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PubMed1992

Unique palindromic sequences in synthetic oligonucleotides are required to induce IFN [correction of INF] and augment IFN-mediated [correction of INF] natural killer activity.

Thirty-mer single-stranded oligonucleotides, with a sequence chosen from the known cDNA encoding the 64-kDa protein named Ag A or the MPB-70 protein of Mycobacterium bovis BCG and the human cellular proteins such as complement component 1 inhibitor and Ig rearranged lambda-chain, were used to dissect the capability to induce IFN and to augment NK cell activity of mouse spleen cells by coincubation in vitro. Three with the hexamer palindromic sequence as GACGTC were active, whereas two kinds of oligonucleotides with no palindrome were inactive. The oligonucleotides containing at least one of the different palindromic sequences showed no activity. When a portion of the sequence of the inactive oligonucleotides was substituted with either palindromic sequence of GACGTC, AGCGCT, or AACGTT, the oligonucleotide acquired the ability to augment NK activity. In contrast, the oligonucleotides substituted with another palindromic sequence such as ACCGGT was without effect. Furthermore, exchange of two neighboring mononucleotides within, but not outside, the active palindromic sequence destroyed the ability of the oligonucleotides to augment NK cell activity. Stimulation of spleen cells with the substituted oligonucleotide, A4a-AAC, induced production of significant amounts of IFN-alpha/beta and small amounts of IFN-gamma. Augmentation of NK activity of the cells by the oligonucleotide was ascribed to IFN-alpha/beta production. These results strongly suggest that the presence of the unique palindromic sequences, such as GACGTC, AGCGCT, and AACGTT, but not ACCGGT, is essential for the immunostimulatory activity of oligonucleotides.

Animals↗
PubMed2003

Human C1 esterase inhibitor attenuates murine mesenteric ischemia/reperfusion induced local organ injury.

BACKGROUND: Complement activation contributes to ischemia and reperfusion (IR)-initiated organ injury. C1 inhibitor (C1 Inh) inhibits the earliest steps of the classical and the mannose binding lectin pathways. MATERIALS AND METHODS: To determine whether C1 Inh prevented tissue injury, we performed intestinal IR experiments in BALB/c and C57BL/6 mice. RESULTS: We found that C1 Inh limits mucosal injury in the two strains in a dose dependent manner. Tissue damage was associated with the accumulation of functional polymorphonuclear cells, which was reduced following C1 Inh treatment. Constitutive nitric oxide synthase activity correlated with the development of injury in the C57BL/6 but not in the BALB/c mouse. CONCLUSIONS: These findings emphasize the importance of complement activation in ischemia/reperfusion and highlight the potential therapeutic use of C1 Inh in limiting or preventing damage caused by IR.

Animals↗
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↗
PubMed1996

Measurement of activated factor XII in health and disease.

We investigated a new ELISA for measuring activated factor XII (FXIIa) in plasma. The intra-assay coefficient of variation was 3.5% and 5.1% for plasma containing 2.5 and 8.2 ng/ml FXIIa. The inter-assay coefficient of variation was 6.2% and 6.6%. FXIIa correlated with age in women older than 55 years (r = 0.55, P = 0.0003). Mean levels in the whole population of 160 healthy individuals included in this study were not different between men and women, but women younger than 55 years had lower levels than older women and men of the corresponding age. In a group of 25 healthy centenarians FXIIa was significantly higher (3.2 ng/ ml, 95% CI 2.3-3.6) than in controls (2.1 ng/ml, 95% CI 1.8-2.4). Increased levels were also found in pregnancy, with higher levels in the third trimester (4.7 ng/ml, 95% CI 3.9-5.5) than in the first trimester (2.9 ng/ml, 95% CI 2.2-3.9). FXIIa was unmeasurable in patients with FXII deficiency, but normal in patients with FXI deficiency and C1-inhibitor deficiency. FXIIa was significantly higher than in normal controls in patients with severe sepsis (3.9 ng/ml, 95% CI 2.8-5.4) and septic shock (5.4 ng/ml, 95% CI 3.7-7.7). After treatment with thrombolytic agents, a marked increase of FXIIa was found in patients with myocardial infarction. In conclusion, the immunoassay of FXIIa permits to study more directly the contact phase of blood coagulation in situations in which the involvement of this system may play a pathophysiological role.

