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PubMed1978

Inhibition of the classical and alternative pathways by amino acids and their derivatives.

Effects of various aminoacids and their derivatives on the classical pathway and alternative pathway of the complement were studied. Leupeptin, acetyl-leucyl-leucyl-arginal, inhibited CH50 and Cl-esterase, but did not inhibit the alternative pathway. When aminoacids of carbon chains of the order of seven were used, arginine and lysine had stronger effects than trans-aminomethyl cyclohexane carboxylic acid (t-AMCHA), cis-aminomethyl cyclohexane carboxylic acid (cis-AMCHA) and epsilon aminocaproic acid (EACA). SH-compounds, cysteine, homocysteine and glutathione, had the strongest inhibitory effects among these aminoacids on both classical and alternative pathways. When effects on Cl esterase were compared, arginine, lysine, t-AMCHA, cis-AMCHA and EACA had weak inhibition while SH-compounds showed strong inhibition. Poly-L-lysine, which had extremely strong inhibition of CH50, had no inhibition of Cl esterase. The inhibitory effects of antifibrinolytic agents, EACA and t-AMCHA, were weak but when effects on early parts of the classical pathway, C(1,4,2)H50 were tested, some inhibitory activities were recognized. Thus inhibitory effects of these agents were due to their activities on the early parts of the classical pathway.

Amino Acids↗
PubMed1987

Interferon-gamma is a major regulator of C1-inhibitor synthesis by human blood monocytes.

C1 inhibitor (C1INH) is the major control factor for the activation of the classical pathway of complement and for contact system activation. Hepatocytes and blood monocytes are known to synthesize this protease inhibitor. We studied the regulation of monocyte C1INH production by mediators that are generated during inflammatory responses. Purified blood monocytes spontaneously synthesized and secreted C1INH only after prolonged culture. In the presence of interferon (IFN)-gamma, C1INH was detectable within 24 hr and continued to be released at high levels throughout an 8-day culture period. Monocyte C1INH was newly synthesized and was functionally active as determined by forming stable complex with C1s. Other monocyte stimuli were either less potent (IFN-alpha, IFN-beta) or not capable of increasing C1INH release (lipopolysaccharide, interleukin 1, and tumor necrosis factor). The second component of complement, C2, was induced by IFN-gamma to a similar extent as C1INH. These findings demonstrate that IFN-gamma is a major regulator of monocyte C1INH production and may warrant consideration of IFN-gamma in the treatment of C1INH deficiency states.

Cells, Cultured↗
PubMedDate not supplied

[Hereditary angioedema by defict of C1 esterase. Our experience in 8 cases].

Eight cases of hereditary angioedema, all of them with low values of C1-sterase inhibitor are analyzed. In 7 cases the C3 and C4 components of the complement were assessed; the results showed marked descent of C4. The 8 patients came from 4 different families; only 2 of them were males. Six patients presented digestive disorders, reporting colic pain, nausea and vomiting. In 1 of them the abdominal picture was the only evidence of the disease. In 5 patients the angioedema episodes occurred following traumatisms and in 3 because of emotional states. The duration of the attacks varied from several hours to six days. There was a familial history in all cases. Three of the patients had repeated episodes of pharyngolaryngeal angioedema, two of them requiring emergency tracheotomy because of suffocating crisis. Six patients were treated with Epsilon aminocaproic acid (16 to 20 gr daily) or with tranexamic acid (1 to 3 gr. daily). In 4 cases the results were excellent with either of these antifibrinolytic drugs. No side effects were observed in the tranexamic acid therapy whilst they were frequent in the treatment with Epsilon aminocaproic acid.

Adolescent↗
PubMed1988

Acquired C1-inhibitor deficiency associated with a lupus-like anticoagulant activity.

