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PubMedDate not supplied

The complement system in host defense and inflammation.

In this discussion I have reviewed the major role of complement in host defense and inflammation. In addition, I have discussed dificiency states. Although these are rare, their clinical signs and symptoms can be predicted, at least in part, on the basis of our current understanding of the biological activities of complement and the various pathways of complement activation. This is not to say that complement plays no role in a wide variety of other illnesses. However, when complement plays a role in an illness, often this is not because it is functioning in an aberrant fashion. The usual situation is that complement is being activated and is serving its normal function in causing inflammation and damage to tissues under abnormal circumstances. Thus, for example, circulating antigen complexes may be deposited in the kidney, activate complement, and mediate tissue inflammation. In this case, complement is functioning normally but is being activated under abnormal circumstances. The same type of analysis can be made for many diseases of many different organ systems. At present, we have no drugs that are effective in humans in controlling the activation of complement and complement-mediated inflammation. We have not yet even established whether local variations in the activity of complement may affect the course of a clinical infection, but there is certainly strongly suggestive evidence to support this idea. It should be clear that under certain circumstances complement may well be a major factor in controlling the course of an infection. The near future should bring a vast expansion in our understanding of how complement contributes to specific clinical illnesses and to the defense of the host against specific microorganisms.

Angioedema↗
PubMed1981

Cleavage of C3 by neutral proteases from granulocytes in pleural empyema.

The possibility of direct inactivation of C3 by granular enzymes from polymorphonuclear leukocytes (PMNLs) in pleural empyema was examined. As a group, pleural empyema from 10 patients with purulent effusions and a positive bacteriologic culture cleaved significantly more 125I-labeled C3 bound to Sepharose (18.4% +/- 7.3%) than did 19 sterile pleural effusions (2.4% +/- 0.9%; P less than 0.001) and sonicates from bacterial strains commonly found in empyema (1.4% +/- 0.2%). Granular enzymes from 7 X 10(6) PMNLs cleaved 78.5% of 125I-labeled C3 bound to Sepharose. When proteolysis of 125I-labeled C3 after incubation with pleural empyema or PMNL granular enzymes was examined with polyacrylamide gel electrophoresis, breakdown products were similar. Granulocyte elastase-like activity was detected in four samples of pleural empyema. Granulocyte elastase inhibitors, as well as 10% human serum, effectively suppressed cleavage of C3 and elastase-like activity. In pleural empyemas, granula enzymes from PMNLs, especially elastase, apparently contribute to low complement-mediated opsonic activity by direct inactivation of C3.

Adult↗
PubMed1984

Isolation and characterization of rabbit H of the alternative complement pathway.

Rabbit factor H, a control protein of the alternative complement pathway, was isolated from rabbit serum by polyethylene glycol precipitation, DEAE-Sephacel chromatography, and gel chromatography on Sephadex G200. The protein migrated as a single-chain polypeptide with a molecular weight of 160,000 on sodium dodecyl sulfate-gel electrophoresis with Laemmli's buffer system, but hardly migrated into the gel with Fairbanks' buffer system. Physical and chemical properties of rabbit H were similar to those of human H, except that fragments produced by limited tryptic digestion from rabbit H had different molecular sizes from those produced from human H. Significant species-specificity was observed in the functional activity of factor H; activation of the alternative complement pathway was inhibited more efficiently with homologous H than with heterologous H. In contrast, factor H inhibited the hemolysis of homologous erythrocytes less than that of heterologous erythrocytes.

Amino Acids↗
PubMed1991

Role for specific complement phenotypes and deficiencies in the clinical expression of IgA nephropathy.

IgA nephropathy, the most commonly occurring type of chronic glomerulonephritis in individuals of European and Asian descent, exhibits marked heterogeneity of clinical signs and ultimate prognosis. Based upon their studies of regional clustering of the ancestors of related patients in eastern Kentucky, the authors have postulated the existence of an inherited disease susceptibility for IgA nephropathy. They examined serum concentrations of individual complement proteins and phenotypes for C3, C4A, C4B, and factor B (Bf) for related and unrelated patients with IgA nephropathy from Kentucky and for patients from the Mid-South region of Tennessee, Mississippi, and Alabama. In these populations, they have described partial complement deficiencies or specific phenotypes which may be associated with the disease. Their findings include the following: (1) partial deficiencies for C2, beta 1H (H), properdin (P), or C4 binding protein (C4BP) in four patients with end-stage renal disease, (2) an association between the C3*F allele with IgA nephropathy in the combined group of unrelated patients from Kentucky and the Mid-South, (3) the occurrence of C4B deficiency in two siblings with IgA nephropathy, and (4) an association between C4A deficiency and poor outcome in patients with IgA nephropathy diagnosed as adults. In addition, the related patients differ from the unrelated patients from Kentucky with respect to frequencies of Bf*F and the BfF (FF + FS + F1F + F1S) phenotype, suggestive of immunogenetic difference between these groups. Important functional differences exist between C4A and C4B isotypes and functional differences are also possible based upon C3 or Bf phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)

