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PubMed1978

Effect of age on C1q and C3 levels in human serum and their presence in colostrum.

The initiating complement component (C1q) in the classical pathway of 730 subjects and the first essential component (C3) in the alternative pathway of 461 subjects in Japan were examined. The study population consisted of normal healthy newborns, infants, children, adults and the old (from birth up to 75 years of age). In cord sera, both C1q and C3 were about 60% to the total mean level. At 3 days of age, C1q markedly increased to the mean level which remained relatively invariable up to 40 years of age. And above 40 years, the C1q level increased steadily with age up to about 75 years of age. C3 reached the mean level at about 1 month of age, and was highest during infancy. This level declined at about puberty and then continued to increase steadily with age up to around 55 years. In normal healthy subjects, a moderate positive rank correlation was found between C1q and C3 amounts. No significant differences of C1q and C3 levels were evident between male and female. No C1q was demonstrable in the colostrum from which lipids were previously removed, but after concentration by precipitation in a chelating agent with a low ionic strength, C1q, measured immunochemically, was detectable at concentrations of 300 ng/ml of colostrum. C3 was also detected at concentrations of about 200 microgram/ml of colostrum.

Adolescent↗
PubMed2001

A recombinant homotrimer, composed of the alpha helical neck region of human surfactant protein D and C1q B chain globular domain, is an inhibitor of the classical complement pathway.

The first step in the activation of the classical complement pathway by immune complexes involves the binding of the six globular heads of C1q to the Fc regions of IgG or IgM. The globular heads of C1q (gC1q domain) are located C-terminal to the six triple-helical stalks present in the molecule, each head being composed of the C-terminal halves of one A, one B, and one C chain. The gC1q modules are also found in a variety of noncomplement proteins, such as type VIII and X collagens, precerebellin, hibernation protein, multimerin, Acrp-30, and saccular collagen. In several of these proteins, the chains containing these gC1q modules appear to form a homotrimeric structure. Here, we report expression of an in-frame fusion of a trimerizing neck region of surfactant protein D with the globular head region of C1q B chain as a fusion to Escherichia coli maltose binding protein. Following cleavage by factor Xa and removal of the maltose binding protein, the neck and globular region, designated ghB(3), formed a soluble, homotrimeric structure and could inhibit C1q-dependent hemolysis of IgG- and IgM-sensitized sheep erythrocytes. The functional properties of ghB(3) indicate that the globular regions of C1q may adopt a modular organization in which each globular head of C1q may be composed of three structurally and functionally independent domains, thus retaining multivalency in the form of a heterotrimer. The finding that ghB(3) is an inhibitor of C1q-mediated complement activation opens up the possibility of blocking activation at the first step of the classical complement pathway.

Animals↗
PubMed1999

[C1q].

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Adolescent↗
PubMed2005

The pathology of multiple sclerosis is location-dependent: no significant complement activation is detected in purely cortical lesions.

Complement activation is known to occur in white matter multiple sclerosis (MS) lesions. It is thought to mediate oligodendrocyte/myelin damage and to be a marker of pathologic heterogeneity among individuals. Less is known about complement deposition in the gray matter in MS. The aim of this study was to characterize the presence and distribution of complement activation products in cortical MS lesions. Immunohistochemical staining was performed on cryostat sections from the brains of 22 MS patients and 5 nonneurologic control patients obtained at autopsy. Deposition of the complement activation products C1q, C3d, and C5b-9 (membrane attack complex) was detected on and within macrophages/microglia and astrocytes and in blood vessel walls in white matter MS lesions. C3d and C4d were detected along myelin sheaths at the edge of the lesions. In the gray matter part of combined gray matter/white matter lesions complement activation was less frequent, but increased immunopositivity was detected for C3d on blood vessels, and for C3d and C4d on myelin at the border of lesions, when compared with control areas. In contrast, in the purely cortical lesions, the extent of complement deposition in general was low. In conclusion, the role of complement in MS pathogenesis seems lesion location-dependent.

Adult↗
PubMed2001

Ellipsometric in vitro studies on blood plasma and serum adsorption to zirconium.

