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PubMed1987

Deficiency of C2, the second complement component, in the family of a patient with SLE-like syndrome: the first case of hereditary C2 deficiency in Czechoslovakia.

A family with hereditary C2 deficiency was discovered in Czechoslovakia. The proband is a 47-year-old female with a SLE-like syndrome and zero activity of the classical complement pathway. Functional CH50, C1, C2, and C4 estimations for all family members revealed a homozygous C2 deficiency in both the proband and her elder sister, and several heterozygotic C2-deficient individuals. The defect segregates with haplo-type HLA A25, B18, DR2.

Adult↗
PubMed1979

Neonatal cellular and humoral immunity to group B streptococci.

The mechanisms of host resistance to group B streptococci have not been defined precisely. In the studies reported here we have assessed the contributions of both humoral and cellular factors in protection against strains of this group. With assays of specific opsonic activity based upon the production of polymorphonuclear leukocyte chemiluminescence and radiolabeled bacterial uptake, we have demonstrated that specific heat-stable antibody and the classic complement pathway are major factors in opsonization of these organisms. In the absence of specific antibody, fresh serum resulted in markedly reduced bacterial uptake indicating, at best, a minor role for the alternative complement pathway. Additional studies have indicated that strain-specific antiphagocytic factors as well as type-specific ones may play a role in the virulence of these organisms. Neonates who developed group B streptococcal sepsis usually lacked opsonic activity in their infecting strain. In addition, polymorphonuclear leukocytes from normal term and stressed neonates showed impaired metabolic activation as measured in the chemiluminescence assay following exposure to opsonized group B streptococci. These results suggest that neonates who develop group B streptococcal disease may have defects in both the humoral and cellular aspects of their acute inflammatory response which may contribute to the high mortality observed in this most fulminant of bacterial infections.

Antibody Formation↗
PubMed1983

Demonstration of beta 1H globulin in pemphigus.

beta 1H globulin is a plasma protein which regulates the biologic activities of the major fragment of the 3rd complement component, C3b. The role of beta 1H globulin in pemphigus was investigated using immunofluorescence in the present study. Lesional skin biopsies from patients with confirmed pemphigus demonstrated in-vivo deposition of beta 1H in addition to C3 in all of four biopsies. Eight serum samples containing C3 fixing intercellular antibodies were then tested for the capacity to fix beta 1H and other complement components. All eight pemphigus sera showed fixation of beta 1H to the intercellular areas of normal human skin. C1q and C4 fixation by pemphigus sera was also demonstrated in 7 of 8 sera, respectively. The experiment using C2-deficient serum indicated that the fixation of beta 1H by intercellular antibodies requires the activation of the classical complement pathway. These data suggested that beta 1H, a co-factor of C3b inactivator, plays a role in the in-vivo regulation of complement activity and supplies additional evidence for the participation of complement system in the pathogenesis of pemphigus.

Antibody Specificity↗
PubMed1980

Depletion of total hemolytic complement in sera from hamsters bearing herpes simplex type 2-induced tumors.

Total hemolytic complement (CH50) levels were compared in sera from normal hamsters and hamsters bearing tumors derived from herpes simplex virus type 2-transformed cells CH50 in normal sera ranged from 160 to 212 while CH50 in tumor bearer sera ranged from 82 to 146. Preincubation of tumor bearer sera with cell surface proteins (CSP) from homologous herpes simplex virus type 2-derived tumor cells resulted in a 66% depletion of CH50 whereas preincubation with heterologous herpes simplex virus type 1-derived tumor CSP resulted in a decrease of 26%. The depletion of CH50 appeared to occur via the classic complement pathway. Similar results were seen using CSP from herpes simplex virus-infected cells although overall depletion of CH50 was considerably less than that seen using tumor cell material. Using the complement subcomponent 1q(C1q)-binding test, tumor bearer sera and tumor bearer sera preincubated with homologous CSP were shown to contain increased levels of immune complexes not present in normal serum. These results indicate that the observed depletion of complement activity in sera from tumor-bearing hamsters could be the result of complement pathway activation by antigen-antibody complexes.

Animals↗
PubMed1995

Clinical significance of longitudinal complement measurements in recipients of bone marrow transplant.

