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PubMed1976

Relationship of functional levels of early components of complement to the H-2 complex of mice.

The relationship between the H-2 complex and the complement system was studied by performing functional assays for whole complement and individual complement components on sera from congenic mice of B10 and C3H backgrounds. Levels of whole complement activity were seen to be influenced by S region genes, confirming the work of others. Levels of C3 through C9, however, were independent of the H-I genotypes suggesting that the differences in whole complement activities were due to variation in levels of C1, C4 or C2. Titrations of these three earliest acting classical complement components were performed on sera from mice of nine strains of the B10 background and four strains of the C3H background. It was shown that functional levels of C1, C4, and C2 were all under control of genes within or very closely linked to the S region.

Animals↗
PubMed1986

Complement genes of the major histocompatibility complex (complotypes), extended haplotypes and disease markers.

The human major histocompatibility complex (MHC)-linked genes C2,BF,C4A,C4B occur in populations and segregate in families as single genetic units or complotypes. Analysis for significant three-point linkage disequilibrium between HLA-B, DR and complotype on normal caucasian chromosomes 6p yields about a dozen haplotypes that account for most of the known HLA-B/HLA-DR linkage disequilibrium pairs previously noted in normal caucasian populations. We refer to the HLA-B/DR/complotype sets with significant linkage disequilibrium as extended haplotypes since they often show limited variation at other MHC-linked loci. From the study of MHC haplotypes in 21-hydroxylase deficiency, C2 deficiency and type 1 diabetes, it is becoming apparent that it is extended haplotypes rather than their individual alleles that are markers for these MHC-associated diseases.

Adrenal Hyperplasia, Congenital↗
PubMed1987

Identification of HLA-B44 subtypes associated with extended MHC haplotypes.

The HLA class I antigen B44 is found in each of two different extended major histocompatibility haplotypes (allele combinations of HLA-B, HLA-DR, and complement genes BF, C2, C4A, and C4B in linkage disequilibrium). Using isoelectric focusing, two variants of HLA-B44 were identified. The basic variant was found in all cell lines with the extended haplotype HLA-B44, DR7, FC31, and the acidic variant in all cell lines with the extended haplotype HLA-B44, DR4, SC30. The occurrence of each antigen variant with a unique extended haplotype explains previous observations concerning the nonrandom association of B44 variants with DR antigens.

Cell Line↗
PubMed1986

Effect of the nephrotic syndrome on the concentration of serum complement components.

The concentration of 12 component and four control proteins of the complement system was measured in serum from 43 children with a nephrotic syndrome, which subsequently proved to be steroid-responsive, and from 13 children with focal glomerulosclerosis (FGS) and was compared with values from 197 normal subjects. Of classical pathway complement components, 40% of patients had low C1q levels and 20%, low C2 levels. Mean serum levels of C1s, C4, C1INH, and C4bp were elevated. Of alternative pathway components, factors B and I were low in one third, while levels of C3 and H were commonly elevated. Of the terminal components, only C8 and C9 were low. In five patients with FGS with hypoalbuminemia without edema, all component levels were normal. With the exception of C1q, C1s, and C8, high molecular weight (mol wt) components were in high concentration and low mol wt components in low concentration. The three exceptions may be explained by the subunit structure of C1 and C8. From a practical standpoint, the study indicates that edematous patients with a nephrotic syndrome may have low serum levels of C1q and C2, simulating classical pathway complement activation such as commonly occurs in glomerulonephritis. However, low levels of C4, and possibly C1s, can be used as indicators of classical pathway activation since their levels are not reduced by a nephrotic syndrome.

Adolescent↗
PubMed1990

Major histocompatibility complex markers and red cell antibodies to the Rh (D) antigen. Absence of association.

Between 20 and 35 percent of Rh(D) antigen-negative individuals do not develop antibodies to D even after multiple transfusions of Rh-positive red cells. To evaluate the possibility that antibody production after exposure to the D antigen was related to a major histocompatibility complex immune response gene, analysis of the HLA genotypes of 38 Rh-sensitized women and their families was performed. No significant deviations were found in the frequency of any individual HLA class I, II, or III allele or of any extended haplotype (fixed allelic combinations of HLA-B, HLA-DR, and the complement components BF, C2, C4A, and C4B). Type 1 errors due to the extreme allelic polymorphism of the HLA system, as well as the ethnic variation in patient groups, may have contributed to HLA allele-antibody responder relationships reported in earlier studies.

Female↗
PubMed2002

C1s, the protease messenger of C1. Structure, function and physiological significance.