Ellipsometry/antibody techniques were used to study the adsorption of heparinized human blood plasma and serum onto spontaneously oxidized zirconium, and a colorimetric assay measured the formation of kallikrein by the surface in citrated plasma. After 10 min incubation in the blood plasma the protein film thickness was approximately 4.2 nm, and the film bound polyclonal antibodies mainly against high molecular weight kininogen (HMWK), immunoglobulin G (IgG) and fibrinogen. After 5 or 60 min of incubations in whole normal or EGTA sera, antibodies against complement factor 3 (C3) and complement factor 3d (C3d) deposited to the surface. Factor H and complement factor 1q (C1q) were detected similarly after 1 and 5 min of incubation in 1-10% normal serum in veronal buffer, respectively. The indications are that upon contact with blood plasma, zirconium activates the intrinsic pathway of coagulation and is opsonized with C3. The failure to detect properdin and transient presence of factor H at the surface suggest that complement binds to zirconium although the activation becomes quickly down-regulated.

Adsorption↗
PubMed1993

Interaction of the capsular polysaccharide of Haemophilus influenzae type B with C1q.

The Gram-negative pleomorphic bacterium Haemophilus influenza type b (Hib) is the most common cause of bacterial meningitis in children below the age of 2. Virtually all infants between 3 and 18 month of age lack anticapsular antibodies. This is typical for the response to a T-cell-independent antigen. 3-5% of this group harbour Hib in the nasopharynx, but the incidence of disease is 1000-fold less. This implicates other factors in host susceptibility in addition to the absence of such antibodies. Under physiological conditions the purified complement subcomponent C1q interacts with polyribosylribitolphosphate (PRP), the capsular polysaccharide of Hib. The complex formation of C1q, the most basic serum protein, with this polyanion was demonstrated by several methods: agarose gel electrophoresis followed by immunoprecipitation in the gel and Coomassie staining; western blot analysis of C1q-PRP complexes; complex formation in electrophoretic separation of PRP; retardation of electrophoretic mobility of PRP was checked by blotting of this polysaccharide. These results were confirmed by time- and dose-dependent alteration of antigenetic properties detected by C1q-Sandwich-ELISA after coincubation with PRP. Preincubation of serum treated Hib with C1q significantly enhanced the O2-metabolism of polymorphonuclear leucocytes in chemiluminescence assay. Infants of the susceptible age group develop antibodies to several Hib outer membrane proteins (OMP) and lipooligosaccharides (LOS) in response to infection. The complement activation by immune complexes might be inhibited by the formation of C1q-PRP complexes. Our results do not support the thesis that C1q can be activated by the interaction with PRP as shown before for other polyanions. Differing C1q to PRP ratios could be a possible explanation for different host susceptibilities.

Animals↗
PubMed2006

Anti-alphaGal-dependent complement-mediated cytotoxicity in metastatic melanoma.

Antibodies to the cell surface disaccharide galactose(alpha1,3)galactose (alphaGal) are the most prevalent natural antibodies in human serum. The anti-alphaGal immunoglobulin M-dependent activation of complement causes hyperacute rejection of organ transplants from discordant species by human recipients. It has been shown in vitro that human tumour cells transduced with the gene that synthesizes alphaGal become sensitive to human serum. A prerequisite for anti-alphaGal antibody-based therapeutic strategies is that patients with cancer have adequate serum levels of anti-alphaGal immunoglobulins and complement. The objective of this work was to measure the levels and function of anti-alphaGal immunoglobulins and complement in the serum of patients with metastatic melanoma and healthy volunteers. Serum complement levels were assayed by radial immunodiffusion. Anti-alphaGal immunoglobulin G and immunoglobulin M titres were measured by enzyme-linked immunosorbent assay. Disaccharide sugar blocking was used to investigate antibody specificity. The functional integrity of anti-alphaGal antibodies and complement was investigated in cell lysis assays. It was found that the levels of the complement components C1q, C3 and C4 and the function of the classical complement pathway were normal in metastatic melanoma patients. Anti-alphaGal antibody titres were as variable in metastatic melanoma patients as in healthy controls, and the lysis of alphaGal-expressing cells correlated with anti-alphaGal immunoglobulin M titre (P < 0.0001). Anti-alphaGal antibody titres, complement levels and overall cytolytic function in the serum of patients with metastatic melanoma were indistinguishable from those of healthy controls. There is thus nothing intrinsic to the disease that will limit anti-alphaGal-based therapeutic strategies for enhanced antigen presentation or induced cell lysis, including the mimicry of hyperacute rejection.

Adult↗
PubMed1997

Intracellular localization of the human receptor for the globular domains of C1q.

