| 2018 | Complete kinetic follow-up of symptoms and complement parameters during a hereditary angioedema attack. | Allergy | We studied the kinetics of C1-inhibitor (C1-INH) and other complement parameters in a self-limited edematous attack (EA) in a patient with hereditary angioedema due to C1-INH deficiency to better understand the pathomechanism of the evolution, course, and complete resolution of EAs. C1-INH concentration and functional activity (C1-INH ), C1(q,r,s), C3, C4, C3a, C4a, C5a, and SC5b-9 levels were measured in blood samples obtained during the 96-hour observation period. The highest C1-INH , C4, and C1(q,r,s) levels were measured at baseline, and their continuous decrease was observed during the entire observation period. C4 depletion started at prodromal phase, and C4 was lowest after the maximum severity peak. Compared to baseline, C4a level was four times higher 7 hours before the onset of the attack. C1-INH did not increase after resolution of the attack suggesting that factors other than C1-INH may be important in this process. C4a may be a useful biomarker for the prediction of EAs. |
| 2015 | Complement system in dermatological diseases - fire under the skin. | Front Med (Lausanne) | The complement system plays a key role in several dermatological diseases. Overactivation, deficiency, or abnormality of the control proteins are often related to a skin disease. Autoimmune mechanisms with autoantibodies and a cytotoxic effect of the complement membrane attack complex on epidermal or vascular cells can cause direct tissue damage and inflammation, e.g., in systemic lupus erythematosus (SLE), phospholipid antibody syndrome, and bullous skin diseases like pemphigoid. By evading complement attack, some microbes like Borrelia spirochetes and staphylococci can persist in the skin and cause prolonged symptoms. In this review, we present the most important skin diseases connected to abnormalities in the function of the complement system. Drugs having an effect on the complement system are also briefly described. On one hand, drugs with free hydroxyl on amino groups (e.g., hydralazine, procainamide) could interact with C4A, C4B, or C3 and cause an SLE-like disease. On the other hand, progress in studies on complement has led to novel anti-complement drugs (recombinant C1-inhibitor and anti-C5 antibody, eculizumab) that could alleviate symptoms in diseases associated with excessive complement activation. The main theme of the manuscript is to show how relevant the complement system is as an immune effector system in contributing to tissue injury and inflammation in a broad range of skin disorders. |
| 2010 | Treatment of episodes of hereditary angioedema with C1 inhibitor: serial assessment of observed abnormalities of the plasma bradykinin-forming pathway and fibrinolysis. | Ann Allergy Asthma Immunol | Hereditary angioedema (HAE) is typically the result of a deficiency of C1 inhibitor (C1-INH) with gene defects that lead to diminished plasma levels or the production of a dysfunctional protein. Replacement therapy with C1-INH has been shown to be effective in ameliorating episodes of swelling. We have reported elevated baseline levels of bradykinin, C4a, and plasmin-alpha2-antiplasmin complexes in the plasma of patients with HAE compared with the plasma of healthy controls. The production of factor XII fragment on in vitro activation of plasma with HAE has also been observed.To perform serial assessment of abnormalities of the bradykinin-forming pathway and fibrinolysis in patients with HAE after treatment of episodes of swelling with intravenous C1-INH.We obtained samples of plasma from 9 patients with HAE at a quiescent period (baseline), during an attack of swelling, and at 1, 4, and 12 hours after termination of an infusion of C1-INH. Factor XIIa, kallikrein, and plasmin were each measured by cleavage of synthetic substrates specific for each item.Each enzyme was strikingly elevated at baseline compared with the levels in pooled healthy plasma, and there was a progressive decline of activity to normal for factor XIIa and plasmin. Kallikrein decreased in 7 of the 9 patients at 1 hour and then decreased in all patients. Bradykinin levels were elevated at the outset in all patients, increased prominently during an attack of swelling, decreased to baseline after 1 hour, and then decreased toward normal by 4 and 12 hours.The plasma levels of factor XIIa, kallikrein, and bradykinin decreased when measured serially subsequent to the infusion of nanofiltered C1-INH. |
| 2008 | Studies of the mechanisms of bradykinin generation in hereditary angioedema plasma. | Ann Allergy Asthma Immunol | Factor XII-dependent bradykinin formation is thought to be responsible for the swelling associated with the various forms of C1 inhibitor deficiency, and complement activation is augmented during attacks of swelling.To further elucidate the interactions of the kinin-forming cascade that lead to complement activation during attacks of swelling and to determine whether fibrinolysis is augmented as well.We compared spontaneous and kaolin-induced activation of normal plasma with the plasma of patients with hereditary angioedema.Hereditary angioedema plasma demonstrated augmented factor XII activation, production of factor XIIf, prekallikrein activation, and high-molecular-weight kininogen cleavage, and, as a result, bradykinin formation was markedly increased. Baseline levels of C4a and plasmin-alpha 2 antiplasmin complexes increased, and, on activation with kaolin, levels increased further.All parameters indicative of activation of the bradykinin-forming cascade are activated in hereditary angioedema plasma vs normal plasma. Production of factor XIIf, demonstrated for the first time in whole plasma, may be responsible for C1 activation based on C4a production. The factor XII-dependent fibrinolytic cascade is also activated. |
