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PubMed1988

C4-binding protein prevents spontaneous cleavage of C3 in sera of patients with hereditary angioedema.

We have studied the effects of polyclonal monospecific Fab' preparations against C1r, C1s, C1INH, C4, C4bp, and fragment Bb of factor B on complement activation in NHS and HAES. Furthermore, we have investigated complement activation in these sera after addition of purified C1s and purified C4bp. Blocking C1INH induced a spontaneous activation of the classical pathway in NHS and to a lesser extent in HAES. Addition of p-C1s resulted in a strong C3 conversion in NHS, but not in HAES. However, after the blocking of C4bp in HAES, addition of p-C1s produced a total C3 consumption. The ration of the protein concentration of C4bp to hemolytically active C4 was eight times higher in HAES than in NHS. This increased ratio may account for the resistance of HAES to the C1s induced C3 cleavage in our in vitro system and the stability of C3 in HAE despite C4 and C2 consumption in vivo.

Angioedema↗
PubMed2000

Usefulness of detection of complement activation products in evaluating SLE activity.

Complement activation products, such as C1rs-C1inh, specific for the activation of the classical pathway, C3b(Bb)P, specific for the activation of the alternative pathway and SC5b-9, specific for common terminal pathway of the complement cascade, were measured in healthy donors and in patients with clinically active and inactive systemic lupus erythematosus (SLE). Plasma levels of C3b(Bb)P and SC5b-9 were moderately, those of C1rs-C1inhibitor (C1rs-C1inh) were markedly elevated in patients with clinically inactive SLE, compared with healthy controls. The difference between active and inactive stages of the disease was best reflected by C3b(Bb)P plasma concentration (P<0.001), which also showed the highest correlation with the SLEDAI (Rs=0.41 P<0.001) and which was the most useful in distinguishing active and inactive sample pairs as well. The difference between SC5b-9 levels in the active and inactive stages was also significant (P=0.007), while that of C1rs-C1inh did not differ significantly (P=0.136). The correlation of the SLEDAI with SC5b-9 was 0.3 (P=0.015), while with C1rs-C1inh it was 0.21 (P=0. 089). These findings suggest that the measurement of complement activation products, especially that of the alternative pathway, are sensitive markers of the activity of SLE and can be used for clinical purposes.

Adult↗
PubMed1993

Complement activation in newborn infants with early onset infection.

The complement system is an important element in host defense. Quantitative deficiencies of total hemolytic complement activity and decreased C3 levels were reported in sera from normal neonates. However, little is known about complement activation products in the newborn. In a prospective study, complement activation products were determined in 32 healthy term neonates, in 41 neonates with colonization of their mothers, in 15 colonized neonates, and in 10 neonates with early onset infection. In all newborns, EDTA plasma was obtained within the first 6 h of life. The anaphylatoxin C3a-desArg was determined with a novel ELISA using an MAb reacting with a neoepitope of C3a-desArg. C3bBbP (alternative pathway convertase) and C1rsC1-inactivator (activation product of classical pathway) were measured with double-sandwich ELISA. C3 was determined by radial immunodiffusion. Plasma concentrations of C3a-desArg were similar in healthy term neonates and healthy adults, whereas diminished C3 levels were observed in the newborn infants. There were no significant differences between healthy neonates, neonates with colonized mothers, and colonized neonates. In neonates with infection, a significant elevation of C3a-desArg was found at the onset of the disease, resulting from alternative pathway activation. In contrast, the C1rsC1-inactivator complex showed no significant differences among healthy, colonized, and infected neonates. The anaphylatoxin C3a mediates inflammatory reactions such as vasodilatation and an increase in microvascular permeability and might therefore play an important role in severe neonatal infection.

Complement Activation↗
PubMed2001

C1-inhibitor: an anti-inflammatory reagent with therapeutic potential.

Excessive activation of the protein cascade systems often leads to severe inflammatory tissue destruction with potential life-threatening outcome. These include clinical disorders, such as capillary leak syndrome, septic shock, myocardial infarction and other ischaemia/reperfusion injuries, trauma, burns, multiple organ failure, as well as graft rejection. A therapeutic substitution of appropriate regulators appears to be a reasonable approach to reduce undesirable inflammatory reactions. C1-inhibitor, a multifunctional regulator of the various kinin-generating cascade systems, is frequently reduced in patients suffering from severe inflammation. C1-inhibitor concentrate has been used for decades as a substitution therapy to treat acute attacks in patients with hereditary angioedema. Studies including pathophysiologically relevant animal models now provide sufficient evidence that C1-inhibitor may also serve as an effective means to protect against inflammatory tissue injury. Promising clinical results are emerging which support C1-inhibitor as a candidate for therapy in severe inflammatory disorders. Although treatment with C1-inhibitor is regarded as safe, recent reports on possible side effects in certain clinical situations emphasise the importance of controlled clinical studies. The following review will focus on the impact of C1-inhibitor treatment on diseases, where complement contributes to the pathogenesis.

