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PubMed1988

[A study on type II collagen induced arthritis in mice].

Pathogenesis and regulation of type II collagen (IIC) induced arthritis (CA) were investigated in mice system. CA could be successfully induced in hundred percent female mice of DBA/1J strain following immunization by an intradermal injection with emulsion of bovine IIC plus Freund's complete adjuvant into the tail base and a subsequent challenge injection with IIC in saline in the same place. The incidence and severity of the CA were suppressed by an intraperitoneal injection with a mouse gamma-globulin: histamine conjugate. On the other hand, neither histamine nor mouse gamma-globulin alone showed no suppressive effect and the former markedly accelerated the onset of the CA and augmented the severity. Next, we analyzed incidence of CA in allogeneic bone marrow chimeras prepared by using the combination of DBA/1J (H-2q, Igh-1c, Hc1) and SWR/J (H-2q, Igh-1c, Hco) mice the latter of which are unable to generate CA. As previously described, only chimeras where DBA/1J were used as recipient of bone marrow showed complement 5 (C5) in sera. Further, CA incidence was quite high (90%) in such chimeras. By contrast, none of chimeric mice where SWR/J were used as recipient showed serum C5 and CA. The result of chimera experiments indicated that C5 level in sera was one of the determinants in CA induction and that lymphoid cells of SWR/J mice themselves had no deficiency in inducing the CA.

Animals↗
PubMed1991

The role of C5 and T-cell receptor Vb genes in susceptibility to collagen-induced arthritis.

Collagen-induced arthritis (CIA) is a rodent arthritis model in which immunization with heterologous type II collagen induces an inflammatory polyarthritis. Susceptibility to the disease is mediated by major histocompatibility complex (MHC) genes as well as genes at other loci. Previous studies of the SWR/J mouse strain, which is resistant to CIA despite bearing the susceptible H-2q haplotype, have suggested that this resistance is the result of a deletion of T-cell receptor (Tcr) Vb gene segments which is carried by this strain. Other studies have implicated a deficiency in complement component C5 as the cause for the resistance. In order to assess the relative importance of these two genes in susceptibility to CIA, and to provide an estimate of the number of independent genes involved in the disease, we analyzed 196 F2 progeny of a (DBA/1 x SWR/J) cross for arthritis susceptibility, and expression of both C5 and Tcr genes. Thirty of the F2 progeny developed arthritis. All of the arthritic mice had at least one copy of the wild-type C5 allele, while the Tcr-Vb haplotypes were distributed in Mendelian fashion. These results demonstrate that C5 sufficiency is an absolute requirement for CIA, but that Tcr-Vb genes located within the SWR deletion have little influence. Genetic analysis of the incidence rate suggests that there is polygenic control of susceptibility to CIA and that in addition to H-2, 5-6 other independent loci (including C5) may be involved.

Analysis of Variance↗
PubMed1982

Lysis of antibody-coated cells by platelets.

Antibody-coated erythrocytes are lysed by murine C5- whole blood but not by plasma separated from such blood. The lytic activity has been shown to derive from platelets that attach to sensitized cells probably through membrane receptors for C3b. Whole blood or platelet-rich plasma (prp) obtained from mice that have been treated with purified cobra venom factor has little or no activity unless it is fortified with fresh C5- plasma. Lysis is observed only if the reactants are incubated at 37 degrees C and mechanical shaking is practiced, at least intermittently, throughout the period of incubation. Adherence of platelets and subsequent lysis are mediated by antibodies of a variety of immunoglobulin classes, including those that fail to mediate complement-dependent lysis. Platelet-mediated lysis is limited to cells to which the platelets adhere; 51Cr labeled, unsensitized cells that are mixed with prp and sensitized, unlabeled cells do not release 51Cr. Normal murine lymphoid cells and ascites tumor cells of mice, rats, and guinea pigs were apparently unaffected by sensitization and incubation with prp. However, because adherence of platelets to these sensitized cells was not observed, it is not clear whether the cells are resistant to the lytic action of platelets or whether the conditions of incubation were unfavorable for the attachment of platelets to the surfaces of nucleated cells. The significance of the lytic reaction described here is not known but may lie in antibody mediated release of microbicidal substances from platelets.

