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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↗
PubMed1985

The C1q subunit of the first component of complement binds to laminin: a mechanism for the deposition and retention of immune complexes in basement membrane.

The C1q subunit of complement component C1 is known to bind to immune complexes, which often are deposited in basement membrane. We investigated the possibility that this deposition is a result of binding to laminin, a large basement membrane glycoprotein. C1q showed saturable binding to immobilized laminin; this binding was increased at reduced ionic strength. Intact C1 did not bind laminin. A ternary complex was formed by laminin, C1q, and aggregated IgG. This complex formation was dependent on and proportional to the amount of C1q bound to the aggregated IgG. Binding of laminin to C1q occurred with a Kd of 2 nM and was stronger than the binding of C1q to fibronectin. Preliminary data, including electron micrographs of rotary-shadowed preparations, suggest that laminin binds to the collagen-like tail of C1q. Electron microscopy localized the site of interaction with C1q to a short arm of laminin. Since laminin is found only in basement membranes, the interaction between laminin and C1q could be involved in the deposition and retention of immune complexes in these structures.

Antigen-Antibody Complex↗
PubMed1990

Limited proteolysis of beta 2-microglobulin at Lys-58 by complement component C1s.

We have now demonstrated that activated complement component C1s cleaves beta 2-microglobulin at the position identical to that at which beta 2-microglobulin is cleaved in serum of patients suffering from lung cancer. The main cleavage is in the disulphide loop C-terminal to Lys-58, generating a modified form of beta 2-microglobulin with a two-chain structure. The C-terminal Lys-58 in the A chain is highly susceptible to removal by a carboxypeptidase-B-like activity causing the formation of des-Lys58-beta 2-microglobulin. This is the first demonstration of a noncomplement protein substrate for the proteolytic activity of C1s. The C1s-induced cleavage of beta 2-microglobulin can be inhibited in the presence of C1 esterase inhibitor, demonstrating a regulatory function of C1 esterase inhibitor in the C1s-induced cleavage of beta 2-microglobulin.

Amino Acid Sequence↗
PubMed1981

C1q binding and complement activation by capsular and cell wall components of S. pneumoniae type XIX.

Cell wall components (purified cell walls, teichoic acid and residual cell walls) from S. pneumoniae type XIX showed antibody independent C1q binding capacity, as assessed by C1q deviation test, with teichoic acid being the most efficient. Specific capsular substance did not bind C1q. All substances tested produced C1 activation in normal human serum, but not in hypo-gamma-globulinemic serum. Thus, teichoic acid showed high C1q binding capacity but did not activate C1 in the absence of antibodies. Teichoic acid was an effective activator of alternative pathway. Specific capsular substance did not activate the alternative pathway in C1q deficient serum or in Mg2+ -EGTA chelated normal serum.

Cell Wall↗
PubMed1996

Complement activation by C-reactive protein on the HEp-2 cell substrate.

The complement (C) activation by C-reactive protein (CRP) in acute-phase sera is routinely tested in our laboratory by means of an indirect immunofluorescence method (C3-IFT) on rat kidney sections. This C3-IFT assay is based on the binding of CRP to the renal tissue followed by the fixation of C4 and C3 components to distinct vessel-associated medullary structures as a result of CRP-mediated C activation in vitro. While the activation cascade leading to the deposition of C4 and C3 could previously be deduced experimentally, we were unable as yet to visualize CRP and the components of the C1 complex on kidney sections when testing patients' sera by indirect immunofluorescence. In an attempt to analyze the mechanisms of unexpectedly negative C3-IFT results (e.g. bacterial endocarditis) we employed monolayers of fixed HEp-2 cells which have previously been shown to be a suitable substrate for CRP binding. By incubating purified native CRP supplemented with normal human serum as a source of C we detected the C components Clq, Clr, Cls, C4 and C3 in the same speckled immunofluorescent pattern on HEp-2 cell nuclei as described characteristically for CRP binding. The serial activation steps from CRP up to C3 could also be followed on HEp-2 cells using C3-IFT-positive acute-phase sera. However, certain C3-IFT-negative acute-phase sera showed an arrest between Cls and C4 of the CRP-mediated C activation cascade. HEp-2 cells can thus be used to monitor the process of autologous C activation initiated by endogeneous CRP in patients' sera. In contrast to native CRP, urea-modified CRP (mCRP) did not bind to HEp-2 cell nuclei, but was detected in association with distinct filamentous cytoplasmic structures. Unlike its native counterpart, binding of mCRP was not followed by a deposition of C components.

Animals↗
PubMed1988

Role of EAC1q4 in C1a transfer reaction (C1aTR) and further information on the nature of the EAC1q4 site.

The complement intermediates EAC1, EAC4, and EAC1q4 were prepared with guinea pig, porcine, as well as human complement. EAC4 and EAC1q4 were made from EC4 and EAC14 respectively. The C1a transfer reaction (C1aTR), the second step of Borsos' C1a fixation and transfer test, was carried out with various combinations of these intermediates. It was found that the EAC1q4, instead of the EAC4, was the C1a acceptor, and the C1rs subcomponents rather than the whole C1 molecule should have to transfer in the C1aTR. The EAC41 derived from EC4 generated no EAC1q4 in EDTA medium as the EAC14 did. This presented evidence for the joining of C4 to A in the EAC1q4 site.

Animals↗