Animals↗
PubMed1992

Hereditary angioedema: a case with ascites yet no symptoms in the family.

An interesting case of hereditary angioedema in a 26-year-old female is reported, with a finding of transient effusion of fluid into the peritoneal cavity during the attacks. The patient suffered from recurrent abdominal pain for several years, but no family members had any similar symptoms. In spite of repeated hospital admissions and many examinations, accurate diagnosis was not made until the most recent admission. The recognition of hereditary angioedema as a cause of acute and/or recurrent abdominal pain may avoid useless invasive procedures and lead to adequate treatment in other similar cases.

Abdominal Pain↗
PubMedDate not supplied

[Disturbances of protein C activity in abdominal sepsis: diagnostic and predictive importance].

BACKGROUND: Despite improved diagnostic modalities, potent antibiotics, modern intensive care, and aggressive surgical treatment, more than one third of patients still die of severe secondary peritonitis. Clinical difficulties in the treatment of abdominal sepsis were related to inherent problems of limited clinical signs and the rapid spread of infection. An inflammatory process is often well under way before the presence of clinical signs and symptoms of sepsis. The aim of this prospective study was to assess diagnostic and prognostic significance of protein C in abdominal sepsis. METHODS: Twenty-two patients with severe intraabdominal infections with sepsis syndrome were treated surgically as compared to 15 patients with hernia repair (control group). During the study, the following parameters were analyzed daily: protein C, AT III, plasminogen, alfa-2 antiplasmin, HMWK, C5a and C5-B9 complement, C1-inhibitor, CRP. RESULTS. The mean APACHE II score was 17 points, with actual mortality rate of 23%. Each parameter evaluated in the abdominal sepsis group differed from the one evaluated in the control group to a great extent (p = 0.001). The results and multivariate regression statystical analysis confirmed the following parameters as sensitive biological markers of septic cascade (p < 0.0001-0.026): protein C, AT III, HMWK, C1-inhibitor and C5-B9 complement. According to the results the low level of protein C consistently correlated with disease severity and suggested the development of septic shock and poor outcome. CONCLUSION: Early diagnosis of plasma proteolytic disturbances was very important, from the diagnostic and predictive point of view, in abdominal sepsis. According to the results protein C was the most significant marker of sepsis and early predictor of the outcome of septic complications during severe intraabdominal infections (r = 0.761; p = 0.0001).

Abdomen↗
PubMed1987

Serum concentrations of immunoglobulins and complement components in women using an intra-uterine contraceptive device (IUCD).

Immunoglobulins A, G and M and the complement components C3, C4 and CI-INH were quantified in sera from 59 women using an intra-uterine contraceptive device (IUCD). Most of the women were using a Cu IUCD, and the mean duration of use was 7.3 years. No differences in the concentrations were detected compared with control subjects. Our data, however, do not exclude a possible temporary change in the concentrations of immunoglobulins and complement components.

Adult↗
PubMed1980

Different serum requirements for opsonization of two serologically identical strains of Pseudomonas aeruginosa.

Two strains of serotype 2 Pseudomonas aeruginosa and one species of E. coli were compared regarding their opsonic requirements using human sera and polymorphonuclear leukocytes. None of the three organisms tested activated exclusively one complement pathway. Both strains of Pseudomonas had an absolute requirement for antibody for opsonization, but differed in complement requirements. The studies described herein showed significant differences in the mechanism of opsonization of the two strains of Pseudomonas.

Binding Sites, Antibody↗
PubMed2000

The Arthus reaction in rodents: species-specific requirement of complement.