Animals↗
PubMed1989

Demonstration of neutrophil chemotactic anaphylatoxins in human dandruff.

In contrast to scales collected from the scalps of nine healthy individuals where a few parakeratotic cells are observable, a large number of parakeratotic cells associated with some infiltrated polymorphonuclear leukocytes (PMNLs) were found in the scales obtained from 11 individuals complaining of dandruff. Therefore, we determined the neutrophil chemotactic properties of the water-soluble extracts of dandruff scales and normal control scalp scales. Aqeous extracts fractionated by Sephadex G-75 showed a potent chemotactic activity only in the fractions of the dandruff patients that eluted with cytochrome C marker (cyt C; molecular weight, 12 kDa). It was comparatively stable to heat but was greatly inhibited by the addition of anti-C5 antiserum. Radioimmunoassay demonstrated that, although small amounts of C5a and C4a anaphylatoxins were demonstratable even in the extracts of normal scalp, they were found in significantly increased amounts in the extracts of dandruff. Moreover, there was a significantly positive correlation between C5a and C4a concentrations in these extracts. These results suggest that classical complement pathway activation with resultant production of C5a anaphylatoxin is involved in the migration of PMNLs into the lesional skin of dandruff.

Adult↗
PubMed1991

Genetic studies on experimental autoimmune gastritis induced by neonatal thymectomy using recombinant inbred strains between a high-incidence strain, BALB/c, and a low-incidence strain, DBA/2.

Thymectomy on day 3 after birth induced autoimmune gastritis (AIG) at the age of 2 months in 51-73% of BALB/c mice, and in only 3-5% of DBA/2 mice. AIG was detected by histological and serological (immunofluorescence staining for detecting anti-parietal cell autoantibody) examination. However, autoantibody was weakly positive in almost all of these DBA/2 mice when measured by ELISA using extract of murine gastric mucosa as the antigen. To investigate genetically the mechanism controlling the incidence of AIG, II recombinant inbred strains established by brother-sister mating of (BALB/c x DBA/2) F2 mice (C x D2 strains) were used. Among 26 markers tested, the Mls-1 locus on BALB/c chromosome 1 and the Hc locus coding a complement component (C5) on BALB/c chromosome 2 were found to be associated with high susceptibility to AIG. However, if one or both of the loci were of DBA/2 origin, mice showed medium or low susceptibility to AIG. For further analysis, F1, F2 and back-cross generations of these two strains were tested, but segregation of a single susceptibility or insusceptibility gene was not obtained. Taken together, it seems probable that two or more genes are involved in the induction mechanism of AIG. We did not detect C5 deposition in AIG lesions, nor complement-dependent cytotoxic antibody to parietal cells in serum from AIG mice. However, injection of irradiated spleen cells of DBA/2 mice into BALB/c mice thymectomized on day 3 augmented the incidence of AIG from 71 to 100%, but not that of oophoritis (33%). A relationship between Mls-1a determinants and the pathogenesis of AIG was further suggested from the fact that V beta 6 TcR-expressing T cells increased in number in AIG-bearing compared with normal BALB/c mice.

Animals↗
PubMed1975

[The complement system].

The complement system may be activated by at least two different pathways: the clinical pathway involving C1, C4 and C2 and the alternative pathway involving properdin, C3, factor B and factor D. The classical pathway can be activated by antigen antibody complexes, while the alternative pathway can be activated by other substances such as natural polysaccharides. Both pathways lead to an activation of C3 and of the last complement components (C5 to C9). Congenital defects of the complement system have been described for several components. Some of these defects are relatively well tolerated, but others, such as C3 deficiency, lead to increased susceptibility to bacterial infections. Acquired complement defects are frequently observed in association with several diseases. Usually they are characterized by an increased level of complement components involved in the classical pathway and therefore reflect activation by antigen antibody complexes. Such changes may be systematic, as in lupus erythematodes, or localized to some biological fluids such as synovial fluid in rheumatoid arthritis. In some renal diseases the complement profile suggests activation of the complement system by the alternative pathway, and this may reflect a different pathogenesis.