Adult↗
PubMed1982

Hypocomplementemic urticarial vasculitis: association with chronic obstructive pulmonary disease.

Since 1973, we have identified and collected follow-up data on 16 patients with hypocomplementemic urticarial vasculitis. Preliminary diagnostic criteria are the presence of typical urticarial skin lesions and low levels of serum complement (all components), plus two of the following: dermal venulitis, arthritis, glomerulo-nephritis, episcleritis or uveitis, recurrent abdominal pain, and C1q precipitin in plasma. Exclusions are systemic lupus erythematosus, mixed cryoglobulinemia, elevated antinuclear antibody titer, hereditary deficiency of a complement component or of C1 esterase inhibitor, and presence of anti-native DNA or hepatitis B antigen. The renal involvement is relatively benign, and generally the patients do well and respond to specific treatment when this is indicated. Eight of 10 smokers studied had evidence of chronic obstructive pulmonary disease, 1 of whom died of this complication. In three patients, severe chronic obstructive pulmonary disease developed at a young age after relatively low pack-year cigarette smoking histories. Lung disease probably results from the interaction of two major risk factors-smoking and an immunologically mediated process that has not been identified.

Adrenal Cortex Hormones↗
PubMed1982

Cold-induced contact surface activation of the prothrombin time in whole blood.

Studies of the prothrombin time (PT) have revealed that contact with borosilicate or commercial siliconized borosilicate markedly shortens the PT. This shortening is related to the activation of the contact phase of blood coagulation. This shortening of the PT occurs in both normal whole blood and plasma when stored in borosilicate or siliconized borosilicate tubes at 4 degree C and to a lesser degree at room temperature. Studies indicated the importance of several coagulation factors in decreasing the PT. The PT did not change in blood deficient in factor XII or in plasma deficient in Fletcher factor or high molecular weight kininogen, while blood deficient in CI esterase inhibitor (CI INH) had the most profound shortening. Shortening of the PT correlated directly with increased levels of factor VII. When purified CI INH was added to normal blood, it markedly reduced the activation of factor VII and the shortening of the PT in a dose-related manner. These studies indicate the pivotal roles of the contact phase of coagulation in initiating activation of the PT and of CI INH in inhibiting the activation of the coagulation factor(s) responsible for the cold-promoted activation of factor VII.

Blood Coagulation Factors↗
PubMed1988

Detection of the terminal complement complex in patient plasma following acute myocardial infarction.

The mechanisms of inflammation responsible for the myocardial tissue damage seen after an acute myocardial infarction (AMI) have not been clearly identified. Recent lines of evidence, demonstrating depressed sera levels of individual complement components in patients after myocardial infarction, have suggested involvement of the complement (C) system in micro- and macrovascular injury subsequent to AMI. The present study assessed the role of complement as a mediator of myocardial inflammation by quantifying products of complement activation including, the terminal complement complex (TCC) the cytolytic component of the complement system, C1rC1s-C1 inhibitor complex and C3bBbP complex, formed following activation of the classical and alternative pathway, respectively, and anaphylatoxins C3a and C5a in 41 patients following AMI. Plasma TCC and C1rC1s-C1 inhibitor complex concentrations increased up to 32-fold (P less than 0.001) and 8-fold (P less than 0.001), respectively, while the C3bBbP complex, C3a des-Arg and C5a des-Arg each increased over 2-fold (P less than 0.001) 16 h after AMI, and were only minimally detectable during non-inflammatory myocardial conditions. Furthermore, TCC concentrations increased over 150% (P less than 0.001) one day after patients reinfarcted, subsequent to hospitalization for a primary AMI. These results demonstrate activation of complement after AMI and suggest that inflammatory mediators of the complement system may contribute to myocardial tissue damage during the infarction process.

Adult↗
PubMed2001

A case of hereditary angioedema associated with idiopathic hypoparathyroidism.

