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PubMed1999

Modular organization of proteins containing C1q-like globular domain.

The first step in the activation of the classical pathway of complement cascade by immune complexes involves the binding of the six globular heads of C1q to the Fc regions of immunoglobulin G (IgG) or immunoglobulin M (IgM). The globular heads of C1q are located C-terminal to the six triple-helical stalks present in the molecule, each head is considered to be composed of the C-terminal halves (3 x 135 residues) of one A-, one B- and one C-chain. It is not known if the C-terminal globular regions, present in each of the three types of chains, are independently folded modules (with each chain having distinct binding properties towards immunoglobulins) or whether the different binding functions of C1q are dependent upon a globular structure which relies on contributions from all three chains. Recent reports of recombinant production and characterisation of soluble globular head regions of all the three chains indicate that the globular regions of C1q may adopt a modular organization, i.e., each globular head of C1q may be composed of three, structurally and functionally, independent domains, thus retaining multivalency in the form of a heterotrimer. Modules of the same type as the C1q C-terminal module are also found in a variety of noncomplement proteins that include the C-terminal regions of the human type VIII and type X collagens, precerebellin, the chipmunk hibernation proteins, the human endothelial cell protein, multimerin, the serum protein, Acrp-30 which is secreted from mouse adipocytes, and the sunfish inner-ear specific structural protein. The C1q molecule is the only one of these proteins for which, to date, a function has been ascribed to the module. The existence of a shared structural region between C1q and certain collagens may suggest an evolutionarily common ancestral precursor. Various structural and biochemical data suggest that these modules may be responsible for multimerisation through patches of aromatic residues within them.

Animals↗

PubMed1998

Detection of complement C1q receptors on human spermatozoa.

Clq, the first component of the classical complement pathway, is known to play roles in promoting phagocytic events, in addition to its role in activation of complement. Although the molecular events in fertilization leading to the entrance of the spermatozoan into the egg are not well understood, ultrastructural observations suggest that the process is quasi-phagocytic in nature. There is increasing evidence that complement components might play roles in fertilization. Previously, we have shown that C1q promoted the agglutination of capacitated human sperm as well as their adhesion to zona-free hamster eggs. In the present experiments, human spermatozoa were solubilized and, following their phase separation in Triton X-114, subject to 1-D polyacrylamide gel electrophoresis and immunoblotting for the presence of C1q receptors. Both gC1q-R and cC1q-R were detected. In addition, the ability of C1q to promote sperm agglutination was shown to be dependent upon capacitation, suggesting the increased expression of C1q receptors during this process.

Agglutination Tests↗

PubMed1998

C1q and systemic lupus erythematosus.

In this chapter we review the association between SLE and C1q. In the first part of the chapter we discuss the clinical associations of C1q deficiency, and tabulate the available information in the literature relating to C1q deficiency and autoimmune disease. Other clinical associations of C1q deficiency are then considered, and we mention briefly the association between other genetically determined complement deficiencies and lupus. In the review we explore the relationship between C1q consumption and lupus and we discuss the occurrence of low molecular weight (7S) C1q in lupus, which raises the possibility that increased C1q turnover in the disease may result in unbalanced chain synthesis of the molecule. Anti-C1q antibodies are also strongly associated with severe SLE affecting the kidney, and with hypocomplementaemic urticarial vasculitis, and these associations are also examined. We address the question of how C1q deficiency may cause SLE, discussing the possibility that this may be due to abnormalities of immune complex processing, which have been well characterised in a umber of different human models. There is clear evidence that immune complex processing is abnormal in patients with hypocomplementaemia, and this is compatible with the hypothesis that ineffective immune complex clearance could cause tissue injury, and this may in turn stimulate an autoantibody response. We have also considered the possibility that C1q-C1q receptor interactions are critical in the regulation of apoptosis, and we explore the hypothesis that dysregulation of apoptosis could explain important features in the development of autoimmune disease associated with C1q deficiency. An abnormally high rate of apoptosis, or defective clearance of apoptotic cells, could promote the accumulation of abnormal cellular products that might drive an autoimmune response. Anti-C1q antibodies have been described in a number of murine models of lupus, and these are also briefly discussed. We focus on the recently developed C1q "knockout" mice, which have been developed in our laboratory. Amongst the C1q deficient mice of a mixed genetic background high titres of antinuclear antibodies were detected in approximately half the animals, and around 25% of the mice, aged eight months had evidence of a glomerulonephritis with immune deposits. Large numbers of apoptotic bodies were also present in diseased glomeruli, and this supports the hypothesis that C1q may have a critical role to play in the physiological clearance of apoptotic cells.