Angioedema↗
PubMed1993

Binding of human immunodeficiency virus type-1 to follicular dendritic cells in vitro is complement dependent.

The authors studied the binding in vitro of HIV-1 virus particles, conjugated to fluorescein isothiocyanate, to follicular dendritic cells (FDC) isolated from human tonsils. Analysis was done using flow cytometry, fluorescence microscopy, and immunogold electron microscopy. The focus of study was on the effect of serum from various origins, including pooled fresh serum and heated serum from control donors and pooled heated serum from HIV-1-infected patients (containing anti-HIV-1 antibodies). In the presence of heated serum, either from controls or from HIV-1-infected patients, the fluorescence signal in flow cytometry was similar to the background value. In the presence of fresh serum, the signal was substantially increased, and an even higher signal was observed in the presence of fresh serum and serum from HIV-1-infected patients. This high fluorescence signal was also found in the presence of serum depleted of complement factor C5, but not with serum deficient in complement factor C3. The binding of HIV-1 virions to FDC in the presence of fresh serum was confirmed by fluorescence microscopy on cytospot preparations. After quenching of the extracellular fluorescence with trypan blue, the fluorescence was reduced to about 30% of the initial value, indicating that most of bound fluorescent virions were present extracellularly. Similar experiments using blood mononuclear cells showed that fluorescent HIV-1 particles after binding to these cells were present intracellularly. This flow cytometry data was confirmed in immunogold electron microscopy demonstrating that most HIV-1 gag p24 or FITC label was present at the outside of FDC and on adherent virus particles. We conclude that HIV-1 virions adhere to FDC in vitro in a complement component C3-dependent way. Anti-HIV-1 antibodies in serum from HIV-1 infected patients enhance binding but, by itself, are unable to mediate binding.

Adhesiveness↗
PubMed1993

Patterns of resistance to Candida albicans in inbred mouse strains.

Candida albicans infections were established in eight inbred strains of mice. Using established histological criteria, only two strains (AKR and CBA/CaH) were found to exhibit severe lesions. The remainder showed only mild tissue damage. Deaths occurred in three strains: CBA/CaH, A/J and DBA/2. The last two strains lack the important complement component C5. Colony counts in the brain varied widely between strains and showed no correlation with the extent or severity of tissue destruction. However, strains lacking C5 had a significantly greater fungal burden in the brain than C5-sufficient mice. The data are discussed in relation to concepts of susceptibility and resistance to C. albicans in experimental infections in mice.

Animals↗
PubMed1999

rC5a directs the in vitro migration of human memory and naive tonsillar B lymphocytes: implications for B cell trafficking in secondary lymphoid tissues.

Human C5a is a potent chemoattractant for granulocytes, monocytes, and dendritic cells. In mice C5a has been shown to be chemotactic for germinal center (GC) B cells. To date, no information is available on the effects of C5a on human B cell locomotion. Here we demonstrate that rC5a increases polarization and migration of human tonsillar B cells. The locomotory response was due to both chemokinetic and chemotactic activities of rC5a. Moreover, memory and, at a lesser extent, naive B cell fractions from purified tonsillar populations displayed rC5a-enhanced migratory properties, whereas GC cells did not. Flow cytometry revealed C5aR (CD88) on approximately 40% memory and 10% naive cells, respectively, whereas GC cells were negative. Immunohistochemistry showed that a few CD88+ cells were of the B cell lineage and localized in tonsillar subepithelial areas, where the majority of memory B cells settle. Pretreatment of memory B cells with the CD88 mAb abolished their migratory responsiveness to rC5a. Finally, the C5 gene was found to be expressed in naive, GC, and memory B lymphocytes at both the mRNA and the protein level. This study delineates a novel role for C5a as a regulator of the trafficking of human memory and naive B lymphocytes and supports the hypothesis that the B cells themselves may serve as source of C5 in secondary lymphoid tissues.

