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PubMed1999

Active sites in complement components C5 and C3 identified by proximity to indels in the C3/4/5 protein family.

We recently suggested that sites of length polymorphisms in protein families (indels) might serve as useful guides for locating protein:protein interaction sites. This report describes additional site-specific mutagenesis and synthetic peptide inhibition studies aimed at testing this idea for the paralogous complement C3, C4, and C5 proteins. A series of C5 mutants was constructed by altering the C5 sequence at each of the 27 indels in this protein family. Mutants were expressed in COS cells and were assayed for hemolytic activity and protease sensitivity. Mutants at five indels showed relatively normal expression but substantially reduced sp. act., indicating that the mutations damaged sites important for C5 function. Twenty-three synthetic peptides with C5 sequences and 10 with C3 sequences were also tested for the ability to inhibit C hemolytic activity. Three of the C5 peptides and one of the C3 peptides showed 50% inhibition of both C hemolytic and bactericidal activities at a concentration of 100 microM. In several cases both the mutational and peptide methods implicated the same indel site. Overall, the results suggest that regions important for function of both C3 and C5 lie proximal to residues 150-200 and 1600-1620 in the precursor sequences. Additional sites potentially important for C5 function are near residue 500 in the beta-chain and at two or three sites between the N-terminus of the alpha'-chain and the C5d fragment. One of the latter sites, near residue 865, appears to be important for proteolytic activation of C5.

Amino Acid Sequence↗
PubMed1985

Mycoplasma pulmonis arthritis in mice: microbiological and immunological features.

Mycoplasma pulmonis m53 was inoculated intraarticularly in the bilateral hind footpads and bilateral knee joints of BALB/c mice. Mycoplasmas were recovered from the affected joints over 20 weeks accompanying acute or subacute inflammation. Intensive deposition of immunoglobulins, a complement (C3) and mycoplasma cell antigens occurred in synovial and adjacent connective tissues. The histopathologically intact kidneys, brain, and lungs showed deposition of IgG and the complement on the endothelial cells of blood vessels. An IgG-rheumatoid factor like substance (RFLS) was detected in the serum of the mice by an enzyme-linked immunoabsorbent assay. Persistence of mycoplasma cells and immune complexes in the articular tissues might cause the prolongation of inflammatory responses in murine mycoplasmal arthritis.

Animals↗
PubMed2006

Induction of complement-fixing autoantibodies against type VII collagen results in subepidermal blistering in mice.

Experimental models reproducing an autoimmune response resulting in skin blistering in immunocompetent animals are lacking. Epidermolysis bullosa acquisita (EBA) is a bullous skin disease caused by autoantibodies to type VII collagen. In this study, we describe an active disease model of EBA by immunizing mice of different strains with murine type VII collagen. All mice developed circulating IgG autoantibodies that recognized type VII collagen and bound to the lamina densa of the dermal-epidermal junction. Importantly, subepidermal blisters developed in 82% of SJL-1, 56% of BALB/c mice, and 45% of Fc gammaRIIb-deficient mice, but not in SKH-1 mice. In susceptible animals, deposits of IgG1, IgG2, and complement C3 were detected at the dermal-epidermal junction. In contrast, in the nondiseased mice, tissue-bound autoantibodies were predominantly of the IgG1 subclass and complement activation was weak or absent. This active disease model reproduces in mice the clinical, histopathological, and immunopathological findings in EBA patients. This robust experimental system should greatly facilitate further studies on the pathogenesis of EBA and the development of novel immunomodulatory therapies for this and other autoimmune diseases.

Animals↗
PubMedDate not supplied

Complement fixing antibodies to DS-DNA in systemic lupus erythematosus: a study using the immunofluorescent Crithidia luciliae method.

Crithidia luciliae, a hemoflagellate, was used in an immunofluorescent procedure to assay for antibodies to ds-DNA and their capacity to fix complement. Positive reactions with this method were limited to systemic lupus erythematosus patients, and sensitivity was comparable to the DNA binding assay. Complement fixing activity of antibodies to ds-DNA in 45 sera was determined using kinetoplast ds-DNA of Crithidia luciliae and an antiserum to C3. Complement fixing antibodies to ds-DNA were found in nearly all patients with documented active renal involvement and absent in nearly all patients with no, or inactive renal involvement.

Antibodies↗
PubMed1976

Complement-mediated acinar cell necroses in pancreatitis induced by basement membrane antibodies.

To study the role of the serum complement system in the early necrosis of acinar cells an acute pancreatitis was produced by injection of basement membrane antibodies into the pancreatic duct of mice and rats. In all animals deposition of complement (C3) and antibasement membrane IgG could be observed in an identical position within areas of acinar cell necrosis. The extent of parenchymal damage and the intensity of complement deposits corresponded to the injected dose of antibodies. The importance of cytolytically active complement components (C5-9) was demonstrated in congenitally C5-defective old line mice which did not show typical centrolobular necroses 1 hr after intraductal injection of antibodies. However, the normocomplementemic mice developed extensive necroses of acinar cells. The results support the hypothesis of a complement-induced acinar cell necrosis in acute pancreatitis.

