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Abdominal Pain↗
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[A 24-year old woman with rash and swelling when using oral contraceptives and during pregnancy].
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Adult↗
[Estrogen-dependent angioedema].
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Angioedema↗
Quality assessment of heparin coatings by their binding capacities of coagulation and complement enzymes.
In vitro testing of blood contacting materials before clinical application is generally advisable. Four heparin coatings from different manufacturers were tested for adsorbed proteins and soluble activation markers. The surface with the highest antithrombin, thrombin, high-molecular-weight-kininogen (HMWK) and the lowest fibrinogen binding capacity (Carmeda, Medtronic) showed significantly lower levels of granulocytes and platelet activation (beta-TG, PMN-elastase release). No statistically significant differences in soluble markers of the coagulation system could be detected (F1 + 2, TAT). Interestingly, complement activation (TCC) was significantly reduced within the group of the lowest adsorption of the complement factor C3. Our data demonstrate that there is a relation between the binding affinity of proteins (C1-inhibitor, C3-complement) and the consecutive changes in complement activation (TCC). Therefore, measuring adsorbed proteins on artificial surfaces is a suitable, sensitive and very reproducible method for assessing the thrombogenicity of biomaterials.
Adsorption↗
Complement activation and the prognostic value of C3a in patients at risk of adult respiratory distress syndrome.
In vivo and in vitro studies have shown that complement activation plays an important role in the pathogenesis of the adult respiratory distress syndrome (ARDS). In a prospective study of polytrauma patients at risk of ARDS (n = 38) complement parameters were determined over a period of 14 days in serial plasma samples (obtained every 6 h during the first 48 h). Polytrauma induced a rapid and remarkable complement activation. Low levels of the complement proteins C3, C4, C1 inhibitor (C1 INH) factor I and factor H during the first 48 h indicated complement consumption in all patients. Elevated C3a levels in the first few hours after injury were associated with the later development of ARDS. A more sensitive indicator than C3a alone was the calculated C3a:C3 ratio discriminating ARDS and non-ARDS patients. A second rise of C3a levels and C3a:C3 ratio from day 4 on paralleled the course of extravascular lung water. To assess the mode of complement activation, the activation-specific protein complexes C1rC1s-C1 INH and C3b(Bb)P were measured in some of the patients. We demonstrate that in the first 48 h complement activation occurred via the alternative pathway only and was later followed by an additional activation via the classical pathway. Our observations suggest that monitoring of C3a and C3 in plasma can identify polytrauma patients at high risk for ARDS at an early stage of the disease.
Adolescent↗
High normal serum levels of C3 and C1 inhibitor, two acute-phase proteins belonging to the complement system, occur more frequently in patients with Crohn's disease than ulcerative colitis.
Few data are available on measurements of serum concentrations of complement proteins in inflammatory bowel disease (IBD). Therefore we measured serum levels of C3, C4, and C1-esterase inhibitor (C1-INH) as well as C-reactive protein (CRP) in 167 patients with Crohn's disease (CD) and 111 patients with ulcerative colitis (UC). Median serum concentrations of C3 and C1-INH were significantly higher in CD than in UC. According to multiple logistic regression analysis adjusted to age, sex, activity of disease, and presence of extraintestinal manifestations, IBD patients with high-normal (> or = 128%, > or = 75th percentile ) C1-INH concentrations had significantly (0.0275) higher odds ratio to have a diagnosis of CD than UC. Patients with high-normal C3 (> or = 1.40 g/liter) and high (> or =20 mg/liter) CRP concentrations had an even higher odds ratio of a CD diagnosis (P = 0.0132). Our findings indicate that measurement of C3, C1-INH, and CRP can be used as an additional marker to pANCA/ASCA for distinguishing patients with CD and UC.
Adult↗
Human inhibitor of the first component of complement, C1: characterization of cDNA clones and localization of the gene to chromosome 11.
