant even after disease has begun. Thus, pharmacological targeting of C5a in IC-mediated GN has potential clinical relevance.展开更多
Immune evasion is a strategy used by pathogenic microbes to evade the host immune system in order to ensure successful propagation. Immune evasion is particularly important for the blood stages of Plasmodium falciparu...Immune evasion is a strategy used by pathogenic microbes to evade the host immune system in order to ensure successful propagation. Immune evasion is particularly important for the blood stages of Plasmodium falciparum, the causative agent of the deadly disease malaria tropica. Because Plasmodium blood stage parasites require human erythrocytes for replication, their ability to evade attack by the human immune system is essential for parasite survival. In order to escape immunity-induced killing, the intraerythrocytic parasites have evolved a variety of evasion mechanisms, including expansion of plasmodial surface proteins, organ-specific sequestration of the infected red blood cells and acquisition of immune-regulatory proteins by the parasite. This review aims to highlight recent advances in the molecular understanding of the immune evasion strategies by P. falciparum, including antigenic variation, surface protein polymorphisms and invasion ligand diversification. The review will further discuss new findings on the regulatory mechanisms applied by P. falciparum to avoid lysis by the human complement as well as killing by immune factors of the mosquito vector.展开更多
Background The present study was undertaken to replicate the associations of representative polymorphisms in three genes （complement factor H （CFH）, complement factor B （BF） and HtrA serine peptidase 1 （HTRA1）...Background The present study was undertaken to replicate the associations of representative polymorphisms in three genes （complement factor H （CFH）, complement factor B （BF） and HtrA serine peptidase 1 （HTRA1）） with exudative age-related macular degeneration （AMD） in a Han Chinese population, and to test if the modifiable environmental factors affect AMD susceptibility associated with different type of genotype in these genes. Methods An age, gender and ethnicity matched case-control study was conducted to genotype the representative single neucleotide polymorphisms （SNPs） loci including rs1061170 and rs1410996 in CFH, rs641153 and rs4151667 in BF and rs11200638 in HTRA1 gene in 144 exudative AMD patients and 126 normal controls using PCR-RFLP and direct resequencing. The demographic characteristics and behavioral risk factors were also recorded. Allelic and genotypic associations for individual SNP and joint associations with two loci were performed. The gene-gene and gene-environment interactions were analyzed using multivariate non-conditional Logistic regression analysis. Results The C risk allele frequencies for CFH Y402H （rs1061170） in cases and controls were 12.5% and 5.4% respectively, which were much lower than those in Caucasians （P 〈0.001）. Compared with TT homozygous genotype, the CT heterozygous genotype was positively associated with AMD with odds ratio （OR） of 3.23 （1.36-5.07）. However, the population attributable risk （PAR） of C allele was only 3.3% （1.4%-4.3%）. rs1410996 was also associated with AMD independent of Y402H. The ORs of exudative AMD for individuals carrying one copy risk allele and two copy risk alleles were 2.57 （1.21-5.45） and 4.76 （2.15-10.55） respectively, with correspondent PARs of 28.3% （2.0%-40.5%） and 38.2% （21.8%-45.4%）. rs11200636 in HTRA1 was another susceptible locus for AMD and the risk homozygotes were significantly susceptible for exudutive AMD （OR=3.98, 1.88-8.43） with PAR of 38.9% （24.3%-45.8%）展开更多
文摘Activation of complement generates C5a which leads to signaling through C5aR 1. This is tightly controlled, including by the plasma proteins factor H （FH） and carboxypeptidase N. Here we studied a chronic serum sickness （CSS） model of glomerulonephritis （GN） in which there is an active humoral immune response, formation of glomerular immune complexes （ICs）, and resulting glomerular inflammation. The antibody response, glomerular IC deposition, the degree of GN, and consequent renal functional insufficiency in CSS were all worse in FH-/- mice compared to wild-type FH＋/＋ animals. This was ameliorated in the former by giving a C5aR1 antagonist for the final 3 weeks of the 5-week protocol. In contrast, blocking CP-mediated inactivation of C5a increased these disease measures. Thus, complement regulation by both plasma FH and CP to limit the quantity of active C5a is important in conditions where the humoral immune response is directed to a continuously present foreign antigen. Signaling through C5aR1 enhances the humoral immune response as well as the inflammatory response to ICs that have formed in glomeruli. Both effects are relevant even after disease has begun. Thus, pharmacological targeting of C5a in IC-mediated GN has potential clinical relevance.
文摘Immune evasion is a strategy used by pathogenic microbes to evade the host immune system in order to ensure successful propagation. Immune evasion is particularly important for the blood stages of Plasmodium falciparum, the causative agent of the deadly disease malaria tropica. Because Plasmodium blood stage parasites require human erythrocytes for replication, their ability to evade attack by the human immune system is essential for parasite survival. In order to escape immunity-induced killing, the intraerythrocytic parasites have evolved a variety of evasion mechanisms, including expansion of plasmodial surface proteins, organ-specific sequestration of the infected red blood cells and acquisition of immune-regulatory proteins by the parasite. This review aims to highlight recent advances in the molecular understanding of the immune evasion strategies by P. falciparum, including antigenic variation, surface protein polymorphisms and invasion ligand diversification. The review will further discuss new findings on the regulatory mechanisms applied by P. falciparum to avoid lysis by the human complement as well as killing by immune factors of the mosquito vector.
文摘Background The present study was undertaken to replicate the associations of representative polymorphisms in three genes （complement factor H （CFH）, complement factor B （BF） and HtrA serine peptidase 1 （HTRA1）） with exudative age-related macular degeneration （AMD） in a Han Chinese population, and to test if the modifiable environmental factors affect AMD susceptibility associated with different type of genotype in these genes. Methods An age, gender and ethnicity matched case-control study was conducted to genotype the representative single neucleotide polymorphisms （SNPs） loci including rs1061170 and rs1410996 in CFH, rs641153 and rs4151667 in BF and rs11200638 in HTRA1 gene in 144 exudative AMD patients and 126 normal controls using PCR-RFLP and direct resequencing. The demographic characteristics and behavioral risk factors were also recorded. Allelic and genotypic associations for individual SNP and joint associations with two loci were performed. The gene-gene and gene-environment interactions were analyzed using multivariate non-conditional Logistic regression analysis. Results The C risk allele frequencies for CFH Y402H （rs1061170） in cases and controls were 12.5% and 5.4% respectively, which were much lower than those in Caucasians （P 〈0.001）. Compared with TT homozygous genotype, the CT heterozygous genotype was positively associated with AMD with odds ratio （OR） of 3.23 （1.36-5.07）. However, the population attributable risk （PAR） of C allele was only 3.3% （1.4%-4.3%）. rs1410996 was also associated with AMD independent of Y402H. The ORs of exudative AMD for individuals carrying one copy risk allele and two copy risk alleles were 2.57 （1.21-5.45） and 4.76 （2.15-10.55） respectively, with correspondent PARs of 28.3% （2.0%-40.5%） and 38.2% （21.8%-45.4%）. rs11200636 in HTRA1 was another susceptible locus for AMD and the risk homozygotes were significantly susceptible for exudutive AMD （OR=3.98, 1.88-8.43） with PAR of 38.9% （24.3%-45.8%）