This study was performed to determine the localization of the recently described receptor for the globular domain of C1q, gC1qR. In contrast to previous reports, we were not able to detect significant surface expression of gC1qR on Raji cells, monocytes, neutrophils, human or rat mesangial cells, the endothelial cell line EA.hy 926, or HUVEC using FACS analysis. Only by using digoxigenin-conjugated Abs could some surface staining of gC1qR be observed on rat mesangial cells and neutrophils. However, after permeabilizing these cells with saponin, a strong positive intracellular staining for gC1qR was observed by FACS, fluorescence microscopy on coverslips, and confocal laser scanning microscopic analysis. By reflection contrast microscopy and electron microscopy on ultrathin sections of permeabilized Raji cells, it was shown that gC1qR is present in double membranous cytoplasmic vesicles located in the proximity of the plasma membrane. To determine whether certain conditions could induce surface expression of gC1qR, Raji cells were either stimulated with T cell growth factor, LPS, or driven to apoptosis by incubation with fenretinide or by serum depletion. None of the conditions resulted in significant surface expression of gC1qR. Our hypothesis that gC1qR is not a surface molecule but a soluble molecule that is secreted by cells is supported by the observation that gC1qR is found in significant concentrations in supernatants of several cultured cells and in normal human and rat sera. Our results suggest that the recently described gC1qR is not a cell surface receptor, but a soluble binding protein with affinity for the globular heads of C1q. Excreted gC1qR might act as a potential fluid phase regulator of complement activation.

Animals↗
PubMed1983

Requirements for the binding of human plasma fibronectin to the C1q subunit of the first component of complement.

We have shown previously that [125I]fibronectin (Fn) binds to solid-phase C1q in a dose-dependent manner. When C1r and C1s were added, the binding of Fn to C1q was abolished; removal of C1r and C1s restored Fn binding to C1q. In this report, we have systematically examined the optimal conditions that favor the Fn-C1q interaction. Our studies show that purified native 125I-Fn binds to C1q in a specific, saturable manner. Maximal 125I-Fn binding to C1q and gelatin occurs at low ionic strength (mu = 0.05) and drops sharply as the ionic strength is increased. At mu = 0.20, the binding to C1q is inhibited by 95%, whereas the binding to gelatin is inhibited by 50%. Optimal binding of Fn to C1q and gelatin occurs between pH 5.5 and 7.5, is decreased by 45% at 4 degrees C, and increases with incubation time; saturation of binding occurs in 60 min at 37 degrees C. Scatchard analysis of binding at mu = 0.05 indicates a single class of high affinity binding sites (Kd = 3.7 X 10(-8) M +/- 0.36 SD). The Kd of the reaction when C1q is bound to either plastic or immune complexes is essentially the same, and, in both cases, increases as the ionic strength of the medium is increased. Finally, significant binding of Fn to C1q can be demonstrated at physiologic ionic strength employing either insoluble immune complexes containing C1q or chemically cross-linked C1q.

Animals↗
PubMed1998

Studies on protein adsorption and activation of complement on hydrated aluminium surfaces in vitro.

Adsorption of human plasma and serum proteins onto hydrated aluminium was studied by ellipsometry/antibody techniques, and soluble complement components iC3b, Bb, and C4d with commercial ELISA plates. Aluminium that was incubated in plasma for 1 min bound significant amounts of anti-lipoproteins (anti-LP), no antibodies against contact activation of coagulation proteins, and no anti-fibrinogen (anti-Fib). Time course studies with serum revealed increasing deposition of anti-C3c with time. Complement factor 1q (C1q) was antibody detectable only after short-time serum incubations, but no anti-IgG and anti-properdin bound to the protein film at any time. Anti-C3c was not deposited after exposure of the surfaces to Clq-depleted serum. Intriguingly, and in spite of increasing deposition of C3 to the surface with time, the combined ellipsometry and ELISA results gave no unequivocal proof of activation of complement by hydrated aluminium.

Adsorption↗
PubMed1983

Antigenic interspecies cross-reaction of subcomponent C1q of the first component of complement: evidence for its cross-reaction in both collagen-like and non-collagen-like regions.