Antigens, CD↗
PubMed1988

Purification of the fifth component of murine complement from ascites fluid.

The murine complement component C5 was purified on an affinity column using a monoclonal anti-mouse C5 antibody. We describe in this paper that ascites fluid from normal (C5-sufficient) mice contains almost as much C5 protein as mouse serum. Since ascites fluid is much easier to obtain in large quantities it is a convenient source for the purification of this mouse serum protein.

Animals↗
PubMed2004

Identification of new quantitative trait loci in mice with collagen-induced arthritis.

OBJECTIVE: Collagen-induced arthritis (CIA) in the mouse is one of the most widely used autoimmune experimental models, with many features similar to rheumatoid arthritis. This study sought to identify potential genetic regulatory mechanisms of CIA in major histocompatibility complex-matched (H2-q) F(2) hybrid mice. METHODS: We used 126 polymorphic markers to perform simple sequence-length polymorphism analysis on 290 F(2) hybrids of arthritis-susceptible (DBA/1J) and arthritis-resistant (FVB/N) inbred mouse strains. The major clinical traits (disease severity and onset) were assessed, and serum antibodies specific to type II collagen (CII) were determined by enzyme-linked immunosorbent assay in 270 F(2) mice. Lymph nodes from 94 F(2) mice were used to test the ratio of CD4 to CD8 by fluorescence-activated cell sorter analysis, and cell proliferation was determined by XTT test. RESULTS: Two quantitative trait loci (QTLs) identified in previous studies were confirmed; these were severity-controlling Cia2 and onset-controlling Cia4 on chromosome 2. Moreover, we identified 5 new QTLs, 1 for CII-specific IgG2a antibodies on chromosome 5, 2 controlling the CII-specific IgG1 antibody response on chromosomes 10 and 13, 1 for the CD4:CD8 ratio on chromosome 2, and 1 for cell proliferation (measured by XTT test) on chromosome 16. Complement component C5 was identified as the probable main candidate gene for the QTLs Cia2 and Cia4. F(2) mice carrying a 2-basepair deletion of C5, the FVB/N allele, had low incidence and less severe disease as compared with those carrying the DBA/1J allele. CONCLUSION: This genome scan provides additional evidence confirming the role of C5 as a probable candidate gene for Cia2 and Cia4 loci, and identifies new QTLs controlling new traits in autoimmune arthritis.

Animals↗
PubMed1976

C3 requirements for formation of alternative pathway C5 convertase.

Although alternative pathway C3 and C5 convertases both have active proteolytic sites dependent on the same protein, Bb, the quantitative requirements for the expression of these activities are sufficiently different to permit their delineation in terms of B input an cell-bound C3b. That the labile component of each active site is Bb was established by their parallel decay rates, regeneration of the original specificities with B in the presence of D, and stabilization of each convertase by C3NeF. The evidence that the spatial relationships of Bb and C3b on the cell surface for C3 and C5 convertase activities are distinct is based not only upon the decay and regeneration of each original convertase but more so upon their interconversion. C3 convertase is converted to C5 convertase by interaction with additional C3 whereas C5 convertase reverts to a C3 convertase by treatment with C3 INA. The capacity of C3 INA treatment to abolish C5 convertase sites without affecting C3 convertase sites indicates the existence of two functional species of C3b, one of which is protected in the C3bBb complex whereas the other is exposed.

Cell Membrane↗
PubMed1976

[Herpes gestationis. Immunopathologic studies in mother and child].