Animals↗

PubMed1998

Mannose-binding lectin (MBL) in health and disease.

Mannose-binding lectin (MBL) is the most intensively studied human collectin. It is recognized to be a versatile macro-molecule with many of the functional characteristics of IgM, IgG and Clq. In the presence of calcium the protein can bind to a wide spectrum of oligosaccharides through multiple lectin domains. Such binding to the repeating sugar arrays on microbial surfaces may result in direct uptake by one or more collectin receptors on phagocyte surface or may trigger the activation of a pro-serine protease complex (MASP 1 and MASP 2) leading to cleavage of C4 and C2 of the classical complement pathway. Although serum levels of MBL are normally rather low (1500 micrograms/litre) there is increasing evidence that the protein plays an important role in immune defence, particularly during the phase of primary contact with a microorganism. This is suggested by the observed association of an increased incidence of infections in individuals with structural mutations in exon 1 of the MBL gene. A cluster of such mutations in codons 52, 54 and 57 lead to secondary structural abnormalities of the collagenous triple helix and a failure to form biologically functional higher order oligomers. The codon 54 mutation has been identified in several Eurasian populations whereas the codon 57 mutation is characteristic of sub-Saharan populations. One intriguing paradox arising from the MBL genotyping studies is the observation that in many populations there are surprisingly high frequencies of either the codon 54 or codon 57 mutation, suggesting that there may be some biological advantage associated with absence of the protein. Nevertheless, various groups have reported either low serum levels of MBL or an increased frequency of the structural gene mutations in patients with suspected immunodeficiencies, those with frequent unexplained infections and those with systemic lupus erythematosus. There is also evidence that the rate of progression of AIDS in HIV positive men is faster in those with such mutations. A recently published study of a consecutive series of admissions to a paediatric unit suggests that children presenting with an infectious aetiology are significantly more likely to have a MBL mutation. Moreover, this association was independent of age. Prospective studies are underway to address the questions raised by these findings.

Abortion, Habitual↗

PubMedDate not supplied

[Complement system].

Explore the source record for details and available documents.

Complement Pathway, Alternative↗

PubMed2000

Degeneration process of Lewy bodies in the brains of patients with dementia with Lewy bodies using alpha-synuclein-immunohistochemistry.

We investigated the degeneration process of Lewy bodies (LB) in the brains of dementia with Lewy bodies, using alpha-synuclein-immunohistochemistry. Intracellular LB, LB-related neurites and some extracellular LB were positively immunostained with anti-alpha-synuclein antibodies. Concentric LB-bearing neurons had no microglial involvement, while degenerated neurons with ill-defined LB displayed intense microglial involvement. The late stage of extracellular LB were immunoelectron-microscopically composed of loose aggregates of filamentous components with lost alpha-synuclein-immunoreactivity and penetrated astroglial processes. These findings suggest that microglias are involved during the stages from degenerated LB-bearing neurons to extracellular LB, while astroglias are involved during the stage of extracellular LB. Some intracellular LB were positive for anti-C3d and -C4d antibodies, suggesting that the classical complement pathway is activated in degenerated LB-bearing neurons, inducing microglial activation and neuronal death.

Aged↗

PubMed1980

Spontaneous immunoglomerulonephritis in Wistar rats.

A strain of rats bred at the Nuclear Study Center of Mol (C.E.N.) develops a nephropathy characterized by granular deposition of immunoglobulin and complement in the renal glomeruli and tubules. We have attempted to specify the complement activation pathways (classical or alternate) in this disease by looking for their initial components (C1q, C3 and C4) in tissue lesions. The immunohistologic and histologic course of the disease has been followed in male and female rats. Immunohistologic results show that glomerular and tubular injury in CEN Wistar rats may be mediated by the classical pathway of complement activation. Histologic data demonstrate that the tubular, glomerular, and interstitial lesions appear in both sexes, but are more extensive and develop earlier in male rats. The lipopigments found in tubular cells suggest a lysosomal dysfunction which might contribute to the progress of the disease.

Animals↗

PubMed1985

The role of complement in inflammation.

The inflammatory process may be initiated by a great variety of stimuli. Amongst the diverse pathogenic pathways that lead from the primary stimulus to the tissue response, the serum complement system (C) seems the most important and, certainly, it is the best analyzed of the mediator systems.

Complement Pathway, Alternative↗

PubMed1996

Antimicrobial and immunological activity of ethanol extracts and fractions from Isopyrum thalictroides.