| 2007 | Relationship between copy number of genes (C4A, C4B) encoding the fourth component of complement and the clinical course of hereditary angioedema (HAE). | Mol Immunol | In order to study if in patients with hereditary angioedema (HAE), copy number of the two genes (C4A and C4A) encoded in the central region of main histocompatibility complex (MHC) influences the diagnostically important C4 serum concentration as well as the clinical course of the disease, we determined copy number of the complement C4A and C4B genes in DNA samples of 95 HAE patients and 246 healthy controls. Distribution of both the C4A and C4B copy numbers significantly (p=0.0183 and 0.0318, respectively) differed between the two groups, the most marked difference we observed was the lower frequency of the high (3 or 4) C4A copy numbers in the patients. As it expected, the dosage of both C4A and C4B genes positively correlated to the longitudinally measured serum C4 concentrations. Moreover, we found an unexpected clinical correlation with the dosage of the C4B gene. The course of the disease was milder in the 9/95 patients carrying 3 or 4 copies of C4B gene, compared to the rest of patients, i.e. diagnosis was established at significantly (p=0.0052) older age (36.0 (31.0-39.5)) years versus 20.5 (7.5-31.5 years), bi-yearly attack rate was significantly (p=0.0145) lower (1.0 (0.0-11.0)) versus 11.0 (3.5-21.5), and the over-all activity of the classical pathway and the enzyme-inhibitor activity of the C1-inhibitor (C1-INH) was closer to the normal values. These observations indicate that high copy number of the C4B gene can be a protective factor against disease severity in HAE and therefore its determination is warranted. |
| 2006 | A rapid and sensitive assay for the quantitation of carboxypeptidase N, an important regulator of inflammation. | Clin Chim Acta | Carboxypeptidase N is a plasma zinc metallocarboxypeptidase which is constitutively expressed in the liver and was identified as the enzyme responsible for inactivating bradykinin and kallidin by removing the C-terminal arginine. Because CPN can cleave the C-terminal arginine of C3a, C4a and C5a it is often referred to as anaphylatoxin inactivator. Markedly reduced levels of circulating CPN are associated with recurrent angioedema and abnormal cutaneous polymorphonuclear cell infiltration.In this paper we describe a fast kinetic coupled enzymatic assay for the sensitive measurement of carboxypeptidase N activities in serum samples. The assay makes use of the excellent CPN substrate Benzoyl-L-Alanyl-L-Arginine.This novel assay is very fast, easy to perform and combines good reliability and reproducibility with excellent correlation with the HPLC-assisted assay (r=0.927; n=140).The presented assay can be used for high throughput screening of this important regulator of inflammation in clinical plasma or serum samples. |
| [Study of functional activity of components and factors of the human complement system]. | Vopr Med Khim | Development suitable for clinical researches of hemolytic methods of determination of functional activity of the first components of a complement has allowed to show diagnostic value of testing activity of complement components in comparison with their contents as antigens. It has predetermined necessity for building modern ELISA tests-systems for quantitative determination of functional activity of complement components. Such methods built for the first time allow to determine activity of components C1q, C2, C3, C4 (and a ratio of isotypes C4A and C4B), C1-inhibitor, factors B and D. Addition of these tests-systems ELISA systems for quantitative determination of components, and in case of C1-inhibitor of presence IgG, IgA and IgM autoantibodies against C1-inhibitor frames opportunities of an evaluation complement status of the patient, hereditary predisposition to such diseases as a stomach ulcer, the glaucoma, a clamidiosis, bacteroidosis, allows to carry out differential diagnostics of angioedema. Inhibition of covalent linkage C4b or C3b various endogenic and exogenous effectors during formation C3- and C5-convertases allows to understand processes of a regulation of a homeostasis, and also the mechanism of action of drugs. |