Hereditary angioedema is a rare autosomal dominant disease characterized by the edema of subcutaneous tissues, respiratory tract and bowel. It is caused by the deficiency of C1 esterase inhibitor. Hereditary angioedema may be associated with autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, autoimmune thyroiditis and glomerulonephritis. We report a 34-year-old male patient with hereditary angioedema who developed idiopathic hypoparathyroidism. Autoimmunity seems to be an important basis of this association and it might be caused by the immune dysfunction due to decreased level of complements; nevertheless, a casual association could not be excluded. To our knowledge, this is the first report of hereditary angioedema in association with idiopathic hypoparathyroidism in the medical literature.

Adult↗
PubMed1990

Immunoblotting of plasma in a pregnant patient with hereditary angioedema.

Hereditary angioedema (HAE), an autosomal disorder caused by a deficiency of C1 inhibitor, is characterized by attacks of localized swelling, laryngeal edema, or abdominal pain. Plasma samples from one pregnant patient were studied serially by functional and quantitative immunochemical assays as well as immunoblot assays for high molecular weight kininogen (HMWK) and/or prekallikrein/kallikrein (PK/K). An immunoblot of this patient's HMWK from plasma obtained before she became pregnant and when she was well revealed that it was mostly an intact protein of 120 kd, similar to immunoblot results of normal plasma HMWK. In plasma samples taken throughout her pregnancy, before, during, and after clinical attacks of angioedema, all of her plasma HMWK was shown to be cleaved into the 45 kd light chain form. After delivery of the infant the 120 kd form of intact plasma HMWK returned to her plasma. In comparison, immunoblot studies on 21 normal and abnormal pregnancies revealed that plasma HMWK was an intact protein at 120 kd. That this patient's plasma during her pregnancy was contact activated was determined by additional immunoblot studies for PK/K. Immunoblot assay for plasma PK/K revealed kallikrein-alpha 2-macroglobulin complexes and a 50 kd PK/K form seen only in activated plasma samples. The findings of kallikrein-alpha 2-macroglobulin complexes and a 50 kd PK/K form disappeared after delivery. These combined studies on this patient show that the structures of HMWK and prekallikrein as indicated by immunoblot assays were altered during pregnancy. Immunoblot assays for detection of changes in the structure of HMWK and prekallikrein may be objective laboratory studies for documenting clinical attacks of hereditary angioedema, their onset, and their resolution.

Adult↗
PubMed1982

A postulated mechanism for heparin's potentiation of C1 inhibitor function.

Conflicting reports exist in the literature concerning the primary mechanism for heparin's inhibition of C1 hemolytic function. We provide evidence here that heparin's most effective inhibition is mediated through interaction with and potentiation of C1-INH. The molecular nature of the interaction between heparin and the C1-INH molecule is evidenced by an anodal shift in the electrophoretic mobility of C1-INH upon the addition of heparin.l We also demonstrate that C3 and C4 conversions in normal human serum by classical pathway activators such as heat-aggregated IgG are inhibited by addition of heparin, yet heparin does not prevent similar C3 conversion in serum depleted of C1-INH Heparin's inhibitory action is restored to C1-INH-depleted serum by the addition of purified C1-INH.

Complement Activation↗
PubMed2005

Ascitic complement system in ovarian cancer.

Ovarian cancer spreads intraperitoneally and forms fluid, whereby the diagnosis and therapy often become delayed. As the complement (C) system may provide a cytotoxic effector arm for both immunological surveillance and mAb-therapy, we have characterised the C system in the intraperitoneal ascitic fluid (AF) from ovarian cancer patients. Most of the AF samples showed alternative and classical pathway haemolytic activity. The levels of C3 and C4 were similar to or in the lower normal range when compared to values in normal sera, respectively. However, elevated levels of C3a and soluble C5b-9 suggested C activation in vivo. Malignant cells isolated from the AF samples had surface deposits of C1q and C3 activation products, but not of C5b-9 (the membrane attack complex; MAC). Activation could have become initiated by anti-tumour cell antibodies that were detected in the AFs and/or by changes on tumour cell surfaces. The lack of MAC was probably due to the expression of C membrane regulators CD46, CD55 and CD59 on the tumour cells. Soluble forms of C1 inhibitor, CD59 and CD46, and the alternative pathway inhibitors factor H and FHL-1 were present in the AF at concentrations higher than in serum samples. Despite the presence of soluble C inhibitors it was possible to use AF as a C source in antibody-initiated killing of ovarian carcinoma cells. These results demonstrate that although the ovarian ascitic C system fails as an effective immunological surveillance mechanism, it could be utilised as an effector mechanism in therapy with intraperitoneally administrated mAbs, especially if the intrinsic C regulators are neutralised.

