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PubMed2007

Bordetella pertussis binds human C1 esterase inhibitor during the virulent phase, to evade complement-mediated killing.

C1 esterase inhibitor (C1inh) is a major inhibitor of several pathways of inflammation in humans. In this study, we show that virulent-phase cultures of Bordetella pertussis, the etiological agent for whooping cough, but not other Bordetella species specifically recruit C1inh from human serum. Using a spontaneous mutant of B. pertussis that was deficient in C1inh binding, we demonstrate that the ability of B. pertussis to acquire high levels of human C1inh and wild-type levels of serum resistance are well correlated, suggesting that, in addition to and independent of BrkA expression, acquisition of C1inh is vital to B. pertussis resistance to complement-mediated killing.

Bordetella pertussis↗
PubMed1985

Activation and inhibition of Hageman factor-dependent pathways and the complement system in uncomplicated bacteremia or bacterial shock.

Levels of components of the contact activation, coagulation, and complement systems and their main inhibitors were measured in 45 critically ill patients during 61 episodes of uncomplicated bacteremia or bacterial shock. Levels of Hageman factor (factor XII), prekallikrein, high-molecular-weight kininogen, factor XI, factor VII, total hemolytic complement, alternative pathway activity, and C3 were within the normal range during uncomplicated bacteremia (n = 29), but during fatal bacterial shock (n = 13) a significant decrease by 40%-50% was observed in all measurements. During nonfatal bacterial shock (n = 19) a moderate decrease was observed in most of these measurements. The capacity of plasma to inactivate kallikrein was significantly higher during bacteremia than during bacterial shock because of a significant increase in the level of C1 esterase inhibitor. Levels of antithrombin III and alpha 2-macroglobulin were below normal in all groups. Thus increased inhibition of the contact activation and complement systems is beneficial during bacteremia.

Angiotensin III↗
PubMed1998

C1-esterase inhibitor blocks T lymphocyte proliferation and cytotoxic T lymphocyte generation in vitro.

We have previously shown that activated C1s complement and activated T cells cleave beta2-microglobulin (beta2m) in vitro leading to the formation of desLys58 beta2m. This process can specifically be inhibited by C1-esterase inhibitor (C1-inh). Furthermore we showed that exogenously added desLys58 beta2m in nanomolar amounts to a one-way allogenic mixed lymphocyte culture (MLC) increased the endogenous production of IL-2 and the generation of allo-specific cytotoxic T lymphocytes. C1-inh was purified from fresh human plasma and added to human or murine MLC and mitogen-stimulated lymphocyte cultures grown in the presence of complement-inactivated serum. Read-outs were cell proliferation, lymphokine production and development of T cell-mediated cytotoxicity. We found that addition of C1-inh to MLC and mitogen-exposed murine and human lymphocyte cultures inhibited proliferation, the development of allospecific cytotoxic activity, and changed the endogenous production of IL-2, IL-4, IL-10, IL-12 and IFN-gamma. These data clearly demonstrate a regulatory function of C1-inh on T cell-mediated immune functions.

Animals↗
PubMedDate not supplied

Changes in complement and coagulation factors in a patient suffering a severe anaphylactoid reaction to injected contrast material: some considerations of pathogenesis.

A patient, suffering a severe anaphylactoid reaction to contrast material injected for an intravenous pyelogram, developed a consumption coagulopathy and evidence of complement activation. Precontrast complement values suggested that the patient had been processing complement via the classical pathway, perhaps as a consequence of an earlier protracted Klebsiella infection. Following contrast injection, a precipitous fall in hemolytic complement (CH50) and in the concentration of the C1 esterase inhibitor (C1INH) developed, as well as a diminution in C4 and C3 with the evolution of C3 conversion products. The possible role that these changes might play in the pathogenesis of idiosyncratic reactions to contrast media is considered.

Adult↗
PubMed2000

Does hypertension confer a hypercoagulable state in stroke-prone spontaneously hypertensive rats?

