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PubMed1985

C1 dissociation in serum: estimation of free C1q by electroimmunoassay.

A two-stage electroimmunoassay was developed for measuring macromolecular C1 (C1qrs) and free C1q. The method was based on Ca2+ dependent fixation of C1qrs to agarose, followed by immune precipitation of dissociated C1s in the presence of EDTA. Free C1q was estimated from the increase in C1qrs resulting from saturation of C1q in the samples with purified C1r-C1s. The assay system was studied under various experimental conditions. Combined analysis by electroimmunoassay and crossed immunoelectrophoresis indicated that part of the free C1q in undiluted normal serum could be attributed to physiological C1 activation. Owing to concentration dependent C1qrs dissociation the proportion of free C1q increased with the dilution of serum. Results obtained with serum and with purified C1qrs were consistent with the formation of an equimolar C1q:C1r-C1s complex. However, the capacity for C1r-C1s binding appeared to be higher in the purified system than in serum. Serum concentrations of free C1q were high in some of the patients with disease conditions characterized by increased C1 activation, such as systemic lupus erythematosus or primary biliary cirrhosis.

Complement Activating Enzymes↗
PubMed1995

Reduction in transmission of hepatitis C after the introduction of a heat-treatment step in the production of C1-inhibitor concentrate.

BACKGROUND: The transmission of viral infections via protein concentrates made from a large pool of plasma depends on the selection of donors, fractionation process, and virucidal methods. To date, no data are available on the infectivity risk of plasma concentrates of the inhibitor of the first component of complement (C1-INH). STUDY DESIGN AND METHODS: The prevalence of blood-borne viral infections and levels of transaminases were evaluated in patients treated with a large-pool plasma concentrate of the inhibitor of C1-INH before and after the introduction of virucidal methods. The study included 85 patients with hereditary angioedema and 4 with acquired angioedema. The patients were divided into three groups: 1) 48 untreated patients; 2) 22 patients treated with non-virus-inactivated C1-INH concentrates; and 3) 19 patients treated with virus-inactivated concentrates. Serum samples obtained at various times after the infusion of concentrate were assayed for alanine amino-transferase and tested for hepatitis B surface antigen and antibodies to hepatitis C virus (anti-HCV) and human immunodeficiency virus (anti-HIV); anti-HCV-negative subjects exposed to the concentrate were also tested for HCV RNA. RESULTS: Prevalences of HCV infection and elevated alanine aminotransferase are significantly lower in patients treated with virus-inactivated concentrates than in those exposed to non-virus-inactivated concentrates. No patients were anti-HIV positive. CONCLUSION: This study suggests that C1-INH concentrates transmitted HCV, but that the virucidal methods adopted are effective in reducing the infectivity.

Adolescent↗
PubMed1996

Human parvovirus infection: rheumatic manifestations, angioedema, C1 esterase inhibitor deficiency, ANA positivity, and possible onset of systemic lupus erythematosus.

OBJECTIVE: To investigate the clinical and serological characteristics of parvovirus infection. METHODS CASE SERIES: during 1993-4, 9 adult patients presented with polyarthralgias/polyarthritis. Clinical evaluation and serological studies of antinuclear antibodies, rheumatoid factor (RF), IgM and IgG antibodies to human parvovirus were done in all patients. Other serologies including anti-DNA, serum complement, and C1 esterase inhibitor levels were obtained in some patients. RESULTS: All 9 patients had polyarthralgias/polyarthritis, serological evidence of parvovirus B19 IgM and IgG antibodies, and normal sedimentation rate. All patients were seronegative for RF. Four women had positive ANA titers. In 2 of them the ANA positivity was transient. One developed systemic lupus erythematosus (SLE). Three women had angioedema of the face and tongue; one had transient C1 esterase inhibitor deficiency and another a transient decrease in C4 levels. CONCLUSION: Parvovirus may be implicated in the development of SLE as well as other chronic arthropathies. This is the first reported case of angioedema and decreased C1 esterase inhibitor levels associated with parvovirus infection.

Adult↗
PubMed1987

Inactivation of influenza B virus by normal guinea-pig serum.