Overall activity of classical complement pathway, C3 and C4 levels, level of circulating immune complexes and concentration of serum immunoglobulins were measured in 38 patients transplanted with HLA-identical bone marrow before and after transplantation for at least 4 years. Changes of complement parameters and their association with acute and chronic GVHD and with infections were analysed. A strong association was found between the development of chronic GVHD and hypercomplementaemia measured in 16 long-term survivors. Low pre-transplantation C4 activity was found to predict the development of severe acute GVHD. These findings indicate that longitudinal complement measurements may have clinical value in BMT patients.

Acute Disease↗
PubMed1994

[Features of complement proteinase function].

Classical and alternative pathways of complement are considered which are stringently controlled cascades of proteolytic reactions. Peculiarities of working of various components of complement are characterized, ways are described of the regulation and inhibition of the system realized in the nature to achieve the highest reliability necessary for homeostasis.

Amino Acid Sequence↗
PubMed1993

Structure and regulation of the C1 inhibitor gene.

C1 esterase inhibitor is a M(r) approximately 105,000 glycoprotein and the sole regulation of the activities of C1r and C1s. As such, it plays an extremely important role in the regulation of the classical complement pathway. Hereditary angioedema (HAE) is the clinical manifestation of C1INH deficiency. Two types of HAE have been described. Type I HAE is characterized by low antigenic and functional levels of C1INH, while Type II HAE is characterized by normal or increased antigenic levels of C1INH with low levels of functionally active protein. C1INH is encoded by a single gene on chromosome 11. The C1INH gene consists of 8 exons and 7 introns and is approximately 1.7 x 10(4) base pairs in length. Expression of C1INH in vivo is enhanced by androgens. In vitro studies indicate that C1INH mRNA and protein levels are increased by up to 20 fold after stimulation with interferon-gamma (gamma-IFN) and to a lesser extent in response to alpha-interferon (alpha-IFN), tumor necrosis factor-alpha (TNF-alpha), Interleukin 6 (IL-6) and monocyte colony stimulating factor (M-CSF). In this chapter, we will discuss the structure of the C1INH gene and mechanisms of its regulation as well as some of the elements which may contribute to its transcriptional regulation.

Angioedema↗
PubMed1996

Behaviour of Acinetobacter strains with normal human serum.

The bactericidal activity of normal human serum (NHS) and treated NHS to avoid either the classical complement pathway (CPC) or the alternative complement pathway (APC) was studied with four strains identified as Acinetobacter baumanii. Three of them were sensitive to serum whereas only one was serum resistant. The serum sensitive strains showed different susceptibility mechanisms: one strain was sensitive to both the CPC and the APC and the others were sensitive only to APC. Serum sensitive and serum resistant strains showed on PAGE-SDS and silver strain incomplete profiles of lipopolysaccharides (LPS). In all cases the carbohydrate percentage of LPS was lower than the value corresponding to Salmonella enteritidis with complete profiles of LPS. The strain sensitive to CPC and APC had a lower carbohydrate content. The serum sensitivity of the three strains could be attributed to the presence of incomplete LPS, while the serum resistance could be assigned either to small variations in the LPS composition or to some particular membrane component.

Acinetobacter↗
PubMed1997

Domain-switched mouse IgM/IgG2b hybrids indicate individual roles for C mu 2, C mu 3, and C mu 4 domains in the regulation of the interaction of IgM with complement C1q.

Although polymeric IgM and monomeric IgG are potent activators of the classical complement pathway, previous studies have indicated that monomeric IgM is inactive. To understand this and to examine the roles of the individual mu domains in complement activation, we created a set of IgM/IgG2b mouse chimeric Abs in which homologous domains of both Abs have been interchanged, either singly or together with adjacent domains. The monomer subunits (H2L2) of the resulting chimeras were analyzed for their capacities to bind C1q and to initiate complement-mediated lysis (CML) of haptenated erythrocytes. When C gamma 2 was flanked by C mu 4, the inherent C1q-binding activity of the C gamma 2 domain was lost. This demonstrates that C mu 4 can suppress the C1q-binding activity of the adjacent C gamma 2 domain, and suggests that C mu 4 may exert a similar effect on the C mu 3 domain in the IgM monomer subunit. When C mu 3 was located in an IgG2b background and potentially freed from the constraints imposed by the IgM background, the monomer was not able to bind C1q or initiate CML. This suggests that these activities are not expressed inherently in the C mu 3 domain. The transplantation of C mu 3 together with C mu 4 into the IgG background permitted polymer formation. This polymer was able to bind C1q, although neither the monomer nor the polymer forms were active in CML; conversely, all IgM polymers with a transplanted C gamma 2 domain were active in both C1q binding and CML, and demonstrated apparent Kd values similar to that of wild-type IgM.