A patient with two attacks of glottis angioedema in a 15-day period without any apparent stimulus was studied. The complement profile of the patient revealed depletion of C4, C2, C1 inhibitor (C1INH) and C1q, with normal values of C3. Patient's offspring had a normal complement profile. Cytofluorographic analysis of the peripheral blood cells showed a marked increase of B cells. In the clotting study, a circulating lupus-like anticoagulant activity (LLA) was detected with a noticeable decrease of prothrombin time. Hepatosplenomegaly was confirmed by abdominal echography and CAT. From the liver biopsy it was concluded to be a lymphoproliferative process compatible with germinal center lymphoma. It is suggested that the neoplasm is probably the origin of the LLA and the cause of C1 activation, producing the biochemical defect of C1INH and the clinical symptoms of angioedema.

Aged↗
PubMed1988

A mechanism for the spontaneous activation of the first component of complement, C1, and its regulation by C1-inhibitor.

We have developed a method to initiate spontaneous activation of the first component of complement in serum, by the removal of C1-inhibitor through complexation with added C1s. Preliminary experiments to test this method using C1 reconstituted from its purified subcomponents led to an unexpected result: pre-incubation of the reassembled subcomponents with C1-inhibitor, followed by its removal with C1s, altered the subsequent pattern of spontaneous activation. Thus, pre-incubation with C1-inhibitor at 37 degrees C for 1 h resulted in sigmoidal activation of C1 with a prolonged lag phase. In contrast, pre-incubation with C1-inhibitor on ice for the same time resulted in subsequent rapid, pseudo first order activation of C1 with a half-life of about 5 min. We have examined the activation kinetics under a variety of conditions, and our data are consistent with a model proposed by Lepow and coworkers in 1965, involving both spontaneous activation and C1 catalyzed activation: (1) C1----k1 C1 (2) C1----k2C1 C1 According to this model, the role of C1-inhibitor is to eliminate the second step by rapidly forming a tight complex with C1 which becomes irreversible at 37 degrees C. When C1s was added to normal human serum, activation at 37 degrees C was also sigmoidal, similar to that of reconstituted C1.

Complement Activating Enzymes↗
PubMed1988

[Familial studies of patients with hereditary angioedema].

25 families with 607 members were studied. 165 persons of them suffer from hereditary angioneurotic edema and 28 persons had died from this disease. The clinical forms of the disease are discussed. A classification of angioneurotic edema caused by C-inactivator deficiency is presented. The importance of the examination of C1 inactivator (quantitatively and qualitatively) and of C4 complement fraction in patients with hereditary angioneurotic edema is pointed out.

Adolescent↗
PubMed1987

[Hereditary angioedema: changes in serum levels of C4 in response to danazol].

12 patients (7 males and 5 females) suffering from the common form of HAE were included in the study protocol. All patients were older than 18 years. They were evaluated Cl INH, C4, Clq, Cls, C3, C5, C8, Bf, CH 50% and CIC. For the purpose of the study they were only considered Cl INH, C4, CH 50%, CIs and CIC levels. The rest of the complement components were among normal values. Data were recorded at day 0 and after 10 days on treatment with 400 mg/day of Danazol. Results were as follows: 50% of the patients had CIC when CH 50% values were below 120 U/ml., after treatment CIC disappeared and CH 50, Cls, C4 and Cl INH increased significatively. C4 seemed to increase more and quicker than Cl INH in terms of absolute values. We postulate that in the group of patients with CIC, the primary cause of the disease may be an alteration in C4 synthesis and that Cl INH may be lowered because of its consumption. We postulate that Danazol could act in these cases stimulating C4 synthesis independently or in accordance with Cl INH.

Adult↗
PubMed1988

Activation of the contact system of plasma proteolysis in the adult respiratory distress syndrome.