OBJECTIVE: To verify whether hypertension confers a hypercoagulable state in a hypertensive animal model. DESIGN: The parameters of blood coagulation were compared between stroke-prone spontaneously hypertensive rats (SHR-SP) and Wistar-Kyoto (WKY) rats. Each rat group consisted of a younger subgroup at 8-12 weeks old (n = 12) and an older subgroup at 16-20 weeks old (n = 12). METHODS: Prothrombin time (PT), activated partial thromboplastin time (APTT), fluorogenic PT, fibrinogen, fibrin/fibrinogen degradation products (FDP), thrombin-anti-thrombin III complex (TAT), factor Xa activity, anti-thrombin III (AT-III), tissue factor pathway inhibitor (TFPI), protein C and C1 inhibitor were measured in both rat groups. RESULTS: There was no significant difference in FDP and TAT levels between SHR-SP and WKY rats even at 16-20 weeks when SHR-SP developed severe hypertensive vascular lesions. Contrary to expectations, fluorogenic PT and factor Xa activity were significantly lower in SHR-SP than in WKY rats. While there was no significant difference in AT-III, TFPI and protein C activities between SHR-SP and WKY rats, C1 inhibitor activity was significantly higher in SHR-SP than in WKY rats. The elevated C1 inhibitor activity was inversely correlated with the reduced factor Xa activity. Gel-filtered fractionated plasma with C1 inhibitor activity had an inhibitory effect on the purified rat factor Xa, and immunodepletion of C1 inhibitor from the fractionated plasma attenuated the inhibitory effect CONCLUSION: These results suggest that SHR-SP get into a hypocoagulable state rather than a hypercoagulable state, and that the reduction of factor Xa activity in SHR-SP may be related to the elevation of C1 inhibitor activity.

Animals↗
PubMed1982

Effect of nonviable tissue and abscesses on complement depletion and the development of bacteremia.

Complement concentrations and blood cultures were compared in 58 patients within 24 hours of injury and weekly thereafter. Extensive amounts of nonviable tissue (n = 40) were associated with a mean depletion of C4, C3, and C5 by 56%, and minor injuries (n = 18) by 22% of normal concentration within 14 hours after injury. The C4, C3, and C5 concentrations returned to normal or above within a week after minor injuries, but not following major injuries. However, C4, c3, and C5 levels remained depressed after major injuries unless necrotic tissue was removed or abscesses were drained. If complement concentration was below 50% of normal for more than a week all patients developed bacteremia. Following debridement or drainage complement returned to normal in 11 patients and blood cultures became negative in seven. Possible consequences by activation and altered availability of complement for chemotaxis, opsonization, and lysis of bacteria have been analyzed and related to the development of bacteremia.

Abscess↗
PubMed1998

The therapeutic effect of C1-inhibitor on gut-derived bacterial translocation after thermal injury.

To test the effects of C1-esterase inhibitor in scald burns on bacterial translocation and intestinal damage, standardized deep partial-thickness burns were inflicted on domestic pigs, scalding 30% of the skin surface for 25 s with 75 degrees C hot water. The animals (n = 17; weight 25-35 kg) were divided into three groups: I) the control group (n = 5) without scald burn; II) the group (n = 6) with scald burn; and III) the group with C1-inhibitor (n = 6): scald burn and treatment with C1-inhibitor (C1-INH; BERINERT, Behring, Marburg, Germany). Parameters measured and compared in this model were activity of complement system, hemodynamics, body weight, pathological organ alterations including intestinal lesions, bacterial translocation, and skin damage. C1-INH administration significantly decreased the plasma levels of the specific soluble membrane attack complex (SC5b-9), bacterial translocation, and the degree of intestinal ischemia in the postburn period compared with untreated animals. Moreover, animals treated with C1-INH exhibited a minor degree of organ alterations including damage of the skin and development of edema. The favorable effects of C1-INH may be explained by the protection of the intestinal and dermal microcirculation in the acute phase of thermal injury.

Animals↗
PubMed2000

The complement regulators C1 inhibitor and soluble complement receptor 1 attenuate acute lung injury in rabbits.

Because activation of the complement system plays a major role in the pathogenesis of acute lung injury, the availability of new specific complement inhibitors represents a promising therapeutic approach. In the present study we investigated pulmonary edema formation and pulmonary artery pressure (PAP) in acute complement-induced lung injury for possible therapeutic impact of the complement regulators C1 inhibitor and soluble complement receptor 1. Eighteen isolated and ventilated rabbit lungs were perfused with pooled normal human serum (NHS, final concentration 35%) in Krebs-Henseleit buffer in a recirculating system. Lung weight gain and PAP were continuously recorded. Complement activation was blocked by the addition of C1 inhibitor (1.0 U/mL, n = 6) or sCR 1 (2.0 microg/mL, n = 6). Lungs that received NHS without inhibitors served as controls (n = 6). This study was performed according to the Helsinki Declaration and approved by the local government. Application of NHS resulted in an increase of PAP within 20 min from 8+/-2 to 42+/-6 mmHg, which was significantly (P < 0.05) decreased by C1-Inh (25+/-5 mmHg) and sCRI (20 +/-3 mmHg). Moreover, pulmonary edema formation after NHS, as assessed by overall weight gain, was reduced by both C1-Inh and sCR1, compared with controls. These findings were paralleled with significantly decreased thromboxane release rates and reduced tissue deposition of C3c and C5b-9. C1 inhibitor and sCR1 attenuate the complement-induced pulmonary capillary leakage and PAP increase, indicating the protective effect of complement inhibition in isolated perfused rabbit lungs.