Animals↗
PubMed1986

Serotherapy of primary rat mammary carcinoma: inhibition by ethylenedinitrilotetraacetic acid but not by [ethylenebis(oxyethylenenitrilo)]tetraacetic acid.

We reported inhibition of growth of primary rat mammary carcinomas after infusions of tumor-bearer plasma absorbed with Protein A-Sepharose or inactivated CNBr Sepharose. Absorbed plasmas were depleted of the third component of complement (C3) (other complement components defined similarly) and C5 but not C1, C4, or C2. These results suggested that activation of the alternative pathway of complement might be involved in the observed antitumor effects. To test this concept sera were treated with ethylenedinitrilotetraacetic acid or [ethylenebis(oxyethylenenitrilo)]tetraacetic acid before absorption with Protein A-Sepharose. Ethylenedinitrilotetraacetic acid, by chelating calcium and magnesium, prevents activation of both the alternative and classical complement pathways. [Ethylenebis(oxyethylenenitrilo)]tetraacetic acid, by chelating calcium but not magnesium, permits activation of the alternative pathway but inhibits activation of the classical complement pathway. Sera in the presence or absence of chelating agent were absorbed with Protein A-Sepharose twice at room temperature. After absorption calcium was added to the sera. Rats were treated by i.v. injection of sera twice a week for 2 weeks. Measurements of tumor size were made weekly for 5-7 weeks and then tumor weight was determined. Groups were compared both for size of index and total tumors. The results can be summarized as follows: tumor-bearer sera before absorption did not inhibit the growth of rat primary mammary carcinomas; tumor-bearer sera after absorption with Protein A-Sepharose showed significant consumption of C3 and did inhibit tumor growth; tumor-bearer sera absorbed in the presence of ethylenedinitrilotetraacetic acid did not show a decrease in C3 functional activity and did not inhibit tumor growth; tumor-bearer sera absorbed in the presence of [ethylenebis(oxyethylenenitrilo)]tetraacetic acid did show a decrease in C3 functional activity and did inhibit tumor growth; sera from normal adult female rats after absorption with Protein A-Sepharose did inhibit tumor growth. The results are consistent with a role for the alternative pathway of complement in the inhibition of growth of rat primary mammary carcinomas observed after treatment with absorbed sera.

Animals↗
PubMed2003

Complete sequencing and expression of three complement components, C1r, C4 and C1 inhibitor, of the classical activation pathway of the complement system in rainbow trout Oncorhynchus mykiss.

Three complement components, C1r, C4 and C1 inhibitor, of the classical activation pathway have been fully sequenced and their expression investigated in rainbow trout (Oncorhynchus mykiss). Trout C1r cDNA encodes a 707-amino-acid (aa) protein with a theoretical M(r) of 77,200. The trout translation shows highest homology with carp C1r/s, and lower, equal homologies to mammalian C1r and C1s, and MASPs from other vertebrate species. However, phylogenetic analysis and structural features suggest that the trout sequence, together with the two carp sequences, are the orthologues of mammalian C1r. The trout C4 cDNA encodes a 1,724-aa protein with a theoretical M(r) of 192,600. The trout translation shows higher homologies to the carp C4B and medaka C4, but lower homologies to C4 from other species and the carp C4A. It has a predicted signal peptide of 22 aa, a alpha-chain of 773 aa, a beta-chain of 635 aa and a lambda-chain of 288 aa. Trout C1 inhibitor cDNA encodes a 611-aa protein with a theoretical M(r) of 68,700. The trout translation has a C-terminal serpin domain with high homologies with mammalian counterparts (~37% identities), and a longer N-terminus, with no significant homology to other serpins, which contains two Ig-like domains. A molecule containing two Ig-like domains followed by a serpin domain, has also been found in an EST clone from another bony fish, the Japanese flounder. This suggests a unique structural feature of C1 inhibitor in fish. The functional significance of the Ig domains is discussed. The liver is the major site of expression of the three trout complement components, C1r, C4 and C1 inhibitor, although their expression is also detectable in other tissues. The extra-hepatic expression of complement genes may be important for local protection and inflammatory responses. Low-level constitutive expression of the three components was also detectable in a trout monocyte/macrophage cell line RTS-11, but only the expression of C4 could be upregulated by LPS.