Acute Disease↗
PubMed2006

Prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H-deficient mice.

Membranoproliferative glomerulonephritis (MPGN) type II (dense deposit disease) is an inflammatory renal disease characterized by electron-dense deposits and complement C3 on the glomerular basement membrane. There is no effective therapy. We investigated the role of C5 activation in a model of MPGN that develops spontaneously in complement factor H-deficient mice (Cfh(-/-)). At 12 months there was a significant reduction in mortality, glomerular cellularity, neutrophil numbers, and serum creatinine levels in Cfh(-/-) mice deficient in C5. Excessive glomerular neutrophil numbers, frequently seen in patients with MPGN during disease flares, were also observed in Cfh(-/-) mice after the administration of an antiglomerular basement membrane antibody. This exaggerated injurious phenotype was absent in Cfh(-/-) mice deficient in C5 but not in Cfh(-/-) mice deficient in C6, indicating a key role for C5 activation in the induction of renal lesions. Importantly, the renal injury was completely reversed in Cfh(-/-) mice pretreated with an anti-murine C5 antibody. These results demonstrate an important role for C5 in both spontaneous MPGN and experimentally induced nephritis in factor H-deficient mice and provide preliminary evidence that C5 inhibition therapy might be useful in human MPGN type II.

Animals↗
PubMed2005

A critical role for complement C3d and the B cell coreceptor (CD19/CD21) complex in the initiation of inflammatory arthritis.

Complement C3 cleavage products mediate the recognition and clearance of toxic or infectious agents. In addition, binding of the C3d fragment to Ag promotes B lymphocyte activation through coengagment of the BCR and complement receptor 2 (CD21). Signal augmentation is thought to be achieved through enhanced recruitment and activation of CD21-associated CD19. In this study we show, using the DBA/1 collagen-induced arthritis (CIA) model, that conjugation of C3d to heterologous type II collagen is sufficient to cause disease in the absence of the mycobacterial components of CFA. Transient depletion of C3 during the inductive phase of CIA delays and lessens the severity of disease, and DBA/1 mice deficient for coreceptor components CD19 or CD21 are not susceptible to CIA. Adoptive transfer experiments revealed that CD21 expression on either B cells or follicular dendritic cells is sufficient to acquire disease susceptibility. Although CD19(-/-) and CD21(-/-) mice produce primary Ab responses to heterologous and autologous type II collagen, they are impaired in the ability to activate T cells, form germinal centers, and produce secondary autoantibody responses. These findings indicate that binding of C3d to self-Ags can promote autoimmunity through enhanced Ag retention and presentation by follicular dendritic cells and B cells, respectively.

Animals↗
PubMedDate not supplied

Intermediate and long-acting insulin preparations without protamine sulphate are complement activators in vitro.

Recently, we have documented an abnormal in vivo complement metabolism in Type 1 diabetic children treated with monocomponent porcine insulin Monotard MC and its correction after switch-over to human insulin Protaphane HM. This prompted us to investigate the ability of different kinds of insulin preparations to induce complement activation in vitro. Freshly collected serum samples from healthy blood donors were incubated with commercial rapid and intermediate or long-acting (by protamine sulphate (PS) or zinc) insulin preparations for 2 hours at 37 degrees C. The C3d content of the supernatants was measured by turbidimetry as a marker of C3 complement fraction consumption. Only long-acting preparations of insulins without protamine sulphate were associated with highly significant increased levels of C3d, whatever the source of insulin, animal or human. Moreover, addition of exogenous protamine sulphate was able to inhibit the C3 conversion. This effect was dose-dependent and peaked at the concentration of commercial NPH insulin preparations. The mechanism by which protamine sulphate inhibits complement activation in vitro could be related to its ability to interfere with the physical nature of the solid surfaces presented by the insulin crystals. Indeed, insulin crystals were rapidly cleared (< 5 min) in the incubated serum when small doses of protamine sulphate were added. The complement activating capacity of long-acting insulin without protamine was dose dependent, equivalent to the known complement activator Zymosan, and abolished in the presence of EDTA. In conclusion, the present study has documented the ability of some protracted insulin preparations to activate the complement system in vitro if they are devoided of protamine sulphate. On the other hand, short-acting and NPH insulins are not complement activators.

Animals↗
PubMed1982

Biosynthesis and processing of a human precursor complement protein, pro-C3, in a hepatoma-derived cell line.

A 180,000-dalton single-chain molecule (human pro-C3) is the precursor of the third component of human complement (C3), a disulfide-linked two-chain protein. The pro-C3 is converted by limited proteolysis to C3. The relationship between pro-C3 and C3 was established with the use of Hep G2, a cell line derived from a human hepatocellular carcinoma, which synthesizes at least 17 plasma proteins.