Adult respiratory distress syndrome (ARDS) is a complex pulmonary clinicopathologic condition associated with pulmonary endothelial injury and blood coagulation activation. In patients with ARDS from all causes, factor VII levels were significantly reduced. Patients with ARDS caused by sepsis had more evidence of intravascular coagulation and fibrinolysis than did patients with trauma-related ARDS by having significantly (p less than or equal to 0.05) increased prothrombin times, activated partial thromboplastin times, and fibrin degradation products, and decreased antithrombin III concentration. We sought to determine whether the proteins of the contact system of plasma proteolysis (factor XII, prekallikrein, high molecular weight kininogen, and C1 inhibitor) were also activated after acute lung injury. Patients with ARDS caused by either trauma or sepsis had significantly (p less than or equal to 0.01) reduced factor XII levels, high molecular weight kininogen functional activity, prekallikrein activity, and prekallikrein antigen levels compared with controls. In both the sepsis-related and trauma-related ARDS groups, C1 inhibitor activity was significantly reduced but C1 inhibitor antigen levels were significantly elevated from control. These findings showed that the proteins of the contact system were more extensively activated in ARDS than were the proteins that contribute to later reactions in intravascular coagulation and fibrinolysis. Activation of the contact system proteins could be the result of endothelial injury occurring as part of ARDS. Intravascular coagulation and fibrinolysis in patients with ARDS also arise from components independent from contact system activation.

Blood Coagulation↗
PubMed1988

Hereditary angioedema in Czechoslovakia. Clinical, immunological, genetic and therapeutic studies of 16 families.

The analysis of the findings in 16 families with hereditary angioedema detected in Czechoslovakia over the years 1975-1986 is being presented. In 14 families C1-inhibitor deficiency and in two families afunction of C1-inhibitor was established. Of the total number of 175 examined family members C1-inhibitor defect was registered in 66 subjects (60 with deficiency and 6 with afunction), and of these 48 suffered from clinical symptoms of edematous attacks affecting the skin, larynx, intestine and urinary tract, whereas 18 subjects were asymptomatic. Genealogical studies confirmed that the defect is inherited as an autosomal dominant trait. In 16 patients long-term prophylactic treatment with Danol was introduced. The effective minimum dosage was tested individually for each patient.

Angioedema↗
PubMedDate not supplied

Hereditary angioedema: a study of three families.

Familial angioedema is an autosomal dominant hereditary disease whose pathogenesis is attributed to a C1 inhibitor (C1 INH) deficit. Two genetic forms have been recognized related to the C1 inhibitor deficiency or its dysfunction. Antifibrinolytics as well as androgenic derivatives have proved to be effective in the prevention and treatment of this pathology. In this paper we present the studies carried out in three families affected by C1 inh. deficit and the treatment employed. Some of the members of these families showed symptoms related with this deficit. A satisfactory explanation has not been formulated to justify the reason why only some of the members in our study showed symptomatology, given that there were no differences between the C1 inh. levels in these patients and those who were not affected. The absence of family history connected with this disease does not necessarily suggest that a genetic mutation has been produced. This deficit could have been present in earlier generations but without clinical manifestations. Stanozolol proved effective in the control of symptoms in the two patients to whom this treatment was applied. However, the rise of C1 inh. levels was significative only in one of them. The lack of connection between the clinical improvement and the normalization of the C1 inh. levels led us to think that the main goal of the therapy should not be directed to the normalization of these levels but to keep the patient asymptomatic with the lowest possible doses of the selected medication.

Adult↗
PubMed1986

Activation of the first component of human complement, C1, by monoclonal antibodies directed against different domains of subcomponent C1q.