Amino Acid Sequence↗
PubMed1979

Requirements of immunoglobulin and the classical and alternative complement pathways for phagocytosis and intracellular killing of multiple strains of Gram-negative aerobic bacilli.

The requirements for immunoglobulin and the alternative and classical complement pathways for phagocytosis and intracellular killing of clinical isolates of Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, and Serratia marcescens by normal human polymorphonuclear leukocytes were determined. Human sera deficient in immunoglobulin or classical pathway activity, or both, were compared for their ability to promote phagocytosis os and killing of 13 bacterial strains by the polymorphonuclear leukocytes. Seven of the thirteen microorganisms required immunoglobulin for phagocytosis and killing and utilized only the classical complement pathway. Three required immunoglobulin and utilized both the classical and alternative pathways. The other three microorganisms required minimal immunoglobulin and utilized the alternative or classical pathway, or both. None of the microorganisms utilized the alternative pathway in immunoglobulin-deficient sera or could be forced to utilize this pathway in sera deficient in both immunoglobulin and classical pathway activity. These results demonstrated a heterogeneity in the requirements for immunoglobulin and the alternative and classical complement pathways for phagocytosis and intracellular killing by polymorphonuclear leukocytes among various genera of gram-negative aerobic bacilli, as well as among strains of the same species. In addition, the results suggested that a mechanism of classical pathway activation dependent upon minimal immunoglobulin participates in phagocytosis and intracellular killing of certain gram-negative aerobic bacilli.

Complement Activation↗
PubMed1990

In vitro phosphorylation of human complement factor C3 by protein kinase A and protein kinase C. Effects on the classical and alternative pathways.

Complement factor C3, recently found to contain covalently bound phosphate, was phosphorylated in vitro by cyclic AMP-dependent protein kinase (protein kinase A) and Ca2(+)-activated, phospholipid-dependent protein kinase (protein kinase C). Both protein kinases phosphorylated the same serine residue(s) located in the C3a portion of the alpha-chain. In addition, protein kinase C phosphorylated the beta-chain to a lesser extent. Protein kinase A gave a maximal incorporation of 1 mol of phosphate/mol of C3 while that value with protein kinase C was 1.5 mol of phosphate/mol of C3. The velocity in pmol of [32P]phosphate/(min x unit kinase) was 20 times higher for protein kinase C than for protein kinase A although a 10 times lower ratio of protein kinase to C3 was used in the former case. The apparent Km for C3 was 2.6 microM when protein kinase C was used. The phosphorylated C3 was found to be more resistant to partial degradation by trypsin than unphosphorylated C3. It was also found that phosphorylation of C3 in the C3a portion of the alpha-chain inhibited both the classical and alternative complement activation pathways on an approximately stoichiometric basis.

Amino Acids↗
PubMedDate not supplied

Role of complement in host resistance against members of the Bacteroidaceae.

Considerable evidence has been reported in recent years suggesting that complement plays an important role in host resistance against members of the Bacteroidaceae. Most of the investigations in this area have focused on the genus Bacteroides because of its clinical importance. Various species of Bacteroides have been shown to activate the complement system in vitro via the classical and alternative pathways. Complement activation results in the generation of chemotactic factors that mobilize polymorphonuclear leukocytes to sites of infection. Activated complement also facilitates bacteriolysis and opsonophagocytic killing by polymorphonuclear leukocytes and macrophages. Strains possessing dense fibrillar polysaccharide capsules are resistant to both of these defense mechanisms. The putative importance of complement-dependent bacteriolysis and opsonophagocytic killing in resistance against Bacteroides infections in vivo requires confirmation. In addition, the role of complement in synergistic interactions between Bacteroides and facultative bacteria remains to be elucidated.