Herpes gestationis is a nosologically undefined uncommon bullous disease in pregnancy. In a patient with herpes gestationis C3, C5 und C9 deposits could be demonstrated by immunohistological methods at the epidermal basement membrane (BM). Deposits of immunoglobulins, properdin and C3PA were absent. Autoantibodies against BM were found in the serum of the mother by using rabbit oesophagus but not with normal human skin as antigen. In the sera of mother and child a factor could be demonstrated which in vitro leads to complement fixation in human epidermal BM. Immunopathological findings may speak in favor of a nosological entity of herpes gestationis with respect to dermatitis herpetiformis and bullous pemphigoid.

Adult↗
PubMed1986

Immune complex induced glomerular lesions in C5 sufficient and deficient mice.

The role in the pathogenesis of immune complex-mediated glomerulonephritis of C5 or some terminal complement component dependent upon C5 for activation was explored in a congenic strain of C5 sufficient (NSN) and C5 deficient (OSN) mice. When these mice were given daily injections of heterologous protein, horse apoferritin (HAF), there were profound differences between the strains in the development of glomerulonephritis and renal dysfunction. When NSN and OSN mice produced low levels of anti-HAF, NSN mice developed extensive glomerular deposits of HAF and immune reactants and a mild proliferative glomerulonephritis. In contrast, comparable OSN mice developed only trace mesangial localization of HAF and no glomerular lesions by light microscopy. When NSN and OSN mice produced high levels of anti-HAF, both strains had equivalent glomerular immune deposits; however, NSN mice developed a severe necrotizing and crescentic glomerulonephritis, while OSN mice had much less glomerular injury. Compared to OSN mice, these NSN mice also had much more severe tubulointerstitial injury, and significantly higher serum creatinine levels. Thus, in this experimental model, the absence of C5 resulted in reduced glomerular immune complex localization when there were small amounts of circulating immune reactants; and in markedly reduced glomerular leukocyte influx, necrosis and crescent formation, when large amounts of immune reactants have localized in glomeruli. These effects could be mediated by C5 (such as C5a) or by some terminal complement component(s) dependent upon C5 for activation.

Age Factors↗
PubMed2005

Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans.

Fibrogenesis or scarring of the liver is a common consequence of all chronic liver diseases. Here we refine a quantitative trait locus that confers susceptibility to hepatic fibrosis by in silico mapping and show, using congenic mice and transgenesis with recombined artificial chromosomes, that the gene Hc (encoding complement factor C5) underlies this locus. Small molecule inhibitors of the C5a receptor had antifibrotic effects in vivo, and common haplotype-tagging polymorphisms of the human gene C5 were associated with advanced fibrosis in chronic hepatitis C virus infection. Thus, the mouse quantitative trait gene led to the identification of an unknown gene underlying human susceptibility to liver fibrosis, supporting the idea that C5 has a causal role in fibrogenesis across species.

Animals↗
PubMed1989

Multimeric C9 within C5b-9 deposits in unique locations in the cell wall of Salmonella typhimurium.

We have shown previously that multimeric C9 within C5b-9 (C9:C5b-8 greater than 3:1) is needed for killing of a rough strain of Escherichia coli. We now extend these studies using serum sensitive, rough (R) and serum resistant, wild type (WT) strains of Salmonella typhimurium as well as a mutant S. typhimurium strain (TS) with a temperature sensitive mutation in synthesis of keto-deoxy-octulosonate, a constituent within the deep core structure of Salmonella LPS. Both R and TS required multimeric C9 within C5b-9 to be killed. Addition at 37 degrees C of increasing inputs of C9 to TS or R bearing C5b-9 led to a dose-related increase in C9 binding and killing. In contrast, addition of high inputs of C9 to the same strains at 4 degrees C, a procedure that limits the C9:C5b-8 ratio to 1:1, resulted in low C9 binding and minimal killing. Bactericidal C5b-9 formed at 37 degrees C on R and TS with high inputs of C9 co-sedimented with the bacterial outer membrane on sucrose density gradient analysis. Non-bactericidal C5b-9 on R, WT, and TS co-sedimented near the inner membrane, despite the presumed lack of association between these constituents. Whereas 125I C9 within the non-bactericidal pools immunoprecipitate with anti-C5, 125I C9 within bactericidal pools did not immunoprecipitate with anti-C5, anti-C7, or anti-C9. These findings suggest that bactericidal C5b-9 may be deposited in a unique location or configuration within the bacterial cell wall.