The antimicrobial and immunological properties of ethanol extracts, non-alkaloid, tertiary alkaloid and quaternary alkaloid fractions, obtained from roots and aerial parts of Isopyrum thalictroides were examined. The non-alkaloid fraction from aerial parts inhibited the growth of seven test microorganisms and was the most effective suppressor of classical pathway (CP) complement activity in normal human serum (NHS) and guinea pig serum (GPS). The alkaloid fractions, containing quaternary alkaloids expressed suppressive effect on mitogen-induced splenocyte proliferation. The in vitro antibody response against sheep red blood cells (anti-SRBC) was inhibited by ethanol extracts and quaternary alkaloid fraction. The intraperitoneal (i.p.) application of ethanol extract and tertiary alkaloid fraction from aerial parts showed that they possess in vivo effect on alternative pathway (AP) complement activity, anti-SRBC response and delayed type hypersensitivity (DTH).

Adjuvants, Immunologic↗

PubMed1997

Immunopotentiating compounds from Tinospora cordifolia.

The active principles of Tinospora cordifolia a traditional Indian plant were found to possess anticomplementary and immunomodulatory activities. Syringin (TC-4) and cordiol (TC-7) inhibited the in vitro immunohaemolysis of antibody-coated sheep erythrocytes by guinea pig serum. The reduced immunohaemolysis was found to be due to inhibition of the C3-convertase of the classical complement pathway. However, higher concentrations showed constant inhibitory effects. The compounds also gave rise to significant increases in IgG antibodies in serum. Humoral and cell-mediated immunity were also dose-dependently enhanced. Macrophage activation was reported for cordioside (TC-2), cordiofolioside A (TC-5) and cordiol (TC-7) and this activation was more pronounced with increasing incubation times.

Adjuvants, Immunologic↗

PubMed2001

Induction of complement C9 messenger RNAs in human neuronal cells by inflammatory stimuli: relevance to neurodegenerative disorders.

Neurons express proteins of the classical complement pathway, including C9. Both the mRNA and protein levels for C9 are sharply upregulated in brain areas affected by Alzheimer's disease (AD). Since little is known about the signals that are responsible for this upregulation, we evaluated in human SH-SY5Y neuroblastoma cells the factors which stimulate C9 production. Interferon-gamma, phorbol myristate acetate and interleukin-6 all stimulated C9 mRNA expression but the inflammatory cytokines tumor necrosis factor-alpha, interleukin-1 beta, as well as the anaphylatoxin C5a and the bacterial lipopolysaccharide, were ineffective. Immunohistochemical analysis of postmortem human brains for C9 protein demonstrated its presence in many cortical pyramidal neurons in AD, Down's syndrome, the parkinsonism dementia complex of Guam and pallido-ponto-nigral degeneration, as well as in thalamic neurons of progressive supranuclear palsy and ballooned neurons of Pick's disease. Since C9 is required for the membrane attack complex of complement to become functional, interfering with signaling pathways that stimulate its production could offer new therapeutic strategies for treating various neurodegenerative disorders.

Aged↗

PubMed2005

[Pathogenesis of primary systemic vasculitides (II): ANCA-negative vasculitides].

The pathogenesis of different types of systemic vasculitis negative for antineutrophil cytoplasm antibodies (ANCA) and involving small or medium-sized vessels is not very well documented. During polyarteritis nodosa (PAN), which is related to hepatitis B virus (HBV) infection, as well as during cryoglobulinemic vasculitides, associated with hepatitis C virus (HCV), and probably during Henoch Schönlein purpura, histological lesions may result from the deposition of immune complexes formed from viral antigens and from antibodies responsible for the activation of the classic complement pathway and for recruitment of polymorphonuclear neutrophils. Two other mechanisms are discussed for other types of ANCA-negative systemic vasculitis: immune complex deposition and sheer stress at arterial bifurcation points. A bacterial superantigen is suspected in Kawasaki disease but remains unproved.

Animals↗

PubMed1998

The complement-killing of Borrelia burgdorferi. Target antigens and sensitizing antibodies.

It had been previously shown by the Microbial Adherence Immobilization Assay (MAIA) that Borrelia burgdorferi sensu stricto, type strain B31 was clumped, immobilized and killed in vitro by sensitizing antibodies that activated the classical complement pathway and the complement-killing of live borrelia. In the present study, the target antigens and sensitizing antibodies responsible for the complement-killing of borrelia were investigated, using MAIA as a selective identification tool. It was found that the fractions containing the 31 and 34 kDa outer surface proteins from strain B31 were the unique antigens producing sensitizing antibodies in rabbits that activated the complement-killing of B31. An anti-OspB, but not an anti-OspA, monoclonal antibody did activate the B31 complement-killing in MAIA. From these results, constraints on the effectiveness of OspB and OspA as immunogens for the prevention and control of Lyme borreliosis in humans are discussed.