Carrier Proteins↗
PubMed1990

Genetic polymorphism of complement factor H in cattle.

Bovine factor H was found to be polymorphic by the combined techniques of SDS-polyacrylamide electrophoresis of bovine plasma and immunoblotting. Three phenotypes (S, SF, F) were identified in a sample population of 149 cattle. Variant S and F differed by an apparent molecular weight of 5000 daltons. Family studies demonstrated Mendelian segregation of variants S and F. The data indicate that these genetic variants of bovine factor H are encoded by two codominant alleles at a single autosomal locus.

Alleles↗
PubMed1990

Peptide inhibitors of C3 breakdown.

We have investigated the development of substrate-based inhibitors of complement enzymes. Sequences around the scissile Arg77-Ser78 bond of C3 have been synthesized and tested as inhibitors of C3 convertase. The best inhibition was found with the tetrapeptide Ac-Arg-Ser-Asn-Leu-OH (H-576); extending this sequence in either direction reduced inhibitory activity. Preliminary experiments with peptides in which the scissile bond--CO--NH--was replaced with non-hydrolysable moieties such as--CO--CH2--(H-497) and--CH2--NH--(H-336) failed to show enhanced inhibition. One of the longer chain inhibitors H-416 containing DArg77-Ser78 was unexpectedly found to potentiate iC3 cleavage by factors I and H but did not inhibit the intact alternative pathway. The same peptide also bound to factor H. It is concluded that the binding requirements of the C3 convertase are more sophisticated than can be satisfactorily imitated simply by linear sequences around the scissile bond of C3.

Complement Activating Enzymes↗
PubMed1991

Anti-inflammatory and immunosuppressive effects of recombinant soluble complement receptors.

CR1 and CR2 have served as unusual probes for the analysis of the two major functions of the immune system involving inflammation and the immune response, respectively. CR1, or some construct containing its active site SCRs, may find a role in the therapy of complement-dependent tissue injury, and may be used to define which diseases are caused by the inappropriate or excessive activation of this system. Although soluble forms of CR2 may be shown to have potential clinical utility when foreign antigen is given prospectively, as in monoclonal antibody therapy, perhaps the most important finding emanating from the analysis of this receptor is the recognition of a previously unrecognized membrane protein complex whose role in B cell development is yet to be determined. It is reasonable to predict that the function of the CD19 complex will be significant as it serves as the link between two evolutionarily distinct systems that share a common purpose of anti-microbial host defense.

Animals↗
PubMed1988

The surfaces of the parasitic nematodes Trichinella spiralis and Toxocara canis differ in the binding of post-C3 components of human complement by the alternative pathway.

The binding of human complement components C3, C5 and C9 to the surface of the infective larvae of the nematode parasites Toxocara canis and Trichinella spiralis, by the alternative pathway, was examined by direct and indirect immunofluorescence on the intact parasites. This showed that although C3 bound to both nematodes, they differed markedly in the binding of C5 and C9; C5 bound only minimally to T. spiralis, and C9 binding to this parasite was barely detectable. In contrast, both early and late components bound to T. canis to a high density, comparable to, or in excess of, the binding of these components to the infective larvae of the trematode Schistosoma mansoni. The lack of binding of the post-C3 components to T. spiralis did not correlate with enhanced binding of the control protein, Factor H.

Animals↗
PubMed1989

Hereditary, complete deficiency of complement factor H associated with recurrent meningococcal disease.