Normal guinea-pig serum (GPS) lacking detectable antiviral antibody efficiently neutralized the infectivity of influenza B virus grown in chick embryos or MDCK cells. The inhibitor was heat-labile and sensitive to trypsin digestion. This beta-like inhibitor required Ca2+ and the complement components C1 and C4 for its activity. In contrast, GPS did not inactivate influenza A virus. Influenza B virus from which the neuraminidase activity of the spikes on the viral envelope had been eliminated by trypsin digestion was also inactivated to a level comparable to untreated virus. Complement component C1 alone bound directly to influenza B virus and inhibited its haemagglutinin activity. We suggest that the beta-like inhibitor in GPS is a component of the classical complement pathway which is triggered by the protein moiety of influenza B virus haemagglutinin, leading to virus neutralization.

Animals↗
PubMed2000

Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema.

BACKGROUND: Two genetic forms of hereditary angioedema (HAE) are currently recognized. Both are transmitted in an autosomal dominant manner and are characterized by recurrent episodes of localized angioedema. Involvement of the gut leads to episodes of severe abdominal pain, and laryngeal involvement can lead to airway obstruction and even death. One type results from heterozygosity for a nonexpressed C1 inhibitor allele, and the other results from heterozygosity for a nonfunctional C1 inhibitor allele. OBJECTIVE: This report identifies a third type of HAE, with a unique estrogen-dependent phenotype. METHODS: Detailed medical histories were obtained from family members, and a pedigree was constructed to ascertain the mode of inheritance. Determination of serum complement factors, C1 inhibitor protein, C1 inhibitor function, coagulation factor XII, plasma prekallikrein, high molecular weight kininogen, and selected DNA sequences were performed in affected members by using standard assays. RESULTS: Episodes of angioedema were clinically indistinguishable from those associated with previously described forms of HAE; however, these occurred only during pregnancy or the use of exogenous estrogens. Patients were otherwise asymptomatic, except for one patient who had acetyl salicylic acid/nonsteroidal anti-inflammatory drug-related angioedema later in life. History was available for members spanning 4 generations, and affected individuals were identified in 3 generations. Of 46 family members, phenotype could be determined in 13 members. Seven were affected, and 6 were not. One male of undetermined phenotype was an obligate carrier. The unique estrogen-dependent nature of the phenotype means that the status of several members in the third and fourth generation remains unknown. The disorder appears to be transmitted in an autosomal dominant fashion, although other modes of inheritance cannot be excluded entirely. C1 inhibitor protein, C1 inhibitor function, C2, C4, C1q, coagulation factor XII, prekallikrein, and high molecular kininogen were normal in 3 affected family members during asymptomatic periods. DNA sequencing revealed no abnormality in 3 patients in the coding region of the gene encoding C1 inhibitor or in the 5' flanking regions of the genes encoding C1 inhibitor and factor XII. CONCLUSIONS: This family appears to have a novel form of inherited angioedema that does not result from C1 inhibitor deficiency or dysfunction. The phenotype is uniquely estrogen dependent. Implications for diagnosis and treatment are discussed. Further studies are required to define the exact nature of the genetic abnormality involved.

Adult↗
PubMed1979

Hereditary angio-oedema and C3 nephritic factor--HL-A study.

In one family of twenty-four members hereditary angio-oedema was present in the family for six generations. The protein C1 esterase inactivator found in nine patients proved to be non-active in a functional test. Another anomaly found in the complementary system was labelled C3 nephritic factor without any renal, or other clinical symptoms. Study of HL-A haplotypes did not show any linkage with the loci A, B and C. Hereditary angio-oedema is a disease arising from a specific defect in the inactivator of the C1 esterase (C1 INA) which is a regulating component of the complement system (Donaldson & Evans, 1963). This system is of current interest because of its interaction with other mechanisms of inflammation. Moreover, some links have been discovered recently between HL-A and hereditary defects of complement. This paper reports new findings in a family with hereditary angio-oedema.

Angioedema↗
PubMed1984

Interaction of C1q with beta 2-microglobulin.

Beta 2-microglobulin aggregated with glutaric dialdehyde was efficiently bound to C1q in fluid and solid phase assay systems. Furthermore, affinity chromatography experiments suggested reactivity of monomeric beta 2-microglobulin with C1q. In spite of its C1q binding capacity, the aggregated beta 2-microglobulin did not activate the C1 complex in serum. This however, might have been due to the mode of aggregation.

Binding Sites↗
PubMed2002

Regulation of the mannan-binding lectin pathway of complement on Neisseria gonorrhoeae by C1-inhibitor and alpha 2-macroglobulin.