| 1999 | Consumption of C4b-binding protein (C4BP) during in vivo activation of the classical complement pathway. | Clin Exp Immunol | C4BP has a central role in regulating the classical complement (C') pathway, but it is still uncertain whether or not it is consumed during in vivo complement activation. Attempts to demonstrate changes in C4BP plasma levels in systemic lupus erythematosus and essential mixed cryoglobulinaemia have failed, probably due to up-regulation of this protein during the inflammatory reaction. We have studied one patient with severe post-transfusion complement-mediated anaphylaxis (CMA), and 67 patients with hereditary C1 inhibitor deficiency (hereditary angioedema (HAE)). The first of these two conditions is characterized by the absence of systemic inflammatory reaction and the second by acute and chronic activation of the C' classical pathway. C4BP, C4BP-C4b complex, and soluble terminal C' complex (sC5b-9) were measured in the patients' plasmas by ELISA techniques and C3a and C4a by radioimmunoassays. In CMA, 15 min after the transfusion, there was a massive C' activation, with increases in C4a, C3a, sC5b-9, C4BP-C4b complexes and decreases in C4, C3 and C4BP. All parameters reverted to preinfusion values within 24 h. Depletion of C4 was correlated with that of C4BP. In patients with HAE, the median value of C4BP (83% range 54-165) was significantly lower (P < 0.0001) than in normal controls (99% range 70-159), with no difference between patients in remission or during acute attacks. C4BP-C4b complexes could not be detected in HAE patients. The results of this study indicate that C4BP is consumed in vivo during acute, and possibly during chronic activation of the C' classical pathway, and that this protein, after interaction with C4b, not longer circulates in plasma. |
| 1992 | Plasma histamine but not anaphylatoxin levels correlate with generalized urticaria from infusions of anti-lymphocyte monoclonal antibodies. | J Lab Clin Med | Anti-lymphocyte monoclonal antibodies have shown promise in trials for therapy of lymphocyte malignancies but are associated with a high frequency of immediate-type anaphylactoid reactions. We have previously demonstrated that these immediate-type anaphylactoid reactions are not mediated by immunoglobulin E to anti-lymphocyte monoclonal antibodies. To gain insight into the mechanisms of these immediate-type anaphylactoid reactions, we measured plasma levels of histamine and anaphylatoxins (C3a, C4a, C5a) during 11 infusions in eight patients who received anti-lymphocyte monoclonal antibodies (T101 and Lym-1). Three patients experienced generalized urticaria (two with severe angioedema); a fourth patient had three isolated hives but without generalized manifestations of an immediate-type anaphylactoid reaction. Plasma histamine levels after infusions that were associated with generalized urticaria were significantly higher than those during infusions that were not associated with generalized urticaria (mean, 3.47 vs 0.18 ng/ml, p less than 0.001). Increases in C3a and C4a levels were observed after some infusions, but these did not correlate with generalized urticaria. Measurable rises in plasma C5a levels after infusions were not detected. Although these data should be viewed as preliminary considering the limited number of patients studied, the observed histamine release demonstrates that mast cell or basophil activation that is not mediated by immunoglobulin E to anti-lymphocyte monoclonal antibodies occurs in the pathogenesis of immediate-type anaphylactoid reactions from anti-lymphocyte monoclonal antibodies. Although activation of the classical complement pathway may occur in some anti-lymphocyte monoclonal antibody infusions, this does not appear to explain immediate-type anaphylactoid reactions.(ABSTRACT TRUNCATED AT 250 WORDS) |
| 1986 | Decreased synthesis of serum carboxypeptidase N (SCPN) in familial SCPN deficiency. | J Clin Immunol | Serum carboxypeptidase N (SCPN) is the primary inactivator of the C3a, C4a, and C5a anaphylatoxins as well as an inactivator of bradykinin. Thus SCPN deficiency potentially could result in significant pathophysiologic consequences. Previous studies identified a deficient subject afflicted with frequent episodes of angioedema, and other family members also had SCPN deficiency. To delineate this abnormality further, the fractional catabolic rate (FRC) and enzyme synthesis were determined in three members of the afflicted kindred as well as in five normal persons following the infusion of homogeneous 125I-SCPN. The mean FCR and synthesis rates for SCPN in the normal subjects were 1.3%/hr and 20,793 U/kg/hr, respectively. Reduced synthesis was concluded to be primarily responsible for the low SCPN levels in the afflicted kindred. The high FRC of SCPN discourages attempted maintenance therapy with infusions of enriched SCPN preparations. |
| 1985 | Complement profile in a C1 inhibitor deficient family. | Br J Dermatol | 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. |
| 1980 | Familial carboxypeptidase N deficiency. | Ann Intern Med | Carboxypeptidase N is a serum metalloenzyme that inactivates C3a, C4a, C5a, bradykinin, kalladin, and fibrinopeptides. Of 172 sera from patients with chronic urticaria or angioedema, one had a remarkably depressed carboxypeptidase N level (21% of normal). Of sera from 103 patients with other diseases, elevated levels were observed in cases of neoplasms, and one abnormally low value was detected in a patient with cirrhosis. The patient with a remarkably low carboxypeptidase N level was a 65-year-old man with an 11-year history of episodic angioedema occurring about 40 times per year. Inactivation of C3a and lysyl-bradykinin by his serum was markedly prolonged. Plasma histamine was elevated during attacks, but serotonin and kinin activity were not. The proband's sister had an equally depressed serum carboxypeptidase N level, and studies of other family members suggested an autosomal recessive inheritance of the enzyme deficiency. |