Human, bovine, and mouse C1q, a subcomponent of the first complement component, were purified, and both globular (GF) and collagen-like fragments (CLF) were isolated from human and bovine C1q. Antisera were produced in rabbits with these C1q or fragments, and F(ab')2 of immunoglobulin G (IgG) was purified from the antisera in order to avoid the possible non-specific binding of C1q of these animals to the Fc portion of rabbit IgG. Immunodiffusion analyses and radioimmune inhibition tests with these F(ab')2 showed that the definitive antigenic cross-reactivity was among C1q molecules of these animals, and that the regions participating in interspecies cross-reactions were located in both GF and CLF of C1q. These results suggest that both the C-terminal non-collagenous globular and the N-terminal collagen-like domains of C1q molecules may have remained highly conserved during evolution.

Animals↗
PubMed1975

Immunofluorescent investigations in cutaneous vasculitis. I. Histotopical demonstration of complement/complement factors.

Using an indirect double layer immunofluorescence method, fresh skin lesions of 10 patients with different forms of cutaneous vasculitis were tested for the occurrence of complement-factors C1q (C1), alpha2D(C3) and beta1F (C5). In contrast to the irregularly found complement fixing immunoglobulins IgG and IgM, complement could be regularly seen bound to the cutaneous vessel walls; mostly the C3-factor alpha2D. C1q was demonstrable, combined with IgG and/or IgM only in 2 cases. In 5 patients there was a non-homogenous, roddy fluorescenece of the epidermal basal membrane zone and the cutaneous vessels, when alpha2D or beta1F were tested. Our findings suggest that the "alternate pathway" beginning with C3-activation is followed in most cases, whereas a typical "immune complex vasculitis" is obviously rare. The constant occurrence of complement in the cutaneous vessel walls of vascultis lesions is consistent with the known chemotactic and destructive role of complement factors in experimental models of angiitis, but it may not necessarily involve a specific immunological process.

Antigen-Antibody Complex↗
PubMed1990

NH2-terminal calcium-binding domain of human complement C1s- mediates the interaction of C1r- with C1q.

The assembly of C1, the first component of human complement, involves interactions between various domains of each of its three subcomponents, C1q, C1r, and C1s. The isolation, assignment of function, and structural characterization of the individual domains of C1r and C1s are critical for a thorough understanding of this complex assembly. The present study describes a 27-kDa plasmin-generated fragment derived from the NH2-terminal half of the heavy A chain of C1s-, the activated form of C1s. This fragment, C1s-alpha, was shown in the presence of Ca2+ to mimic the ability of whole C1s- to self-associate, bind to C1r-, and facilitate the binding of C1r to C1q. These results directly prove that the Ca2(+)-binding sites of C1s as well as all of the determinants necessary for binding of C1s- to C1r- and C1q are located in the NH2-terminal 27-kDa alpha region of the A chain.

Amino Acid Sequence↗
PubMedDate not supplied

Cytomorphological, ultrastructural and immunological characteristics of the ovialsyn fluid in seropositive rheumatoid arthritis.

Experiments have been performed on 15 samples of synovial fluid (SF) from patients with seropositive rheumatoid arthritis (RA) (Latex 1/280 and Waaler Rose 1/1024) versus 10 SF samples from patients with hydroarthrosis, used as control. By cytomorphologic studies, we determined the cellularity, ragocytosis and synoviocytogram of the SF cellular pellet and found out that rheumatoid SF is characterized by cytosis (9953/mm3), ragocytosis (70%) and polynucleosis (73%) whereas hydroarthrotic SF is characterized by lymphocytosis (54.6%). Ultrastructurally, rheumatoid SF ragocytes present numerous intracytoplasmic inclusions and phagolysosomes, a fact that certainly evidences an endocytotic activity. At the level degenerative of PMN cells, (6%), the experiments evidenced the presence of some lysis cytoplasmic plateau associated with the absence of cellular organelles, as well as an alteration of the granulofibrillar structure of the nucleus. We also noticed cellular debris consisting of partially destroyed cellular organelles. By immunologic studies we obtained seric pathologic values for CIC (mean = 108.05 U), IgM (mean = 420 Ul/ml), IgG (mean = 355 Ul/ml), anti DNA antibodies (mean = 405 U) and anti collagen II antibodies (mean = 558 U). As regards the seric complement activity of C1q and C3 fractions, it was higher (mean = 18.87 mg% and mean = 109.94 mg%, respectively) than in the SF (mean = 5.78mg% and mean = 30.83 mg%, respectively). Corroborating the cytomorphological, ultrastructural and immunological data, we could better explain the lesional types examined and emphasize the importance of the immunomorphological changes in RA diagnosis.

Antibodies↗