Adenocarcinoma↗
PubMed1998

Inhibition of activation of the classical pathway of complement by human neutrophil defensins.

Defensins are small, cationic antimicrobial peptides that are present in the azurophilic granules of neutrophils. Earlier studies have shown that defensins may influence complement activation by specific interaction with activated C1, C1q, and C1-inhibitor. In the present study, we show that the defensin human neutrophil peptide-1 (HNP-1) is able to inhibit activation of the classical complement pathway by inhibition of C1q hemolytic activity. The binding site for HNP-1 on C1q is most likely located on the collagen-like stalks, as a clear, dose-dependent binding of HNP-1 to either intact C1q or to the collagen-like stalks of C1q was demonstrated using enzyme-linked immunosorbent assay (ELISA). Besides binding of HNP-1 to C1q, also a limited binding to C1 and to a mixture of C1r and C1s was observed, whereas no binding to C1-inhibitor was found. Because binding of HNP-1 to C1-inhibitor has been suggested in earlier studies, we also assessed the binding of HNP-1 to mixtures of C1-inhibitor with either C1r/ C1s or C1. No binding was found. Using a competition ELISA, it was found that HNP-1, but not protamine, inhibited binding of biotin-labeled HNP-1 to C1q in a dose-dependent fashion. In the fluid phase, preincubation of HNP-1 with C1q resulted in complex formation of HNP-1 and C1q and generation of stable complexes. In conclusion, HNP-1 is able to bind to C1q in the fluid phase and inhibits the classical complement pathway. This mechanism may be involved in the control of an inflammatory response in vivo.

Binding Sites↗
PubMed2003

How do we treat patients with hereditary angioedema.

Hereditary angioedema (HAE) is due to the inherited deficiency of C1-Inhibitor (C1-Inh). When specific treatment was not available, the mortality rate for this disease was as high as 50% and the disability up to 100-150 days per year (Agostoni and Cicardi, Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients). Such a worrying scenario dramatically improves upon appropriate treatment. Nevertheless, the disease still frequently goes undiagnosed or misdiagnosed as an allergic condition. Both circumstances prevent patients from receiving drugs that could save and/or improve the quality of their life. The interest of our group for patients with HAE goes back to the early seventies. Since that time, 441 such patients have been examined and treated at our department; 403 are still actively followed. Here we present our experience on the treatment of HAE.

Acute Disease↗
PubMed1978

Meningococcal infection and proteolytic control.

Cascade enzyme inhibitors (C1-esterase inhibitor, C3b inactivator, antithrombin III) and other major proteolytic enzyme inhibitors (alpha 1 trypsin inhibitor, alpha 1 chymotrypsin inhibitor, inter-alpha-trypsin inhibitor, alpha 2 macroglobulin) as well as C3 and alpha 1 acid glycoprotein, have been examined in the sera of Nigerian patients suffering from meningococcal infection of varied severity. Patients with meningococcaemia had lower serum concentrations of important inhibitors than did patients with localised meningitic infection. Within the coccaemic group, those who died had the lowest values, notably of antithrombin III and alpha 2 macroglobulin (and also of C3). The clinical end-result of meningococcal infection may be related to the degree of disequilibrium of the linked system of proteolytic control induced by the meningococcal endotoxin.

Antithrombin III↗
PubMed1986

Acquired C1 esterase-inhibitor deficiency: case report with emphasis on complement and kallikrein activation during two patterns of clinical manifestations.

A case of severe angioedema with several episodes of life-threatening attacks during a follow-up of 7 years is presented. Although the biologic profile is that of an acquired C1 INH deficiency, no lymphoproliferative malignancy or immune-complex disease could be proven until now. However, the patient has had a small monoclonal IgG lambda-gammopathy for 4 years. During the last 4 years, edematous manifestations have stopped. The patient now suffers at regular intervals of about a week from short-lasting attacks with digestive and vasomotor symptoms. This clinical evolution is accompanied by a worsening in the complement abnormalities. The digestive and vasomotor attacks were found to be correlated with sudden prekallikrein and high-molecular-weight kininogen consumption. These findings demonstrate that prekallikrein is activated during acquired C1 INH deficiency and that the products of this pathway such as bradykinin are probably responsible for a part of the clinical manifestations associated with this disorder.