C1s is the modular serine protease, which executes the catalytic function of the C1 complex: the cleavage of C4 and C2. Like other complement serine proteases C1s has restricted substrate specificity and it is engaged into specific interactions with other subcomponents of the complement system. There has been a rapid progress in determining the 3D structure of complement serine proteases and in revealing the role of the individual domains in the protein-protein interaction properties. In this review we summarize recent findings on the structure of C1s, and on the mechanism of action of this protease. The results obtained by genetic engineering, physico-chemical and functional studies are reviewed. The physiological relevance of the proteolytic action of C1s and its possible implications in health and disease will also be discussed.

Animals↗
PubMed1983

Intra HLA-D/DR region recombinant detected by primed lymphocyte typing (PLT).

The chromosome 6 markers, HLA-ABC, D, DR, MT, properdin factor Bf, and complement factors 2 (C2) and 5 (C4), were studied in three families, each of which included two HLA identical siblings, one or both of whom were known to be HLA-B: GLO recombinants. The families were also typed with primed lymphocyte typing (PLT) for HLA-D/DR region associated DP antigens. None of these studies gave evidence that the recombinations had occurred within the HLA region. Mixed leucocyte culture (MLC) tests within the families showed no detectable stimulation between the HLA identical siblings in two of the families, but a very weak stimulation between the HLA identical siblings (H and G) in the third family (GG). No reactive PLT reagents were generated when cells from the HLA identical siblings of the first two families were primed against each other. In contrast, priming between cells of H and G gave rise to reactive reagents. One of these (GHx), reacted with a determinant which segregated within the GG family as if child G was a paternal recombinant between the HLA-D, DR, DP, and C4 loci, on the one hand, and on the other hand one or more loci governing other HLA-D/DR region controlled lymphocyte activating determinants. This reagent was only restimulated by cells from two of 47 unrelated individuals. The other PLT reagent (HGx) did not give a clearcut pattern within the family because it was weakly positive with all family members (most of whom were D/DR2-positive) except the specific responder; in the panel it reacted with a determinant significantly associated with D/DR/DP2. Other PLT reagents could be generated within the family against lymphocyte activating determinants controlled by genes in the two paternal haplotypes telomeric to the assumed recombinational site. These reagents gave stronger reactions than the HGx and GHx reagents and reacted with two determinants in the unrelated panel strongly associated with D/DR/DP2 and D/DR/DP6, respectively. It seems likely that the GG family represents a third example of a recombination between the HLA-DR and SB loci. Our findings further support the assumption that the DR determinants may be immunodominant in lymphocyte activation.

Chromosomes, Human, 6-12 and X↗
PubMed2006

Membrane-spanning and periplasmic segments of CcmI have distinct functions during cytochrome c Biogenesis in Rhodobacter capsulatus.

In gram-negative bacteria, like Rhodobacter capsulatus, about 10 membrane-bound components (CcmABCDEFGHI and CcdA) are required for periplasmic maturation of c-type cytochromes. These components perform the chaperoning and thio-oxidoreduction of the apoproteins as well as the delivery and ligation of the heme cofactors. In the absence of any of these components, including CcmI, proposed to act as an apocytochrome c chaperone, R. capsulatus does not have the ability to produce holocytochromes c or consequently to exhibit photosynthetic growth and cytochrome cbb3 oxidase activity. Previously, we have demonstrated that null mutants of CcmI partially overcome cytochrome c deficiency phenotypes upon overproduction of the CcmF-R. capsulatus CcmH (CcmF-CcmH(Rc)) couple in a growth medium-dependent manner and fully bypass these defects by additional overproduction of CcmG. Here, we show that overproduction of the CcmF-CcmH(Rc) couple and overproduction of the N-terminal membrane-spanning segment of CcmI (CcmI-1) have similar suppression effects of cytochrome c maturation defects in CcmI-null mutants. Likewise, additional overproduction of CcmG, the C-terminal periplasmic segment of CcmI (CcmI-2), or even of apocytochrome c2 also provides complementation abilities similar to those of these mutants. These results indicate that the two segments of CcmI have different functions and support our earlier findings that two independent steps are required for full recovery of the loss of CcmI function. We therefore propose that CcmI-1 is part of the CcmF-CcmH(Rc)-dependent heme ligation, while CcmI-2 is involved in the CcdA- and CcmG-dependent apoprotein thioreduction steps, which intersect at the level of CcmI during cytochrome c biogenesis.

