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PubMedDate not supplied

The binding of immune complexes by the erythrocyte complement receptor 1 (CR1).

Immune complexes, which have reacted with complement and bear C3b fragments, bind to the complement receptor 1 (CR1) on human erythrocytes. Indeed, CR1 on erythrocyte serves as a transport system for immune complexes in the circulation so as to prevent immune complex deposition outside the fixed macrophage system. A defect in this transport system has been described in several diseases, in which either complement levels or CR1 number on erythrocytes are diminished. Recent studies have shown that the binding of immune complexes to erythrocytes is favored by the multiple C3b binding sites per receptor and the clustered distribution of CR1 on the erythrocyte surface. Only a few immune complexes bind per erythrocyte but these complexes are tightly bound. The other main function of CR1 on erythrocytes is to enhance the inactivation of C3b by factor I present in plasma. This reaction allows the release of immune complexes from the erythrocyte surface and their transfer to fixed macrophages.

Animals↗
PubMed1982

Fibronectin interacts with Clq, a subcomponent of the first component of complement.

Human Clq, a subcomponent of the first component of complement interacts with human fibronectin. Using ELISA methodology fixation of Clq to solid phase fibronectin, as well as fibronectin to solid phase Clq has been demonstrated. Cl in its native macromolecular form displays little reactivity for fibronectin, nor does Cl reconstituted from Clq, Clr and Cls in the presence of Ca2+ ions. Heating of Clq above its thermal transition temperature (51 degrees C) induces an increased binding capacity for fibronectin. On the other hand, a mixture of the dissociated A, B and C chains of Clq is less active than native Clq. The binding of fibronectin appears to be mediated by the A chain. Studies with Clq deprived of its globular parts by peptic digestion indicate that the collagen-like regions of Clq are involved in fibronectin binding. In contrast, collagenase treatment of Clq abrogates its fibronectin binding capacity.

Animals↗
PubMed2025

Extracellular vesicle proteomic expression is influenced by mining tenure in former uranium miners.

BACKGROUND: Chronic exposure to uranium (U) rich environments poses significant health risks, yet the molecular mechanisms underlying these effects remain poorly understood. Extracellular vesicles (EVs) are membrane-bound vesicles that transfer multiple biomolecules between cells and can regulate cellular function. OBJECTIVE: To determine whether U-mining tenure is associated with specific alterations in serum-derived EV proteomic and plasma cytokine profiles among former U-miners, and to assess the potential of EV-derived proteins as robust biomarkers of chronic U-exposure relative to canonical cytokines. METHODS: Serum and plasma samples were obtained from 39 former U-miners. Small and large EVs were isolated via differential ultracentrifugation and characterized by nanoparticle tracking and western blotting. EV proteomic profiles were analyzed using liquid chromatography-tandem mass spectrometry. Plasma cytokines were quantified using multiplex immunoassays. Age-adjusted linear regression was used to assess associations with mining tenure, and pathway enrichment analysis was performed on significant EV proteins. RESULTS: Eight small-EV and four large-EV proteins significantly correlated with mining tenure after age adjustment. Notably, Complement C1r subcomponent and Vitamin K-dependent protein S, and Fibrinogen alpha chain exhibited strong inverse correlations. Enrichment analyses highlighted immune-related and extracellular matrix pathways. Six cytokines were initially associated with mining tenure but lost significance after age adjustment. In contrast, EV protein associations appeared more robust for this confounding, underscoring their potential as exposure biomarkers. CONCLUSIONS: Serum EV-derived protein signatures were nominally associated with U-mining tenure independent of age, whereas cytokine profiles were confounded by age. These findings suggest that EV-derived proteins may provide sensitive biomarkers for monitoring long-term health effects of U-exposure, which warrants further investigation in larger cohorts.

Humans↗
PubMed2004

The structure of MBL-associated serine protease-2 reveals that identical substrate specificities of C1s and MASP-2 are realized through different sets of enzyme-substrate interactions.