We examined complement activation by Neisseria gonorrhoeae via the mannan-binding lectin (MBL) pathway in normal human serum. Maximal binding of MBL complexed with MBL-associated serine proteases (MASPs) to N. gonorrhoeae was achieved at a concentration of 0.3 microg/ml. Preopsonization with MBL-MASP at concentrations as low as 0.03 microg/ml resulted in approximately 60% killing of otherwise fully serum-resistant gonococci. However, MBL-depleted serum (MBLdS) reconstituted with MBL-MASP before incubation with organisms (postopsonization) failed to kill at a 100-fold higher concentration. Preopsonized organisms showed a 1.5-fold increase in C4, a 2.5-fold increase in C3b, and an approximately 25-fold increase in factor Bb binding; enhanced C3b and factor Bb binding was classical pathway dependent. Preopsonization of bacteria with a mixture of pure C1-inhibitor and/or alpha(2)-macroglobulin added together with MBL-MASP, all at physiologic concentrations before adding MBLdS, totally reversed killing in 10% reconstituted serum. Reconstitution of MBLdS with supraphysiologic (24 microg/ml) concentrations of MBL-MASP partially overcame the effects of inhibitors (57% killing in 10% reconstituted serum). We also examined the effect of sialylation of gonococcal lipooligosaccharide (LOS) on MBL function. Partial sialylation of LOS did not decrease MBL or C4 binding but did decrease C3b binding by 50% and resulted in 80% survival in 10% serum (lacking bacteria-specific Abs) even when sialylated organisms were preopsonized with MBL. Full sialylation of LOS abolished MBL, C4, and C3b binding, resulting in 100% survival. Our studies indicate that MBL does not participate in complement activation on N. gonorrhoeae in the presence of "complete" serum that contains C1-inhibitor and alpha(2)-macroglobulin.

Adult↗
PubMed1987

Biological properties of chimeric antibodies. Interaction with complement.

Genetic engineering allows the production of chimeric immunoglobulins where the same variable region is expressed in conjunction with constant regions of different species. We have compared the capacity of mouse and chimeric (mouse variable region/human constant region) immunoglobulin M (IgM) to trigger complement-dependent lysis and to bind complement component C1. Guinea pig and human C1 were bound more efficiently by mouse IgM than by chimeric IgM, whereas rat and rabbit C1 were bound more efficiently by chimeric IgM. Comparable results were obtained for complement as measured by the lysis of sensitized erythrocytes. These results indicated that differences between the human and mouse mu heavy chain constant regions define structures that are important in the C1-IgM interaction. Furthermore, species-specific differences in C1 also influence this interaction.

Animals↗
PubMed1986

Activation of complement by myelin: identification of C1-binding proteins of human myelin from central nervous tissue.

Myelin isolated from central nervous tissue activates the classic pathway of complement by directly activating C1. Activation of C1 can proceed to form membrane attack complex, C5b-9, in the myelin. Such an interaction between myelin and complement may be important in diseases involving myelin damage, in view of the role of complement in membrane attack and inflammation. To identify the C1-activating protein, myelin was subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot. The blots were incubated with C1 or with whole serum complement, followed by immunostaining for C1 or C3, respectively. A duplicate strip was stained with amido black or anti-myelin antibody to visualize the myelin proteins. The results showed that two major protein bands were capable of activating C1. An approximately 56-58-kilodalton band comigrated with the W2 protein and an approximately 45-47-kilodalton band migrated along with, but slightly behind, the W1 Wolfgram doublet.

Complement Activating Enzymes↗
PubMed1976

The importance of quaternary structure in the expression of the C1-binding site of IgM.