Aged↗
PubMed1984

Hereditary Angio-Edema (HAE).

Hereditary Angio-Edema (HAE) is manifested by recurrent attacks of acute circumscribed edema of the extremities, face, trunk, and respiratory or abdominal tract, occurring after minor physical or emotional trauma, or spontaneously. The clinical diagnosis can be confirmed by low serum-levels of the inhibitor of the activated first component of complement (C1-INH). A family of 35 members over six generations was investigated. About 40 per cent of the members were HAE-patients. An autosomal dominant inheritance with high penetrance was present. Four patients died by suffocation from laryngeal edema. In all HAE-patients the C1-INH serum-level was diminished, and also in two children who have yet had no complaints. Adequate medical advice, including the provision of a medical alert card and the prescription of C1-INH concentrate (for short-term prophylaxis and the treatment of attacks of laryngeal edema), is necessary. In patients with frequent serious attacks, long-term prophylaxis with Danazol is indicated.

Abdomen↗
PubMed1985

The study of local fibrinolysis in abortion.

The etiology of abortion, which is still a moot question, is now under intense investigation. The present study discussed the possible role of local fibrinolysis (villous tissue fibrinolysis) in the pathogenesis of abortion by studying tissue fibrinolytic activity in tissue culture as well as blood coagulation, fibrinolysis and the kinin system. Subjects studied include: 1) normal villous tissue (n=46), early pregnancy loss, whose fetal cardiac activity had once been identified (n=22) designated as Group A, and Group B whose fetal cardiac activity had never been identified (n=82). The villous tissues were cultured for 24 hours and then the urokinase (UK) inhibition activity in the medium was determined. 2) Threatened abortion resulted in abortion (poor prognosis, n=42) or the pregnancy continued (good prognosis, n=81). In these patients the following substances in plasma were determined: Prekallikrein, alpha 2-plasmin inhibitor, alpha 1-antitrypsin, alpha 2-macroglobulin, C1-inactivator, antithrombin-III, plasminogen, fibrinogen, fibrin degradation products (FDP). The results are: 1) UK inhibition activity (against UK 2.5 iu), normal villous tissue 26.3 +/- 14.6%, Group A 26.0 +/- 10.3%, Group B 9.6 +/- 10.7%, a significant difference between the normal villous tissue and Group B villous tissue was observed. This suggested that the increased villous tissue fibrinolytic activity due to decreased UK inhibition activity may be one of the causes of abortion. 2) Prekallikrein was significantly reduced in patients with abdominal pain. Also, a significant reduction in plasminogen and elevated C1-inactivator was observed in patients with poor prognosis. The significance of these findings was discussed.

Abortion, Threatened↗
PubMed1985

Changes in intravascular complement, kininogen, and histamine during Jarisch-Herxheimer reaction in secondary syphilis.

Nine patients with secondary syphilis and one control subject were observed for eight hours after the administration of penicillin. Serial clinical observations were made, and blood samples were obtained for the analysis of complement, histamine, and kininogen. Six patients showed Jarisch-Herxheimer reactions, the intensities of which were found to parallel certain changes in activity of complement and concentrations of histamine and kininogen. Results were analysed statistically. Significant falls were seen in: total haemolytic complement (CH50), C1 inhibitor, C3, functional (haemolytic) C4, and to a lesser extent total C4. Split products of C3 were shown in five of the six patients who had a reaction. There was no change in total glycine rich beta-glycoprotein (GBG) or glycine rich gamma-glycoprotein (GGG) or evidence of conversion of GBG to GGG. Plasma kininogen concentrations fell and plasma histamine concentrations rose appreciably before and during the clinical phase of the reaction. These results are discussed in relation to the clinical features and possible pathogenic mechanisms of the Jarisch-Herxheimer reaction.

Adult↗