A family of serine proteases mediates the proteolytic cascades of several defense mechanisms in vertebrates, such as the complement system, blood coagulation and fibrinolysis. These proteases usually form large complexes with other glycoproteins. Their common features are their modular structures and restricted substrate specificities. The lectin pathway of complement, where mannose-binding lectin (MBL) recognizes the carbohydrate structures on pathogens, is activated by mannose-binding lectin-associated serine protease-2 (MASP-2). We present the 2.25A resolution structure of the catalytic fragment of MASP-2 encompassing the second complement control protein module (CCP2) and the serine protease (SP) domain. The CCP2 module stabilizes the structure of the SP domain as demonstrated by differential scanning calorimetry measurements. The asymmetric unit contains two molecules with different CCP-SP domain orientations, reflecting increased modular flexibility at the CCP2/SP joint. This flexibility may partly explain the ability of the MASP-2 dimer to perform all of its functions alone, whereas the same functions are mediated by the much larger C1r2-C1s2 tetramer in the C1 complex of the classical pathway. The main scaffold of the MASP-2 SP domain is chymotrypsin-like. Eight surface loops determine the S1 and other subsite specificities. Surprisingly, some surface loops of MASP-2, e.g. loop 1 and loop 2, which form the S1 pocket are similar to those of trypsin, and show significant differences if compared with those of C1s, indicating that the nearly identical substrate specificities of C1s and MASP-2 are realized through different sets of enzyme-substrate interactions.

Binding Sites↗
PubMed1983

Conformation and restricted segmental flexibility of C1, the first component of human complement.

Seventy selected images of chemically crosslinked C1 are analyzed to illustrate structural details of the C1qC1r2C1s2 complex. From inspection of these images, the C1r2C1s2 tetramer can be seen to be located in the region of the C1q arms, cleanly separated from the C1q heads and from at least 90%, if not all, of the C1q stem. From measurements made upon 65 images, the semicone angles formed between the spreading arms and the symmetry axis passing through the stem of C1 may be calculated. Unlike C1q, for which a wide variety of angles is found, the C1 complex appears to possess a restricted range of angular flexibility with an average value of about 50 degrees. The volume inside the cone formed by the spreading arms of C1q is too small to contain the entire C1r2C1s2 tetramer; at least some of the tetramer must lie outside the cone when it is bound to C1q to form C1. From our knowledge of the sizes and structures of its subunits, and from symmetry considerations, a model is proposed for the configuration of the C1 complex in which the middle portion of the C1r2C1s2 tetramer is centrally located among the arms close to the stem of the C1q and with the two protruding ends of the tetramer wrapped around the outside of the cone. Functional implications of this more rigid structure are discussed with relevance to C1q-induced aggregation of latex beads and C1-induced disaggregation.

Complement Activating Enzymes↗
PubMedDate not supplied

Opsonic complement system of the solitary ascidian, Halocynthia roretzi.

To elucidate the molecular architecture and function of the possibly primitive complement system of the solitary ascidian. Halochynthia roretzi, cDNA clones for the third component (C3) and mannose-binding lectin (MBL)-associated serine protease (MASP) were isolated from the hepatopancreas cDNA library. The deduced primary structure of ascidian C3 (AsC3) shows overall similarity to mammalian C3 including a typical thioester site. Two distinct ascidian MASPs, termed AsMASPa and AsMASPb, have the same domain structure as mammalian Clr/ Cls/MASP-1/MASP-2. Both of them show a closer similarity to mammalian MASP-1 than to mammalian Clr/Cls/ MASP-2. Ascidian body fluid contains an opsonic activity which enhances phagocytosis of yeast by ascidian blood cells, and an antibody against AsC3 inhibits this opsonic activity. These results indicate that the lectin-dependent, opsonic complement system was present prior to the emergence of the vertebrates and well ahead of the establishment of adaptive immunity.

Animals↗
PubMed1997

Inhibition of complement activation by soluble recombinant CR1 under conditions resembling those in a cardiopulmonary circuit: reduced up-regulation of CD11b and complete abrogation of binding of PMNs to the biomaterial surface.

The influence of soluble recombinant CR1 (sCR1) on complement activation, and its indirect effects on the coagulation system and cellular responses were assessed in two models for the study of blood/surface and blood/air interactions, as are encountered in e.g. cardiopulmonary bypass circuits. The concentrations of C3a and sC5b-9 and the amount of bound C3/C3 fragments were analyzed as indicators of complement activation. Thrombin-antithrombin complexes, the platelet count, surface-ATP, beta-thromboglobulin, and the expression of CD11b on leukocytes were the parameters analyzed to reflect coagulation and cellular responses. In addition, immunochemical analyses of the phenotypes of surface-bound leukocytes and platelets were performed. Recombinant sCR1, at doses ranging between 0.1-0.25 mg/ml, was found to completely inhibit the generation of sC5b-9, and of C3a by two thirds; the binding of C3 and/or C3 fragments to the surface was almost entirely abolished. As a result of the inhibition of complement activation, the expression of CD11b on PMNs, and the binding of these cells to the biomaterial surface was almost completely lost. In contrast, the thrombin-antithrombin complexes, the platelet count, and the adherence of platelets to the surface, as reflected by the ATP binding and the release of beta-thromboglobulin, were not affected. These data show that complement activation, in association with extra-corporeal treatment, causes activation and binding of PMNs to the biomaterial and that these effects can be completely abolished by the addition of soluble recombinant sCR1.