Complement factor H (beta-1H globulin) is an important regulatory protein which inhibits the spontaneous complement activation via the alternative pathway. We describe a 15-year-old girl without any detectable factor H in plasma. She has had two episodes of meningococcal disease, but is otherwise completely healthy. Secondary to the factor-H deficiency, the levels of factor B, properdin, C3, and C5-C9 were strongly reduced due to spontaneous in vivo activation of the alternative complement pathway. Plasma C3dg was strongly elevated in spite of the factor-H deficiency; apparently erythrocyte CR1 substitutes for factor H in C3 degradation. Neither C3 nor complement lesions were demonstrable on her erythrocytes which did, however, show increased, spontaneous haemolysis in vitro in citrate plasma, but not in serum. The patient is a single child and her parents, who are unrelated and healthy, had half-normal levels of factor H. This reduction of factor H is sufficient to cause increased, spontaneous activation of the alternative pathway.

Antibodies, Bacterial↗
PubMed1991

Human complement factor H. Tissue specificity in the expression of three different mRNA species.

Using cDNA clones H-19 and H-46, we have shown previously that three different mRNA species (4.3 kb, 1.8 kb and 1.4 kb) for complement factor H are expressed constitutively in human liver. Here we report data suggesting that the expression of these different factor-H mRNA species is regulated by tissue-specific control mechanisms. Total RNA and poly(A)-enriched RNA from various human tissues (heart, lung, temporal cortex, kidney, spleen, bone marrow and muscle) various cell lines (HepG2, HepG3, HepG4, Hep3B, H-4, Jurkat, Molt4, H-9, KHos24Os, A-431, U937, Mono Mac 6 and Raji) and from primary cultures of peripheral blood monocytes, fibroblasts and human umbilical vein endothelial cells (HUVEC) were investigated for the expression of factor-H mRNA. In RNA preparations from extrahepatic tissue, factor-H mRNA was only detected in biopsies from the lung. Using 20 micrograms total RNA isolated from all 13 cell lines it was not possible to detect any factor-H mRNA, while mRNA for factor H was expressed in monocytes, HUVEC and fibroblasts. When expressed in extrahepatic tissues, only the 4.3-kb and the 1.8-kb mRNA species were detected, while the 1.4-kb mRNA is expressed abundantly in liver. Interferon-gamma did not induce the expression of factor-H mRNA in any of the cell lines tested. On the other hand, tumour necrosis factor-alpha induced the expression of the 4.3-kb mRNA species in U937 cells. In HUVEC and fibroblasts the relative quantities of the 4.3-kb and the 1.8-kb mRNA species and the regulatory effects of interferon-gamma, interleukin-1, dexamethasone and retinoic acid on their expression showed significant tissue specificity.

Blotting, Northern↗
PubMed1982

Double immunofluorescence studies of immunoglobulins, complement components and their control proteins in patients with IgA nephropathy.

A study on double immunofluorescent staining of immunoglobulins, complement components, and their control proteins in renal tissues from patients with IgA nephropathy is described. Renal biopsy specimens were obtained from patients with IgA nephropathy. These biopsy specimens were stained with anti sera to human C1q, C4-binding protein, and beta 1H globulin by indirect immunofluorescent staining. These samples were then stained with rhodamine-conjugated anti human IgG, IgM, and IgA. Although C1q and C4-binding protein do not combine with IgA, they ubiquitously combine with IgG and/or IgM. beta 1H globulin also combine with IgG, IgM and/or IgA. It was demonstrated that the complement system activated in IgA nephropathy was via both alternative and classical pathways. The presence of C4-binding protein in glomeruli appeared to be a more sensitive indicator of classical pathway activation than the presence of C4.

Carrier Proteins↗
PubMed1988

Complement factors in fetal and maternal blood and amniotic fluid during the second trimester of normal pregnancy.

Complement factors (C3, C4, C5; Factors B, H and I) were measured in maternal and fetal serum and amniotic fluid obtained from 55 women with singleton pregnancy undergoing diagnostic fetoscopy at 15 to 28 weeks gestation. Maternal serum levels were consistently 10 times higher than fetal levels which in turn were 10 times higher than levels in amniotic fluid. Spearman rank correlation analysis at weeks 20 to 22 (n = 20) revealed a statistically significant correlation between maternal and fetal levels of C3 and Factors B and I, and between maternal and amniotic fluid levels of Factors B and I. A significant increase in fetal levels of C3, C4 and Factor H, and in amniotic fluid levels of C3 and Factor B was seen in relation to advancing gestational age. These differences were not seen in maternal serum during the short interval of pregnancy studied. These data confirm earlier assumptions of fetal synthesis of complement factors, and provide normal reference ranges of complement factors in fetal blood and amniotic fluid.

Amniotic Fluid↗