Animals↗

PubMed1988

Immunogenetics of SLE and primary Sjögren's syndrome.

SLE is a syndrome defined by clinical criteria and by the presence of autoantibodies reactive with nucleic acids and proteins concerned with transcription and translation. Breeding experiments in mice have illustrated the enormous genetic heterogeneity of this syndrome, of which the final common pathway is a widespread immune complex disease. The causes of SLE in humans are likely to be equally multifactorial. Family studies have demonstrated that genetic factors exist, but each factor appears to be a relatively weak disease-susceptibility gene. The major exceptions to this are the very rare complete deficiencies of classical pathway complement components, which are almost invariably accompanied by the development of SLE. Observations of these patients have led to the formulation of hypotheses relating complement and its receptor, CR1, to the defective removal of immune complexes from the circulation.

Animals↗

PubMed1998

Microbial immunology: a new mechanism for immune subversion.

The number of mechanisms that have evolved in microbes to subvert the immune response seems limitless. Tubercle bacilli have found a novel way to coat themselves with the C3 complement protein and invade macrophages by interactions with complement receptors.

Bacterial Proteins↗

PubMed2002

Monomeric structures of the zymogen and active catalytic domain of complement protease c1r: further insights into the c1 activation mechanism.

C1r is the serine protease (SP) that mediates autoactivation of C1, the complex that triggers the classical complement pathway. We have determined the crystal structure of two fragments from the human C1r catalytic domain, each encompassing the second complement control protein (CCP2) module and the SP domain. The wild-type species has an active structure, whereas the S637A mutant is a zymogen. The structures reveal a restricted hinge flexibility of the CCP2-SP interface, and both are characterized by the unique alpha-helical conformation of loop E. The zymogen activation domain exhibits high mobility, and the active structure shows a restricted access to most substrate binding subsites. Further implications relevant to the C1r self-activation process are derived from protein-protein interactions in the crystals.

Binding Sites↗

PubMed1999

The physiological structure of human C-reactive protein and its complex with phosphocholine.

BACKGROUND: Human C-reactive protein (CRP) is the classical acute phase reactant, the circulating concentration of which rises rapidly and extensively in a cytokine-mediated response to tissue injury, infection and inflammation. Serum CRP values are routinely measured, empirically, to detect and monitor many human diseases. However, CRP is likely to have important host defence, scavenging and metabolic functions through its capacity for calcium-dependent binding to exogenous and autologous molecules containing phosphocholine (PC) and then activating the classical complement pathway. CRP may also have pathogenic effects and the recent discovery of a prognostic association between increased CRP production and coronary atherothrombotic events is of particular interest. RESULTS: The X-ray structures of fully calcified C-reactive protein, in the presence and absence of bound PC, reveal that although the subunit beta-sheet jellyroll fold is very similar to that of the homologous pentameric protein serum amyloid P component, each subunit is tipped towards the fivefold axis. PC is bound in a shallow surface pocket on each subunit, interacting with the two protein-bound calcium ions via the phosphate group and with Glu81 via the choline moiety. There is also an unexpected hydrophobic pocket adjacent to the ligand. CONCLUSIONS: The structure shows how large ligands containing PC may be bound by CRP via a phosphate oxygen that projects away from the surface of the protein. Multipoint attachment of one planar face of the CRP molecule to a PC-bearing surface would leave available, on the opposite exposed face, the recognition sites for C1q, which have been identified by mutagenesis. This would enable CRP to target physiologically and/or pathologically significant complement activation. The hydrophobic pocket adjacent to bound PC invites the design of inhibitors of CRP binding that may have therapeutic relevance to the possible role of CRP in atherothrombotic events.

Binding Sites↗

PubMed1995

Tissue synthesis of complement as an immune regulator.

Evidence is accumulating that a variety of tissues produce complement components, and that production in each tissue is differentially regulated by inflammatory cytokines. This locally produced complement could have protective or injurious actions, depending upon local circumstances. Techniques for analysing separately the contributions of local complement synthesis and complement derived from the circulation are now becoming available. We argue that an appreciation of the role of local complement synthesis may help to explain many features of organ- and tissue-specific immunological disease.

Animals↗