The ability of C1 to bind to the Fc5mu-fragment of a monoclonal IgM was determined by means of a haemolytic C1-inhibition assay. Fc5mu fragments were produced by trypsin digestion at five different temperatures ranging from 54-62 degrees (2 degrees increments) and were purified by immunoadsorption through a column of monospecific anti-Fabmu and by molecular exclusion chromatography. Analytical ultracentrifugation showed the final preparations to be free of aggregates. A plot of mug Fc5mu required to inhibit 50% of available C1 versus temperatures of production of the fragment yielded a curve with a minimum at 58-60 degrees. Upon mild reduction and alkylation of these Fc5mu fragments their C1-fixing capacity became approximately the same irrespective of temperature of production. Fc5mu was also prepared at 25 degrees in the presence of 5 M urea, purified by immunoadsorption as before and aliquots then exposed to temperatures ranging from 40-70 degrees (5 degrees increments) for 15 min. After aggregates had been removed by chromatography a similar minimum in C1-fixation was again observed at 60 degrees. Reduction and alkylation once more abolished these differences. Fc5mu and its reduced and alkylated subunits, produced at 60 degrees and then exposed to various concentrations of urea (0-7 M) for 24 hd did not yield a minimum in C1 fixation. Reduced and alkylated Fcmu incubated at various temperatures (40-70 degrees) also did not fix C1 differentially. Examination in the near and far u.v. region of the circular dichroism spectra of different Fc5mu preparations showed a gradual loss of structure associated with restricted aromatic chromophores and secondary (beta) structure with increased temperature. Urea denaturation had a more pronounced and irreversible effect on Fc5 mu conformation. These changes could not be correlated with the CU-fixation patterns observed. It would therefore appear that elevated temperatures induce a static change in the pentameric FC-part of IgM which in turn directly influences or modulates the availability of the C1-binding site. The importance of disulphide bonds in maintaining these temperature-induced changes in Fc5mu was also indicated.

Binding Sites↗
PubMed1976

C1 and human platelets. II. Detection by immunological methods and role.

A C1 haemolytic activity was previously shown to be associated with platelets. The presence of C1 on human gel filtered platelets is confirmed by Ouchterlony analysis, and platelet aggregation induced by anti-c1 q antisera. After cleavage of C1 by EDTA, platelet aggregation induced by aggregated was decreased and was restored by the addition of C1. The possible role of C1 in human platelet aggregation induced by aggregated immunoglobulins or immune complexes is discussed.

Blood Cell Count↗
PubMed1999

Angioedema due to acquired C1-esterase inhibitor deficiency in a patient with Helicobacter pylori infection.

The first component of the classical pathway of the complement system, C1 is regulated by a serum protein, the C1-esterase inhibitor (C1-INH). Deficiency of this protein leads to the release of vasoactive mediators (C2 kinin and bradykinin) that increase vascular permeability and can induce edema formation in subcutaneous and submucosal tissues. The genetic variant of C1-INH deficiency is inherited as an autosomal dominant trait and causes hereditary angioneurotic edema. The acquired form of C1-INH deficiency is characterized by similar manifestations and can occur in association with lymphoproliferative diseases, malignancy, immune disorders, and infections. The authors present a case of acquired C1-INH deficiency in a patient with Helicobacter pylori infection. Complete eradication of this pathogen was followed by the resolution of symptoms and normalization of serum complement levels. It seems therefore probable that in this patient, acquired C1-INH deficiency was related to Helicobacter pylori infection. To our best knowledge, no similar observations have been published so far. Specific immune reactions are important contributing factors in H. pylori. Excessive consumption of complement by antibodies directed against H. pylori is a potential cause of C1-INH deficiency observed in our case.

Adult↗
PubMed2001

Ex-vivo hemoperfusion (eHPS) of pig-lungs with whole human blood: effects of complement inhibition with a soluble C1-esterase-inhibitor.

OBJECTIVES: Xenotransplantation could be a future alternative to allotransplantation due to increasing organ shortage. Complement activation plays a major role in hyperacute rejection (HAR) in pig-to-human combinations. We developed an ex-vivo hemoperfusion (EHP) system to investigate pathophysiology of HAR in the lung. After standardizing the model, the effect of a soluble complement inhibitor (C1-INH, Berinert) was investigated. METHODS: Pig lungs were harvested following cold perfusion with Celsior preservation solution. EHP was performed using fresh heparinized human blood plus C1-INH (n = 6) or heparinized human blood as control (n = 4). Bloodgas analyses (BGA), pulmonalarterial pressure (PAP) were monitored. P-selectin and L-selectin were measured. Tissue samples were taken and microscopic changes evaluated. RESULTS: BGA, PAP, macroscopic and microscopic changes in the control group showed HAR, while the C1-INH group showed significantly longer function. Leucocytes and platelets were markedly activated in the control, whereas in the treated group L-selectin and P-selectin values indicated lower activation. HE stainings showed maintained lung architecture after perfusion of pig-lungs with human blood plus C1-INH. Immunohistochemistry showed less C1q, C3, C5b-9 activation in the C1-INH group. CONCLUSIONS: Investigation of interaction of human blood with pig lung endothelium could be done in this model. C1-INH attenuates HAR in a pig-to-human lung transplantation model by decreasing the activation of adhesion molecules. C1-INH could play a role in induction therapy of future lung xenotransplantation.

Animals↗