C1 inhibitor is a heavily glycosylated plasma protein that regulates the activity of the first component of complement (C1) by inactivation of the serine protease subcomponents, C1r and C1s. C1 inhibitor cDNA clones have been isolated, and one of these (pC1INH1, 950 base pairs) has been partially sequenced. Sequence analysis demonstrates that the C1 inhibitor is a member of the serpin "superfamily" of protease inhibitors. In the region sequenced, C1 inhibitor has 22% identity with antithrombin III, 26% with alpha 1-antitrypsin and alpha 1-antichymotrypsin, and 18% with human angiotensinogen. C1 inhibitor has a larger amino-terminal extension than do the other plasma protease inhibitors. In addition, inspection of residues that are invariant among the other protease inhibitors shows that C1 inhibitor differs at 14 of 41 of these positions. Thus, it appears that C1 inhibitor diverged from the group relatively early in evolution, although probably after the divergence of angiotensinogen. Southern blot analysis of BamHI-digested DNA from normal individuals and from rodent-human somatic cell hybrid cell lines (that contain a limited but varied human chromosome complement) was used to localize the human C1 inhibitor gene to chromosome 11.
Amino Acid Sequence↗
Complement activation and complement control proteins in acute pancreatitis.
Serum levels of the complement proteins C3, C4, C1 inhibitor (C1 INH), factor I (C3b inactivator) and factor H (BIH) and plasma levels of cleavage products of C3 (C3c) and factor B were measured in 26 patients with acute pancreatitis. Breakdown of C3 occurred in 19 patients, as shown by a reduction in C3 level and the presence of C3c. C4 levels, however, did not fall and factor B breakdown products were not detected, thus suggesting that enzymatic cleavage of C3 occurred without significant involvement of either the early classical pathway or the alternative pathway. C1 INH and factor H both showed increases, presumably reflecting an acute phase response. Factor I showed an initial fall followed by a rise. There was no correlation between the presence or extent of C3 breakdown and the clinical condition of the patients. It is concluded that C3 cleavage in pancreatitis probably results from tryptic activity and that the measurement of complement components has no part to play in the management of the disease.
Acute Disease↗
Molecular weights and isoelectric points of sperm antigens relevant to autoimmune infertility in men.
PURPOSE: We determined the molecular weights and isoelectric points of antigens in the uncapacitated and capacitated spermatozoa of fertile men binding to the serum immunoglobulin G (IgG) from 8 autoimmune infertile men and 8 fertile nonautoimmune men. MATERIALS AND METHODS: We used double fluorochrome cytotoxicity and immunobead binding assays to determine the sperm antibody status of the study subjects. 2-Dimensional gel electrophoresis and Western blot analysis were used to determine the molecular weights and isoelectric points of sperm antigens binding to serum IgG from these men. Amino acid sequencing of the digested peptides of chosen proteins was accomplished. Immune reactivity to the proteins in autoimmune infertile men was further verified. RESULTS: Serum IgG from fertile men failed to react significantly. Serum IgG from all autoimmune men (100%) showed significant binding to proteins with a molecular weight of 92 kDa. and isoelectric points of 3.5 to 4.0 in the capacitated spermatozoa. Six of 8 infertile men (75%) had serum IgG binding to capacitated sperm antigens with a molecular weight of 18 kDa. and isoelectric points of 4.5 to 5.2. Amino acid sequencing of peptides of the 92 kDa. protein matched complement component 1 (C1) inhibitor, with noted differences in the amino acid sequencing from the latter. The 18 kDa. protein matched calmodulin. We verified that serum IgG from autoimmune infertile men bound with C1 inhibitor and ascertained that the 92 kDa. protein in the spermatozoa was C1 inhibitor-like protein. CONCLUSIONS: Significant antibody responses to C1 inhibitor-like protein and calmodulin were noted in autoimmune men. Both of these proteins may be of testicular origin and these autoimmune responses may be highly relevant to infertility.
Amino Acid Sequence↗
Immunologic manipulation for the threatened fetus.