Cell Wall↗
PubMed1997

Activation of complement by tissue plasminogen activator, but not acute cerebral ischemia, in a rabbit model of thromboembolic stroke.

Although complement activation is associated with tissue injury during inflammatory and ischemic states, complement activation in states of acute cerebral ischemia before and after administration of tissue plasminogen activator (TPA) has not yet been examined and is the focus of this investigation. Twenty-four New Zealand White rabbits weighing 3 to 3.5 kg were used for this study. Of these, 20 were subjected to intracranial autologous clot embolization via the internal carotid artery. Three hours postembolization, rabbits received an intravenous infusion of TPA (6.3 mg/kg, 20% bolus with the remainder infused over a 2-hour interval; 12 animals) or vehicle (eight animals). All animals were observed for a total of 7 or 8 hours postembolization. These two groups were compared to a cohort undergoing sham operation with subsequent TPA infusion (four animals). Plasma samples to quantify complement component C5 hemolytic activity (C5H5O) were obtained at the following time points: 30 minutes before and after clot embolization; 1 hour before and 1 hour after the initiation of therapy with TPA or vehicle and at the completion of the protocol; 7 to 8 hours after clot embolization. The C5 activation was not detected as the result of acute cerebral ischemia. However, animals receiving TPA with or without concomitant clot embolization exhibited C5 activation as assessed by a reduction in C5 hemolytic function, both 1 hour after initiation of TPA infusion (78.7 +/- 10.3% and 77.5 +/- 9.9% of baseline value, respectively; mean +/- standard error of the mean [SEM]) and at the end of the protocol, 2 hours after the completion of the TPA infusion (72.5 +/- 8.8% and 53.3 +/- 8.1%, respectively; mean +/- SEM, p < 0.05, each group). This study supports the conclusion that TPA, but not acute cerebral ischemia, may activate the complement cascade in this rabbit model of thromboembolic stroke.

Animals↗
PubMed1986

Chemotactic peptides modulate adherence of human polymorphonuclear leukocytes to monolayers of cultured endothelial cells.

We have used a new centrifugation assay to examine the effects of highly purified human C5a and C5a des Arg, as well as effects of N-formyl-methionyl-leucyl-phenylalanine (FMLP), on both the extent and strength of human polymorphonuclear leukocyte (PMN) adherence to monolayers of cultured human umbilical vein endothelial cells. At concentrations that were chemotactic for PMN, C5a (0.1 nM), C5a des Arg (5.0 nM), and FMLP (1.0 nM) significantly reduced the percentage of PMN that adhered to endothelial monolayers. Adherence also was reduced by C5a des Arg that was generated by incubating (37 degrees C, 30 min) fresh human serum with either zymosan or purified C5a. High concentrations of C5a (greater than 1.0 nM) and FMLP (greater than 50 nM) that diminished PMN chemotaxis significantly enhanced the percentage of PMN that adhered tightly to endothelial cells (adherent cells resisted a dislodgment force of 1200 X G). Tight adherence of PMN to endothelial cells also was increased by high concentrations of C5a that were added to human serum in which carboxypeptidase N activity was destroyed by heating (56 degrees C, 30 min), and by C5a that was generated by incubating (37 degrees C, 30 min) fresh human serum with zymosan in the presence of the carboxypeptidase N inhibitor, epsilon-aminocaproic acid. High concentrations of C5a des Arg (up to 80 nM) neither enhanced adherence of PMN to endothelial cells nor decreased PMN migration. Thus, a reciprocal relation exists between PMN migration and PMN adherence to endothelial cells in response to chemotactic factors. At concentrations that are chemotactic for human PMN, C5-derived peptides and FMLP reduce the adherence of PMN to endothelial monolayers. Only at concentrations that decrease PMN migration do C5a and FMLP augment PMN adherence.

Adult↗