Biocompatible Materials↗
PubMed1997

Catabolism of the human erythrocyte C3b/C4b receptor (CR1, CD35): vesiculation and/or proteolysis?

Human erythrocytes (E) react by exocytosis of membrane vesicles to various stresses including the fixation of the membrane attack complex of Complement. E from normal individuals loose a notable proportion of their initial number of surface CR1 molecules during the ageing process. An acquired decrease of CR1 on E also occurs in pathological conditions such as Systemic Lupus Erythematosus or AIDS. The present study investigated whether calcium ionophore A23187 (Ca-ion) induced vesicle formation of human E in vitro is responsible for a preferential loss of CR1 as well as whether CR1 molecules at the surface of Ca-ion treated E or vesicles are: (i) functional, (ii) native or protease degraded, or (iii) more clustered than CR1 on native E. A study of E from 137 normal individuals showed that a one-hour Ca-ion induced vesicle formation preferentially removed one third of E surface CR1. Kinetic experiments suggested that all surface CR1 could be removed from E upon longer incubation times. CR1 molecules on vesicles were still able to inhibit Complement activation, and were found in larger clusters than on native E. These data suggest that a significant part of surface CR1 molecules may be removed from E by vesicle formation during the life of E in normal individuals. This phenomenon could be exacerbated in pathological conditions.

Aging↗
PubMed1983

Inherited disorders of complement.

Isolated complement component deficiencies are uncommon. Deficiencies of all eleven components and two inhibitors of the classical pathway have been described. Complete absence of the components of the alternative pathway has not been described. The consequences of a single defect in complement are often predictable from an understanding of the biologic activities associated with activation of the complement system. Deficiency of C1 esterase inhibitor gives rise to the disease, hereditary angioedema; deficiency of the early components of the classical pathway are associated with lupus erythematosus; C3 and C3 inactivator deficiencies with pyogenic infections; C5 dysfunction with Leiner's disease; deficiencies of the terminal components with recurrent Neisseria bacteremia; and C9 deficiency with normal health. The complement system and its associated biologic activities are reviewed. The present knowledge of the inherited complement deficiencies and associated diseases, with particular emphasis on the dermatologic manifestations, genetics, and diagnosis, is summarized.

Angioedema↗
PubMed1987

Complete cDNA sequence of human complement Cls and close physical linkage of the homologous genes Cls and Clr.

Overlapping molecular clones encoding the complement subcomponent Cls were isolated from a human liver cDNA library. The nucleotide sequence reconstructed from these clones spans about 85% of the length of the liver Cls messenger RNAs, which occur in three distinct size classes around 3 kilobases in length. Comparisons with the sequence of Clr, the other enzymatic subcomponent of Cl, reveal 40% amino acid identity and conservation of all the cysteine residues. Beside the serine protease domain, the following sequence motifs, previously described in Clr, were also found in Cls: (a) two repeats of the type found in the Ba fragment of complement factor B and in several other complement but also noncomplement proteins, (b) a cysteine-rich segment homologous to the repeats of epidermal growth factor precursor, and (c) a duplicated segment found only in Clr and Cls. Differences in each of these structural motifs provide significant clues for the interpretation of the functional divergence of these interacting serine protease zymogens. Hybridizations of Clr and Cls probes to restriction endonuclease fragments of genomic DNA demonstrate close physical linkage of the corresponding genes. The implications of this finding are discussed with respect to the evolution of Clr and Cls after their origin by tandem gene duplication and to the previously observed combined hereditary deficiencies of Clr and Cls.

Amino Acid Sequence↗
PubMed1988

Domain structure, stability, and interactions of human complement C1s-: characterization of a derivative lacking most of the B chain.