Antibodies, Bacterial↗
PubMed1986

The pathogenesis of hyaline arteriolosclerosis.

Although hyaline arteriolosclerosis is very common and has been of interest to pathologists for well over 100 years, its pathogenesis has never been determined. This study demonstrates that iC3b bound via an ester linkage to hydroxyl groups on the repeating disaccharide units of hyaluronic acid is a major component of arteriolar hyaline. The deposition of iC3b within the walls of arterioles appears to be due to slow spontaneous activation of the alternative complement pathway and random binding of metastable C3b to proximate hyaluronic acid within the arteriolar wall. Since hyaluronic acid does not activate the alternative complement pathway, bound C3b is rapidly inactivated by factors I and H to iC3b, which, along with factor H, remains bound to hyaluronic acid. The hyaline in some hyalinized arterioles also contains IgM and early and late classical complement pathway components. Indirect evidence suggests that the IgM represents immunoconglutinin, an autoantibody to neoantigens on iC3b and that their interaction results in activation of the classical complement pathway. The gradual accumulation of iC3b, factor H, and, at times, IgM and classical complement pathway components within the walls of arterioles is considered to be a physiologic consequence of aging and probably cannot be prevented, because interruption of the initial binding of metastable C3b to hyaluronic acid would require abrogation of the critically important functions of the alternative complement pathway.

Adolescent↗
PubMed1991

The role of immunoglobulin and complement in enhancing the respiratory burst of neutrophils against Trichomonas vaginalis.

Human neutrophils, alone, did not kill Trichomonas vaginalis. More than 90% of T. vaginalis (10(5)/ml) survived in the presence of 10% normal human serum (NHS) while 90% of these organisms were killed in the presence of a combination of neutrophils (10(6)/ml) and 10% NHS. Mechanisms responsible for this serum-mediated neutrophil killing of T. vaginalis were demonstrated through a process of lucigenin-amplified neutrophil chemiluminescence. As evidenced by indirect immunofluorescence, NHS showed specific immunoglobulin G (IgG) titre of 1:8 for T. vaginalis. Purified IgG, at 1.6 mg/ml, showed no direct opsonizing or lytic effect on this organism. Formalin-fixed trichomonads opsonized by C2 deficient human serum promote 4 times more neutrophil chemiluminescence than those opsonized by Factor B deficient human serum. With the addition of purified IgG (5 mg/ml) neutrophil chemiluminescence was increased by 4 times and further improved trichomonal killing by neutrophils (from 5 +/- 4% to 78 +/- 16%) via activation of the classical complement pathway, but did not alter that due to activation of the alternative complement pathway. These studies indicate that both an IgG-enhanced classical complement pathway activation and an antibody-independent alternative complement pathway activation provide opsonin (C3) for T. vaginalis to facilitate the neutrophil killing mechanism.

Adult↗
PubMed1984

Serum sensitivity of Neisseria gonorrhoeae: the role of lipopolysaccharide.

A lipopolysaccharide (LPS) mutant (FA5100) of a serum-resistant strain of Neisseria gonorrhoeae (FA19) was found to be highly sensitive to the bactericidal activity of normal human serum (NHS). Both strain FA5100 and an unrelated serum-sensitive clinical isolate (F62) were killed by NHS via the classical complement pathway since killing required C2 and Ca++. However, the fact that only strain FA5100 was sensitive to human hypogammaglobulinemic and cord serum suggested that this strain might activate the classical complement pathway in the absence of antibody. Anticomplementary concentrations of LPS from strain FA5100 inhibited the bactericidal activity of NHS against either strain FA5100 or strain F62. However, concentrations of LPS from strain FA5100 that exhibited marginal anticomplementary behavior also inhibited the killing of strain F62 by NHS. The ability of LPS from strain FA5100 to inhibit the bactericidal activity of NHS against strain FA5100 and to activate complement was reduced by treatment with mild alkali. However, alkali-treated LPS from strain FA5100 still inhibited the bactericidal activity of NHS against strain F62.

Agammaglobulinemia↗