We induced reverse passive Arthus (RPA) reactions in the skin of rodents and found that the contribution of complement to immune complex-mediated inflammation is species specific. Complement was found to be necessary in rats and guinea pigs but not in C57BL/6J mice. In rats, within 4 h after initiation of an RPA reaction, serum alternative pathway hemolytic titers decreased significantly below basal levels, whereas classical pathway titers were unchanged. Thus the dermal reaction proceeds coincident with systemic activation of complement. The serine protease inhibitor BCX 1470, which blocks the esterolytic and hemolytic activities of the complement enzymes Cls and factor D in vitro, also blocked development of RPA-induced edema in the rat. These data support the proposal that complement-mediated processes are of major importance in the Arthus reaction in rats and guinea pigs, and suggest that BCX 1470 will be useful as an anti-inflammatory agent in diseases where complement activation is known to be detrimental.

Animals↗
PubMed2004

Mutational analyses of the recombinant globular regions of human C1q A, B, and C chains suggest an essential role for arginine and histidine residues in the C1q-IgG interaction.

The first step in the activation of the classical complement pathway by immune complexes involves the binding of the globular domain (gC1q) of C1q to the Fc regions of aggregated IgG or IgM. Each gC1q domain is a heterotrimer of the C-terminal halves of one A (ghA), one B (ghB), and one C (ghC) chain. Our recent studies have suggested a modular organization of gC1q, consistent with the view that ghA, ghB, and ghC are functionally autonomous modules and have distinct and differential ligand-binding properties. Although C1q binding sites on IgG have been previously identified, the complementary interacting sites on the gC1q domain have not been precisely defined. The availability of the recombinant constructs expressing ghA, ghB, and ghC has allowed us, for the first time, to engineer single-residue substitution mutations and identify residues on the gC1q domain, which are involved in the interaction between C1q and IgG. Because C1q is a charge pattern recognition molecule, we have sequentially targeted arginine and histidine residues in each chain. Consistent with previous chemical modification studies and the recent crystal structure of gC1q, our results support a central role for arginine and histidine residues, especially Arg(114) and Arg(129) of the ghB module, in the C1q-IgG interaction.

Alanine↗
PubMed2005

A direct role for C1 inhibitor in regulation of leukocyte adhesion.

Plasma C1 inhibitor (C1INH) is a natural inhibitor of complement and contact system proteases. Heterozygosity for C1INH deficiency results in hereditary angioedema, which is mediated by bradykinin. Treatment with plasma C1INH is effective not only in patients with hereditary angioedema, but also in a variety of other disease models, in which such therapy is accompanied by diminished neutrophil infiltration. The underlying mechanism has been explained primarily as a result of the inhibition of the complement and contact systems. We have shown that C1INH expresses the sialyl-Lewis(x) tetrasaccharide on its N-linked glycan, via which it binds to E- and P-selectins and interferes with leukocyte-endothelial adhesion in vitro. Here we show that both native C1INH and reactive center cleaved C1INH significantly inhibit selectin-mediated leukocyte adhesion in several in vitro and in vivo models, whereas N-deglycosylated C1INH loses such activities. The data support the hypothesis that C1INH plays a direct role in leukocyte-endothelial cell adhesion, that the activity is mediated by carbohydrate, and that it is independent of protease inhibitory activity. Direct involvement of C1INH in modulation of selectin-mediated cell adhesion may be an important mechanism in the physiologic suppression of inflammation, and may partially explain its utility in therapy of inflammatory diseases.

Animals↗
PubMed2000

[Acquired angioneurotic edema. Clinical and biological characteristics in 9 patients].

OBJECTIVE: Angioneurotic edema (AE) is a rare but severe disease. Hereditary AE is the more well-known form. The acquired form is exceptional: the symptoms are the same but there are some biologic and treatment differences. We investigated the clinical and biochemical features in nine patients with acquired angioneurotic edema (AAE). PATIENTS AND METHODS: Four of the patients with type I AAE presented an accelerated metabolism of C1Inh, associated with a hematology disease. Their C4, C1q and C1Inh plasma levels were low. Four patients had type II AAE associated with an autoantibody to C1Inh. Their C1Inh plasma levels were normal or low but the functional levels were low in all four. One patient had AAE induced by oral contraceptives. The C1Inh plasma level was normal but the functional level was very low; there were no autoantibodies. Symptoms resolved when oral contraceptives were withdrawn and the C1Inh level returned to normal. DISCUSSION: Treatment of AAE is a difficult matter. For type I AAE, it consists in treating the associated disease. For type II AAE, the treatment goal is to lower the autoantibody level. Management of these diseases requires close collaboration between clinicians and biologists.

Adult↗