A better understanding of the structure and function of C1 requires knowledge of the regions (domains) of the subcomponents that are responsible for Ca2+-dependent assembly. Toward this end, C1-s was digested with trypsin in the presence of Ca2+, a treatment that rapidly degraded the B chain, leaving a 56-kDa fragment comprised of a complete A chain disulfide linked to a small (less than 4-kDa) residual piece of the B chain. The purified fragment, referred to as C1-s-A, was shown by fast exclusion chromatography to be similar to C1-s in its ability to (1) reversibly dimerize in the presence of Ca2+, (2) substitute for C1-s in the formation of C1-r2-s2 tetramers, and (3) associate with C1-r and C1q to form macromolecular C1. Although C1-s-A was itself catalytically and hemolytically inactive, it competitively inhibited the expression of the hemolytic activity of C1-s in a reconstitution assay. When heated in the absence of Ca2+, C1-s exhibited a low-temperature transition (LTT) near 31 degrees C and a high-temperature transition (HTT) near 51 degrees C, similar to those previously observed in the homologous protein C1-r [Busby, T. F., & Ingham, K. C. (1987) Biochemistry 26, 5564-5571]. The midpoint of the LTT was shifted to 58 degrees C in 5 mM Ca2+ whereas the HTT was unaffected by Ca2+. C1-s-A exhibited only a LTT whose midpoint and Ca2+ dependence were similar to those of the LTT in C1-s. The HTT, which was accompanied by a loss of esterolytic activity, was reproduced in a plasmin-derived fragment representing the catalytic domain. These results provide strong support for the structural and functional independence of the catalytic and interaction domains of C1-s and strengthen current models regarding the role of these domains in various interactions. They also provide direct proof for the occurrence of Ca2+ binding sites on the A chain and demonstrate that all or most of the sites on C1-s that are responsible for its interaction with C1-r and C1q are located on the A chain.

Amino Acid Sequence↗
PubMed1985

Molecular modelling of human complement subcomponent C1q and its complex with C1r2C1s2 derived from neutron-scattering curves and hydrodynamic properties.

Models for the structures of subcomponent C1q of first component C1 of human complement and its complex with subunit C1r2C1s2 are compared with experimental neutron-scattering curves. The length of the C1q collagenous arm is closer to 14.5 nm than to 11.5 nm proposed from electron microscopy, and this is consistent with the primary sequence of C1q. The mean C1q base-arm angle is 40-45 degrees and C1q is found to be flexible: the base-arm angle can vary up to 30 degrees from equilibrium at any moment. The complex of C1r2C1s2 and C1q requires a large shape change in C1r2C1s2. Ring-like models for C1r2C1s2 are not as successful at rationalizing the scattering data as are models that involve C1r2C1s2 binding to one side of C1q. Hydrodynamic calculations of the sedimentation coefficients for C1q and C1 are generally consistent with these neutron models.

Complement Activating Enzymes↗
PubMed1998

Immunoglobulin prolongs survival of pig kidneys perfused ex vivo with human blood.

Intravenous immunoglobulin (IVIG) (Octagam), was used to determine the effect on hyperacute rejection in an ex vivo xenograft model. Six pig kidneys were perfused with IVIG and fresh human AB blood, and six control pig kidneys were simultaneously perfused with albumin and blood from the same donation. The survival of the IVIG-perfused xenografts (median, 6.5 h) was significantly (P = 0.03) longer than the albumin-perfused xenografts (median, 3.5 h). Complement was activated in both groups. The administration of IVIG to the perfused blood resulted in immediate and significantly higher complement activation in the fluid phase as compared with the albumin group. At rejection the fluid phase complement activation was higher in the IVIG group than in the albumin group for C1rs/C1inh complexes, C4bc, Bb and TCC. At the time of rejection both the albumin and the IVIG group demonstrated interstitial tubular haemorrhage, vasculitis or necrosis of glomerular capillaries and glomerular microthrombi. IgM, C1q, C3c, C4 and fibrin were located in arteries and glomeruli and IgG in the interstitium in both groups at rejection. The fluid phase findings are consistent with a modulatory effect of IVIG on complement activation by deviating the classical pathway activation towards the fluid phase. The prolonged survival of the IVIG-perfused kidneys suggests that IVIG may be useful to dampen hyperacute rejection.

Animals↗
PubMed1983

Neutron scattering studies of the isolated C1r2C1s2 subunit of first component of human complement in solution.

The subunit complex C1r2C1s2 of the first component of complement was investigated by small-angle neutron scattering in both the activated and unactivated forms. From these experiments, a molecular weight of 390,000 for C1r2C1s2 was found. The matchpoint was determined to be 43% 2H2O. Both results are consistent with composition data. The partial specific volume is 0.751 ml/mg. The radius of gyration at infinite contrast was found to be 17 nm for C1r2C1s2 and 1.1 nm for the cross section. Models for C1r2C1s2 were computed by the method of hard spheres, in which C1r2C1s2 was represented by spheres 0.87 nm diameter arranged in a straight rod of length 59 nm and a circular cross section of 3.2 nm. This rod can be bent at one or two places by up to 60 degrees without significant effect on the calculated radii of gyration. The model is in agreement with published ultracentrifugation and electron microscopy data.

Amino Acids↗