Bacterial Outer Membrane Proteins↗
PubMed2025

Transcriptome-wide analysis reveals potential roles of CFD and ANGPTL4 in fibroblasts regulating B cell lineage for extracellular matrix-driven clustering and novel avenues for immunotherapy in breast cancer.

BACKGROUND: The remodeling of the extracellular matrix (ECM) plays a pivotal role in tumor progression and drug resistance. However, the compositional patterns of ECM in breast cancer and their underlying biological functions remain elusive. METHODS: Transcriptome and genome data of breast cancer patients from TCGA database was downloaded. Patients were classified into different clusters by using non-negative matrix factorization (NMF) based on signatures of ECM components and regulators. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify core genes related to ECM clusters. Additional 10 independent public cohorts including Metabric, SCAN_B, GSE12276, GSE16446, GSE19615, GSE20685, GSE21653, GSE58644, GSE58812, and GSE88770 were collected to construct Training or Testing cohort, following machine learning calculating ECM correlated index (ECI) for survival analysis. Pathway enrichment and correlation analysis were used to explore the relationship among ECM clusters, ECI and TME. Single-cell transcriptome data from GSE161529 was processed for uncovering the differences among ECM clusters. RESULTS: Using NMF, we identified three ECM clusters in the TCGA database: C1 (Neuron), C2 (ECM), and C3 (Immune). Subsequently, WGCNA was employed to pinpoint cluster-specific genes and develop a prognostic model. This model demonstrated robust predictive power for breast cancer patient survival in both the Training cohort (n = 5,392, AUC = 0.861) and the Testing cohort (n = 1,344, AUC = 0.711). Upon analyzing the tumor microenvironment (TME), we discovered that fibroblasts and B cell lineage were the core cell types associated with the ECM cluster phenotypes. Single-cell RNA sequencing data further revealed that angiopoietin like 4 (ANGPTL4)+ fibroblasts were specifically linked to the C2 phenotype, while complement factor D (CFD)+ fibroblasts characterized the other ECM clusters. CellChat analysis indicated that ANGPTL4+ and CFD+ fibroblasts regulate B cell lineage via distinct signaling pathways. Additionally, analysis using the Kaplan-Meier Plotter website showed that CFD was favorable for immunotherapy response, whereas ANGPTL4 negatively impacted the outcomes of cancer patients receiving immunotherapy. CONCLUSION: We identified distinct ECM clusters in breast cancer patients, irrespective of molecular subtypes. Additionally, we constructed an effective prognostic model based on these ECM clusters and recognized ANGPTL4+ and CFD+ fibroblasts as potential biomarkers for immunotherapy in breast cancer.

Humans↗
PubMedDate not supplied

[Complex studies of virology, microbiology, biochemistry and epidemiology in the adults of a semi-closed community vaccinated against influenza with the inactivated NIVGRIP vaccine intranasally].

A study was conducted on the specific and non specific immunomodulator effects of the inactivated vaccine NIVGRIP. The results revealed the seroconversion of HAI antibodies against influenza and mumps viruses and the reduction of viral and microbial flora of the pharynx. The kinetics of some proteins specific to the acute stage (siderophiline antitrypsin, microglobulin, complement C1q and C2 factors, C reactive protein and fibronectin) was also investigated and significant quantitative modifications were noticed in vaccinated subjects. The mean illness duration (acute respiratory disease) was three times as short in vaccinated subjects as in controls.

Acute-Phase Proteins↗
PubMed2006

'Ovar-Mhc' - ovine major histocompatibility complex: structure and gene polymorphisms.

The major histocompatibility complex (MHC) in sheep, Ovar-Mhc, is poorly characterised, when compared to other domestic animals. However, its basic structure is similar to that of other mammals, comprising class I, II and III regions. Currently, there is evidence for the existence of four class I loci. The class II region is better characterised, with evidence of one DRA, four DRB (one coding and three non-coding), one DQA1, two DQA2, and one each of the DQB1, DQB2, DNA, DOB, DYA, DYB, DMA, and DMB genes in the region. The class III region is the least characterised, with the known presence of complement cascade (C4, C2 and Bf), TNFalpha and CYP21 genes. Products of the class I and II genes, MHC molecules, play a pivotal role in antigen presentation required for eliciting immune responses against invading pathogens. Several studies have focused on polymorphisms of Ovar-Mhc genes and their association with disease resistance. However, more research emphasis is needed on characterising the remaining Ovar-Mhc genes and developing simplified and cost-effective methods to score gene polymorphisms. Haplotype screening, employing multiple markers rather than single genes, would be more meaningful in MHC-disease association studies, as it is well known that most of the MHC loci are tightly linked, exhibiting very little recombination. This review summarises the current knowledge of the structure of Ovar-Mhc and polymorphisms of genes located in the complex.