Two monoclonal antibodies directed against C1q, and their (Fab)2 and Fab fragments, were used to study the mechanism of C1 activation. Monoclonal antibody 2A10, an IgG2a, was digested by pepsin to yield fully immunoreactive (Fab')2. Monoclonal antibody 1H11, an IgG1, was digested by papain to yield fully immunoreactive, bivalent (Fab)2. Previously 1H11 had been shown to bind to the C1q "heads," whereas 2A10 bound to stalks. Activation of C1 was followed by the cleavage of 125I-C1s in the presence of C1 inhibitor (C1-Inh) at 37 degrees C. Spontaneous activation was minimal at inhibitor concentrations above 0.4 micron (1.3 X physiologic inhibitor concentration); all results were corrected for the spontaneous activation background. Heat-aggregated IgG activated completely in this system and was taken as 100% activation. Monoclonal antibody 2A10 caused precipitation of C1 and slow activation; neither the (Fab')2 nor the Fab' derived from 2A10-caused activation. Probably, aggregates of intact 2A10 and C1 were serving as immune complexes to activate other molecules of C1. In contrast, both 1H11 and its (Fab)2 activated completely and stoichiometrically; that is, maximal activation was achieved at a ratio of one C1q head to one antibody combining site. The monovalent Fab derived from 1H11 bound well to C1q, but no activation of C1 was observed. Thus, bivalent binding of this head-binding monoclonal is required for C1 activation, but not the presence of the antibody Fc portion. Neither 1H11 nor its (Fab)2 fragments caused C1 precipitation; however, the 1H11 did form complexes composed of two C1q cross-linked by multiple 1H11, which were visualized by electron microscopy. The presence of these dimeric complexes correlated well with activation. A model for C1 activation is proposed in which two C1q subcomponents are held together by multiple (Fab)2 bridging C1q heads. The model is roughly analogous to touching opposing pairs of fingers and thumb tips, the two hands representing the two C1q, forming a cage. C1-Inh, which probably binds to C1r through the open end of the C1 cone, is too long asymmetric to be included within the cage. Thus, according to this model, the dimers of C1 are released from the inhibitory action of C1-Inh, and activation proceeds spontaneously and rapidly at 37 degrees C.

Animals↗
PubMed1986

Surface-bound capsular polysaccharide of type Ia group B Streptococcus mediates C1 binding and activation of the classic complement pathway.

The role of surface-bound type Ia group B Streptococcus (GBS) capsular polysaccharide in antibody-independent binding of C1 and activation of the classic complement pathway was investigated. In a radiolabeled bacterial-polymorphonuclear leukocyte (PMN) association assay, a measure of bacterial opsonization, preincubation of 3H-type Ia GBS with purified F(ab')2 to the organism blocked the association of the bacteria with PMN', and the inhibitory effect was dose dependent. The specificity of F(ab')2 blocking was shown after adsorption of F(ab')2 with type Ia polysaccharide-sensitized erythrocytes. Polysaccharide-adsorbed F(ab')2 had a 70% decrease in ability to block the association of bacteria with PMN. Evidence for the requirement of the capsular polysaccharide in classic complement pathway activation came from a C1 transfer assay with the use of neuraminidase-digested type Ia GBS. Neuraminidase digestion removed 80% of the terminal sialic acid residues from the native polysaccharide. These neuraminidase-digested organisms had a 72% decrease in binding and transfer of purified C1 compared with non-enzyme-treated organisms. Type Ia capsular polysaccharide bound to sheep erythrocytes promoted classic complement pathway-mediated hemolysis of the cells. The role of C1 inhibitor (INH) in modulation of C1 activation by the organisms was investigated. The possibility existed that the C1 INH could be bound by the bacteria, allowing C1 activation to occur in the fluid phase. The inhibitor was purified from human serum, and its activity was measured before and after incubation with type Ia GBS. The organisms had no effect on C1 INH activity. Thus surface-bound capsular polysaccharide of type Ia GBS mediates C1 binding and classic pathway activation, and this does not involve the C1 INH.

Adsorption↗
PubMed1987

Serum concentrations of immunoglobulins and complement components in patients with recurrence after resection of gastric carcinoma.

Immunoglobulins and complement components were quantitated in sera sampled at 3-6-month intervals from 20 patients with recurrence after resection of gastric carcinoma stages I-III (pTNM). Concentrations of IgA, C3, C4, and C1-INH at clinical recurrence were increased in a significant number of patients as compared to the concentrations 3-6 months prior to recurrence. The mean concentration of C3, C4, and C1-INH were higher than prior to recurrence. At the time of recurrence, the concentrations of C3, C4, and C1-INH were higher than the corresponding postoperative concentrations among 14 patients alive and disease-free for 5 years or more. Three to six months prior to recurrence, the concentrations of C4 and C1-INH were also higher than those of the 5-year survivors. The data indicate that serial quantitation of immunoglobulins and complement components may beof value in the follow-up after resection of gastric carcinoma.

Aged↗