Management of the pregnant woman with the antiphospholipid syndrome (APLS) has improved over the last 10 years. The recurrent pregnancy loss that is associated with this disease is managed with prophylactic low dose aspirin and heparin therapy. This therapy leads to a 40% absolute risk reduction in pregnancy loss. However, many women still fail to deliver a live infant despite this therapy so immunologic manipulation of the mother's disease in this group needs to be considered. Intravenous immunoglobulin and plasma exchange may have a role. New immunosuppressive drugs such as tacrolimus have yet to be tried. Monoclonal antibodies to B cells, B-cell growth factors, complement proteins and integrin molecules, all of which appear to play a role in the disease process, may also offer patients some hope. Similarly, biologics such as C1 esterase inhibitor protein, cell surface complement regulator proteins or interleukin-3 need to be tried given their efficacy in models of antibody-induced cell injury.
Abortion, Habitual↗
Evaluation of complement activation in premature newborn infants with hyaline membrane disease.
Fifteen premature newborns with hyaline membrane disease causing acute respiratory distress were evaluated for complement activation. A high intrapulmonary right-to-left shunt and marked arterial-alveolar oxygen difference indicated the severity of the respiratory failure. Twenty preterm healthy infants served as controls. Total haemolytic activity, plasma concentrations of complement components and regulatory proteins (C3, C4, C1-inhibitor, factors H and I) as well as activation products (C3a, C3dg, C1rsC1-inhibitor, C3b(Bb)P) gave no evidence of significant complement activation. Functional activity of the ubiquitous regulatory protein C1-inhibitor was significantly reduced without impact on classical pathway activation. These data suggest that, in contrast to the adult form of respiratory distress syndrome, the low-pressure pulmonary oedema characterising hyaline membrane disease is not mediated by activation of the complement system.
Biomarkers↗
Alzheimer disease and neuroinflammation.
It is now generally accepted that the lesions of Alzheimer disease (AD) are associated with a host of inflammatory molecules, including complement proteins, as well as with many activated microglia. Most inflammatory components are synthesized by brain cells. In order to estimate the intensity of the inflammatory reaction, we have measured the levels of the mRNAs for complement proteins, two complement regulators (CD59 and C1 inhibitors), an acute phase reactant (C-reactive protein, CRP) and two microglial markers, (HLA-DR and CD11b), in normal and AD brain. The mRNAs for inflammatory mediators are markedly upregulated in AD tissue while those of the complement inhibitors are almost unchanged. The upregulations for CRP and CD11b in AD hippocampus are comparable to those in osteoarthritic joints. This lends further support to the hypothesis that chronic inflammation may be causing neuronal death in AD.
Alzheimer Disease↗
Hypocomplementemia with low C1s-C1 inhibitor complex in systemic lupus erythematosus.
Ninety-three serum and plasma samples from 45 patients with systemic lupus erythematosus were analyzed for the complex formed by C1s and its inhibitor, as well as for C3, C4, C4a desarginine, and staphylococcal protein A-bound immune complexes. There were statistically significant correlations between C1s-C1 inhibitor complex and CH50, between C1s-C1 inhibitor complex and C4, and between C1s-C1 inhibitor complex and C4a desarginine. Serial studies were performed on 24 patients over a period of 6 months. Seven of 21 patients with hypocomplementemia had persistently normal levels of C1s-C1 inhibitor complex, 7 had transiently abnormal levels of C1s-C1 inhibitor complex, and 7 had sustained abnormal levels of C1s-C1 inhibitor complex. Two of 3 pregnant patients with normal levels of complement had abnormal levels of C1s-C1 inhibitor complex. Staphylococcal protein A-bound immune complexes demonstrated no correlation with any of the complement assays. Complement activation, as measured by C1s-C1 inhibitor complex, is often a transient phenomenon in systemic lupus erythematosus patients with persistent hypocomplementemia.
Antigen-Antibody Complex↗
Prevention of complement-mediated activation of xenogeneic endothelial cells in an in vitro model of xenograft hyperacute rejection by C1 inhibitor.