Animals↗
PubMed1984

Inherited complement deficiencies.

Isolated genetic deficiencies of individual components of the complementary system have been described in man for all the components of the classical pathway and the membrane attack complex as well as for Factor I, Factor H and properdin. It is only for Factor B and Factor D of the alternative pathway that homozygous deficiency states are not so far known. Complement deficiency states provide the most direct way of looking at the role of the complement system in vivo and emphasize the importance of complement in resistance to bacterial infection and in particular to infection with Neisseria. This association is not unexpected since in vitro studies have shown complement to be an efficient enhancer of phagocytosis and inflammation. The particularly frequent occurrence of neisserial infection may be ascribed to the ability of these organisms to survive in phagocytic cells so that the plasma cytolytic activity provided by complement is needed to kill them. On the other hand the strong association between complement deficiencies and immune-complex diseases--especially systemic lupus erythematosus--was unexpected and seems paradoxical in view of the large part played by complement in the pathogenesis of immune complex mediated tissue damage. The paradox can be explained in part by the necessity for an intact complement system in the solubilization and the proper handling of immune complexes. It is also likely that complement deficiency can allow the persistence of low virulence organisms that produce disease solely by an immune complex mechanism. Recently described deficiencies of complement receptors and their effects in vivo are described.

Blood Donors↗
PubMed1979

Hereditary angio-oedema: treatment with danazol. Report of a case.

An 8-year-old boy with hereditary angio-oedema was treated with danazol under close endocrinological supervision. The boy's C1 esterase inhibitor (C1inh) and C4 levels increased rapidly to near normal values under a daily dose of 400 mg and were maintained at about 50% of the normal by maintenance doses of 200 mg danazol every other day. Throughout the entire treatment period (11 months) the boy has been maintained free from attacks of angio-oedema. No hormonal imbalance was detected in the follow-up period. Our results indicate that danazol should be suitable for the treatment of HAE not only in adults but also in prepubescent children.

Angioedema↗
PubMed1979

Complement abnormalities in diffuse plane xanthomatosis with paraproteinaemia.

Paraproteinaemia may be associated with xanthomatous skin deposits and these can arise in the absence of elevated lipid levels. Two cases of benign monoclonal gammopathy with diffuse plane xanthomatosis are reported. Case 1 exhibited hypolipidaemia and a functional deficiency of C1 esterase inhibitor. Case 2 showed a normal lipoprotein profile, abnormal platelet aggregation, and a cutaneous vasculitis with evidence of complement consumption via the classical pathway. The significance of these abnormalities is discussed.

Aged↗
PubMed1980

treatment of hereditary angio-oedema by low dose attenuated androgens: disassociation of clinical response from levels of C1 esterase inhibitor and C4.

Nine patients with hereditary angio-oedema (H.A.E.) with a deficiency of C1 esterase inhibitor (C1 INH), have been treated with low dose attenuated androgenic drugs, with complete control of their disease. The C1 esterase inhibitor and C4 levels became normal in only one patient. It is concluded that H.A.E. can be controlled in the absence of correction of the reduced levels of C1 INH and C4. The mode of action of these drugs appears to be more complex than is generally realized.

Adult↗
PubMed1982

C1 inhibitor deficiency simulating systemic lupus erythematosus.

A 48-year-old Japanese woman with systemic lupus erythematosus-like lesions of the skin and lips was found to have hereditary angio-oedema. Complement studies revealed low CH50, C1q, C4 and C1 inhibitor levels, with normal C3 and C5 levels. Dramatic clinical improvement followed fresh normal human blood transfusion and systemic betamethasone administration, while the deficient complement component levels were unchanged.

Angioedema↗
PubMed1985

Complement profile in a C1 inhibitor deficient family.

Complement components and anaphylatoxins in a C1 inhibitor (C1INH) deficient family were studied. C4a was increased when C1INH was decreased, and C3a was increased in subjects with systemic lupus erythematosus (SLE)-like symptoms and with angioedema attacks. Danazol was effective in controlling the clinical as well as complement abnormalities including low CH50, C1INH and C4, which increased within 10 days after danazol treatment was started. Two-dimensional immunoelectrophoresis of C1INH showed that there was no functionally or electrophoretically abnormal C1INH present before or after danazol treatment. C3a and C4a were considered to play important roles in the pathogenesis of angioedema and associated SLE-like symptoms.

Anaphylatoxins↗