Animals↗
PubMed1984

MHC determinants of response to Rh immunization.

The demonstration of immune response genes in man has been difficult, although there is evidence for genes linked to the MHC in mouse and guinea pig that control both the specificity and magnitude of immune responses. A number of features of the antibody response to the Rh D antigen, such as the failure of some individuals at risk to respond, the restricted immunoglobulin class, subclass, and light chain type of the antibody produced, and the presumed minor structural difference between Rh D antigen and its allelic product, all suggest that one or at most a few immune response genes are involved. Typing for the four MHC-linked complement genes BF, C2, C4A, and C4B was carried out in 52 independently ascertained Caucasian individuals with significant anti-D titers. A control population of 623 normal Caucasian chromosomes was also studied. In patients with anti-D antibodies, the frequency of BF F1 (0.04 vs 0.0064 for 623 chromosomes, p less than 0.003); of C4A 3 (0.769 vs 0.631, p less than 0.006); and of C4B Q0 (0.25 vs 0.104, p less than 0.00004) were all increased. These three alleles are found in the common complotype BF 8F1,C2 C,C2A 3, C4B Q0, and presumably represent a single extended haplotype of 6p associated with (and presumably containing a gene for) the immune response to RhD. This complotype has a 0.6% frequency in 623 normal control chromosomes, but is also increased in patients with insulin-dependent diabetes mellitus and with membranous glomerulonephritis.

Blood Group Incompatibility↗
PubMed1983

The genetics of Type 1 (insulin-dependent) diabetes.

The major genetic susceptibility to Type 1 (insulin-dependent) diabetes is determined by genes within the HLA region located on the short arm of chromosome 6. Ninety-seven percent of Type 1 diabetic patients belonging to the Barts-Windsor family study possess either DR3 or DR4 and about 50% possess both these antigens. This excess of DR3, DR4 heterozygosity can be best explained by postulating two different susceptibility genes which react in an interactive way. No increase in DR3 or DR4 homozygosity is found, nor is there an increase in recombination frequency in these families. Linkage disequilibrium between certain B and DR antigens differs in "diabetic" compared to "non-diabetic" haplotypes. In families with two or more Type 1 diabetic children, the affected siblings are with rare exception either HLA identical or haplo-identical. The results from the prospective Barts-Windsor family study indicate that complement fixing islet cell antibodies are a good marker of on-going immune destruction in the pancreatic islets. There is also a high prevalence of antibodies reacting with certain cells in the pituitary gland in newly diagnosed cases and their unaffected first degree relatives. A possible explanation is that a common virus may be acting to produce damage in several endocrine tissues. The Barts-Windsor family study was initiated in 1978 by the late Andrew Cudworth as a prospective family study to investigate the genetic, immunological and environmental factors involved in Type 1 (insulin-dependent) diabetes. About 200 families with a Type 1 diabetic child and at least one other unaffected sibling under the age of 20 years were ascertained from a defined geographical area of approximately 1500 square km, centered around Windsor, East Berkshire, UK. These families are visited every 3 to 4 months and are regularly screened for autoantibodies, in particular islet cell antibodies, and for viral antibodies and they have all been HLA-A, B, C genotyped. A large proportion have also been genotyped for HLA-DR and for the complement factors Bf, C2 and C4, which are coded by genes within the HLA-region.

Adolescent↗
PubMed1980

The interaction of heparin with plasma proteins. Demonstration of different binding sites for antithrombin III complexes and antithrombin III.

Affinity chromatography of plasma and serum with the use of heparin conjugated Sepharose has confirmed the existence of two types of protein binding sites. A minor heparin fraction binds free AT III selectively and firmly but not its protease complexes. The complexes bind less firmly to another, much larger heparin fraction together with a select group of the plasma proteins at physiological pH and ionic strength. These included complement proteins (C1q, C2, factor B, properdin, and beta 1H), protease inhibitors (inter-alpha-trypsin inhibitor and C3b inactivator) and cell surface proteins (protein HC and fibronectin) as well as beta-lipoproteins. The results demonstrate that affinity chromatography with heparin-Sepharose is extremely useful as an early preparative step in the isolation of these minor plasma components. The results also indicate that the said proteins can be linked to cell surfaces carrying heparinoids in the intercellular space.

Antithrombin III↗
PubMed1995

Synthesis of complement proteins in amnion.