Animals↗
PubMed1993

Serological findings in patients with allergic bronchopulmonary aspergillosis during remission.

The concentrations of total IgG, complement C3 and circulating immune complexes (CIC) were studied in 15 patients with allergic bronchopulmonary aspergillosis (ABPA) during remission and compared with those of 10 matched controls. The concentrations of complement and circulating immune complexes were similar to those of the controls but 33% of patients with ABPA in remission still had circulating immune complexes, mainly of IgG. Even so, the concentrations of IgG were significantly higher in patients during remission compared to controls but were lower than those observed during the acute stage of ABPA.

Acute Disease↗
PubMed1991

Mechanisms of clearance of immune complexes from peritubular capillaries in the rat.

These experiments evaluated extraglomerular sites of renal immune complex (IC) deposition and specific features of host capability to remove these IC. Ex vivo perfusion of rat kidneys with the endothelium binding lectin concanavalin A (con A) followed by rabbit anti con A IgG results in a subendothelial IC nephritis in glomerular capillaries (GC) and diffuse IC formation with complement (C3) deposition in peritubular capillaries (PC). Histologic, immunofluorescence, and ultrastructural studies were performed at 10 minutes and 1, 4, and 24 hours after perfusion. At 10 minutes, strong linear binding of con A, rabbit IgG, and rat C3 to the endothelium was detected by immunofluorescence in both GC and PC. In GC this was followed by endothelial cell swelling and denudation (1 hour) with platelet and neutrophil infiltration and formation of subendothelial IC deposits which persisted at 4 and 24 hours. In contrast, some PC endothelial swelling was also present at 10 minutes and 1 hour, but ICs (IgG, con A, C3) were capped and shed into capillary lumina at 1 to 2 hours with complete clearance of IC by 4 hours. Selective neutrophil depletion, by antisera and irradiation, and complement depletion with cobra venom factor, delayed clearance of PC IC by several hours but complete clearance of IC with restored structural integrity of PC was still achieved by 24 hours. Platelet depletion had no effect on PC IC clearance. These studies demonstrate a model for study of PC IC. Such a model may aid our understanding of lupus nephritis in which extensive GC IC deposits associated with severe inflammatory injury may coexist with PC deposits. Efficient clearance of IC in PC compared with GC may be due to differences in hemodynamic forces, amounts of IC formed in each of these sites, differences in binding of IC to subendothelial basement membrane, or phenotypic specialization of the endothelium lining these two different capillary beds.

Animals↗
PubMed1974

Mechanisms of immune lysis of the red cells in hereditary erythroblastic multinuclearity with a positive acidified serum test and paroxysmal nocturnal hemoglobinuria.

The red cells of patients with hereditary erythroblastic multinuclearity with a positive acidified serum test (HEMPAS), a form of congenital dyserythropoietic anemia, and the cells of patients with paroxysmal nocturnal hemoglobinuria (PNH) are lysed more readily than normal cells by certain antibodies, notably cold agglutinins (anti-I) and complement. With some but not other examples of anti-I, HEMPAS and PNH cells adsorbed more antibody than normal cells. Equal quantities of adsorbed antibody bound equal quantities of the first component of complement (C1) to normal, PNH, and HEMPAS cells. However, for a given quantity of bound antibody and C1, much more of the fourth component of complement (C4) was bound to HEMPAS cells than to normal cells. This resulted in the binding of proportionately larger quantities of the third component of complement (C3) to these cells. The same amount of bound C3 was found on the membranes of normal and HEMPAS cells for a given degree of lysis. Hence, the marked increase in lysis of HEMPAS cells is due to the increased adsorption of antibody and/or increased binding of C4.PNH cells bound the same amount of C4 per bound C1 as normal cells but bound more C3 than normal cells. However, the mean concentration of C3 on the membrane of PNH cells was one-third to one-fifth that on normal cells for a given degree of lysis. Hence, the increased lysis of PNH cells is due to the increased binding of C3 and increased hemolytic effectiveness of the bound C3.

Adsorption↗
PubMed1998

X-ray crystal structure of C3d: a C3 fragment and ligand for complement receptor 2.

Activation and covalent attachment of complement component C3 to pathogens is the key step in complement-mediated host defense. Additionally, the antigen-bound C3d fragment interacts with complement receptor 2 (CR2; also known as CD21) on B cells and thereby contributes to the initiation of an acquired humoral response. The x-ray crystal structure of human C3d solved at 2.0 angstroms resolution reveals an alpha-alpha barrel with the residues responsible for thioester formation and covalent attachment at one end and an acidic pocket at the other. The structure supports a model whereby the transition of native C3 to its functionally active state involves the disruption of a complementary domain interface and provides insight into the basis for the interaction between C3d and CR2.

Amino Acid Sequence↗