The complement system plays a major role in hyperacute rejection of discordant xenografts. In an immediately vascularized xenograft of a porcine organ to a primate, natural antibodies bind to the vascular endothelium of the graft, triggering activation of complement via the classical pathway. One consequence of antibody binding and complement activation is the activation of endothelial cells leading to the loss from the cells of heparan sulfate. We explored to what extent the classical pathway regulatory protein C1 inhibitor (C1 inh) would inhibit complement-mediated cytotoxicity and activation of endothelial cells. Cultured porcine aortic endothelial cells were used as a model for a xenogeneic organ and human serum as a source of xenoreactive natural antibody and complement. Addition of purified human C1 inh to human serum inhibited deposition of C4b and iC3b and cytotoxicity after the serum was reacted with the cultured cells. C1 inh prevented, in a dose-dependent manner, activation of the endothelial cells, as manifested by release of heparan sulfate. These observations demonstrate that C1 inh added in sufficient amounts to human serum can effectively inhibit C1 activation in an antigen-antibody system. These studies extend our previous findings consistent with the concept that complement activation occurs via the classical pathway in models of hyperacute rejection in which porcine vascular endothelial cells are in contact with human serum containing xenogeneic natural antibodies against the endothelial cells. Thus, our results suggest a potential clinical use of C1 inh in conjunction with other therapies to prevent hyperacute rejection in xenogeneic combinations mediated by complement activation via the classical pathway.
Animals↗
[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↗
Complement inhibitors in normal cornea and aqueous humor.
C1 inhibitor, beta 1H and C3b inactivator are important inhibitory proteins that regulate the complement system. These inhibitor proteins were detected by gel double diffusion in eluates from normal corneas, but not in normal aqueous humor. Functional tests of C1 inhibitor and C3b inactivator showed low-to-absent levels of these inhibitory proteins in normal aqueous humor. On the other hand, the mean activities of C1 inhibitor and C3 inactivator in corneas were nearly as high as those in sera, and there were no statistically significant differences between the values. The lower molecular weights of complement inhibitors, relative to other complement components, may account for their higher levels in normal cornea and may tip the balance in favor of inhibition of complement activation in the noninflamed cornea.
Adolescent↗
Heparin and derivatized heparin inhibit zymosan and cobra venom factor activation of complement in serum.
Heparin has been shown to inhibit activity of the alternative, classical and terminal pathways of complement by regulating C1, C1 inhibitor, C4 binding protein, C3b, factor H and S-protein. In vivo, heparin inhibits cobra venom factor activation of complement in a dose-related manner in guinea pigs. However, the ability of heparin and of modified heparin to inhibit complement activation in serum has not been examined systematically. The present study compared commercial heparin with a modified heparin that has reduced anticoagulant activity (N-desulfated, N-acetylated heparin) for ability to inhibit cobra venom factor and zymosan-induced complement activation in guinea pig and human serum. Both heparins inhibited cobra venom factor and zymosan-induced consumption of C3 activity in both human and guinea pig serum. In both serum types, commercial heparin was about twice as active as modified heparin on a weight basis for ability to inhibit cobra venom factor-induced complement activation. Both heparins also inhibited zymosan-induced complement activation in human serum. About four times more heparin was required to inhibit cobra venom factor-induced complement activation in guinea pig serum than in human serum while heparin was more than ten times more active in human serum than in guinea pig serum when zymosan was used as the activator of complement. This study suggests that heparin is considerably more effective in regulating complement activity in humans than in guinea pigs, an animal model in which heparin clearly has in vivo capacity to regulate complement activity. These observations represent an important step in the development of new clinically relevant oligosaccharide-derived pharmacologic agents to regulate complement activity.
Animals↗
Effects of choline-esterase inhibitor in experimental acute pancreatitis in rats. Preliminary results.
Choline-esterase inhibitor (C1-INH), a regulatory alpha-glycoprotein, was administered at different dosages and intervals to rats with induced acute pancreatitis. When compared to controls, treated rats showed no significant differences in the severity of histopathological lesions, such as edema and single cell necrosis. On the other hand, both mortality and extent of massive necrosis were significantly affected by C1-INH administration regardless of the dosages.
Acute Disease↗