The amnion is a metabolically active tissue that has been identified as a site of synthesis of numerous products. We report that amnion tissue explants and amnion-derived epithelial cells synthesize and secrete six proteins of the complement system, C1r, C1s, C1 inhibitor, factor B, C3, and factor H. Synthesis of C2 was minimal and variable, and C5 was not detected. The six synthesized proteins had size and subunit composition characteristic of proteins synthesized in HEp2, a long term cell line derived from malignant epithelial cells. Constitutive and regulated synthesis of five of the six proteins was similar in amnion tissue and cells. However, synthesis of factor B was different in tissue and cells; constitutive synthesis was 12-fold higher in tissue than in cells, and interleukin-1 did not alter synthesis in tissue, but increased synthesis by 11.7-fold in cells. These results indicate that amnion may be a source of complement proteins present in the amnion fluid and may contribute to local host defense along with endometrial glandular epithelial cells, which synthesize C3. Furthermore, our results suggest that amnion tissue is stimulated in vivo to synthesize factor B and cannot respond to interleukin-1 with a further increase in the synthesis rate.

Adult↗
PubMed1978

Hereditary C2 deficiency and systemic lupus erythematosus associated with severe glomerulonephritis.

Although an unusually high incidence of immunological diseases has been described in patients with hereditary C2 deficiency, the severity of these illnesses has been relatively mild, suggesting that blocking complement activation beyond C4 may protect against significant complement-mediated inflammation. This report describes studies in a C2-deficient patient with severe systemic lupus erythematosus (SLE) and diffuse proliferative glomerulonephritis. An immunopathological study of the kidney revealed the deposition of properdin, properdin factor B, C3 and C5 in a pattern similar to immunoglobulin G deposits. Serum properdin and properdin factor B levels were low at various times during the patient's course. In vitro complement fixation studies showed C3 fixation by glomerular deposits could occur via the alternative pathway. Studies of the immune deposits in the patients' skin revealed similar results. These studies suggest that inflammation may be effectively mediated via the alternative complement pathway in the C2 deficiency-lupus syndrome.

Adolescent↗
PubMed1992

An association between homozygous C3 deficiency and low levels of anti-pneumococcal capsular polysaccharide antibodies.

Inherited deficiencies of complement components are associated with an increased risk of infection by encapsulated, high grade bacterial pathogens such as Streptococcus pneumoniae, Haemophilus influenzae type b and Neisseria meningitidis. Hence, the levels of antibodies to bacterial capsular polysaccharide antigens were measured using ELISA in 65 patients with inherited deficiencies covering the classical, alternative and terminal components of the complement cascade. Three of the four C3-deficient individuals studied were found to be almost totally deficient in specific anti-pneumococcal capsular polysaccharide (PCP) antibodies. These individuals had a history of recurrent pneumococcal sepsis. While single individuals with C1r, C2 and C1Inh deficiency were found to have low anti-PCP antibody levels, no other group of complement deficiency had significantly reduced anti-PCP antibody levels compared with 100 controls. Antibody levels to the other two polysaccharides were not significantly lower in the patient groups. These findings suggest that C3 may be able to provide a stimulatory signal to promote the production of anti-PCP antibodies.

Adolescent↗
PubMed2007

Conformationally altered hyaluronan restricts complement classical pathway activation by binding to C1q, C1r, C1s, C2, C5 and C9, and suppresses WOX1 expression in prostate DU145 cells.

Linear non-sulfated hyaluronan (HA) does not bind complement proteins yet inhibits their hemolytic function. We have previously induced the complement inhibitory function of HA by heat treatment. However, heated HA readily loses its anti-complementary activity probably due to instantaneous interchain re-association. Here, HA solutions were heated and then freeze-dried. Compared to native HA, heated/freeze-dried HA stably restricted serum complement-mediated hemolysis via the classical pathway, in which serum C1 hemolytic function and C3 activation were blocked. Also, treated HA had a significantly increased binding of component C1q, C1r, C1s, C2, C5, C9, P, D and H. Further, when HA was gel-fractionated by electrophoresis and then freeze-dried, its anti-complementary activity was stably induced. Both native and heated/freeze-dried HA stimulated ERK phosphorylation in prostate DU145 cells. However, treated HA suppressed the expression of tumor suppressors WOX1 and WOX2. Together, HA with an altered conformation stabilizes its inhibition and binding of complement proteins. It may recognize cell surface receptors differently from native HA, thereby differentially regulating the expression of cellular proteins.

Cell Line, Tumor↗