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At least 919 records · Page 51Linked to original sources
PubMed1999

Preparation of fcgamma for addition to sulfhydryl-expressing ligands with minimal disturbance of the hinge.

We described previously a scheme for linking functionally intact human normal Fcgamma1, via a thioether linkage emerging from its hinge, to any molecule expressing a free sulfhydryl group (SH). The scheme entails reducing the Fc to release four SH from the two inter-gamma disulfide bonds (SS) in the hinge, blocking one SH by a stochastic alkylation, restoring by SS-interchange the inter-gamma SS whose two SH are still available, and attaching a bismaleimide linker to the one remaining SH. One thereby obtains Fc with a single maleimide group (Fc-maleimide) for attachment to the SH-displaying partner. Restoration of the inter-gamma SS is necessary if the final chimeric construct is to be able to activate the classical complement pathway. However, during this preparation of Fc-maleimide, there is apparently some SS-formation between non-homologous SH, so that not all hinges emerge with a reconstituted inter-gamma SS. To reduce this error we have modified the preparative procedure after investigating an initial partial reduction of the hinge, and reviewing the conditions for stochastic alkylation. During partial reduction by dithiothreitol, the two hinge SS were cleaved apparently randomly: there was no evidence for one bond being more susceptible to reduction than the other, and little indication that the reduction of one bond enhanced the susceptibility of the other. By limiting reduction to an average of one SS per molecule, and alkylation to 0.8 SH per molecule, a final Fc-maleimide product is obtained in which most of the molecules have passed through the entire preparation with one of their hinge SS, and by inference much of the hinge conformation, remaining intact.

Humans↗
PubMed1984

Restoration of complement function in vivo by plasma infusion in factor I (C3b inactivator) deficiency.

The serum complement activities of a 1-year-old infant with recurrent life-threatening bacterial infections and persistent C3-Coombs-positive red blood cells were investigated. The patient's serum had a depressed serum level of CH50, C3, factor B, and factor H as well as undetectable antigenic or functional factor I. The complement profile of the parents was normal, with the exception of factor I, which was approximately 50% of normal in each parent. The Coombs positivity of the patient's red blood cells could be reversed in vitro by incubation with normal serum containing factor I. Infusion of normal plasma into the patient resulted in increased levels of CH50, with concomitant increases in serum C3, factor B, and factor H levels. The patient's red blood cells became transiently Coombs negative. At no time after plasma infusion was factor I detectable in the patient's serum. All complement functions and the C3 Coombs reactivity of the patient's red blood cells returned to preinfusion levels within 14 days. These findings are consistent with an inherited deficiency of factor I and emphasize the critical role this protein plays in the regulation of the alternative complement pathway. Plasma therapy may be an adjunct to the management of acute infection in patients with factor I deficiency.

Afibrinogenemia↗
PubMed1986

Human surfactant treatment of severe respiratory distress syndrome: pulmonary effluent indicators of lung inflammation.

Pulmonary effluent from infants who received exogenous human surfactant for severe respiratory distress syndrome was evaluated for inflammatory changes previously identified with lung injury during the first 2 weeks after birth. The number of pulmonary effluent inflammatory cells was higher only on day 1 in infants given surfactant. No other evidence of enhanced inflammation was detected in cytologic assessment of tracheal secretions. The classical pathway of complement was not activated in infants given surfactant or in control infants 2 weeks after birth. Albumin content of airway secretions was higher on the first day but not significantly altered on subsequent days. Human surfactant treatment was not associated with increased proteolytic activity, measured as neutrophilic elastase per milligram of albumin in lung effluent, but was associated with significantly higher alpha 1-proteinase inhibitor levels than in control infants from days 2 to 7 after birth. These findings provide evidence that exogenous human surfactant instilled into the lungs of preterm infants with severe respiratory distress syndrome is not associated with enhanced lung inflammation, compared with conventional mechanical ventilation alone. These data support additional clinical trials using human surfactant.

Albumins↗
PubMed2000

Complement deficiencies.

The complement proteins play an important role in innate immunity, promoting inflammation and microbial killing. They play a role in the adaptive immune response, as well. Inherited total deficiencies of complement proteins are extremely rare. Table 1 lists more than 40 proteins that comprise the elements of the complement system. Deficiency of the proteins that promote lysis and opsonization is so rare that two papers are able to list all the observed cases to 1991. The exception is mannan-binding lectin, in which deficiency may be commoner. Diseases of regulatory proteins, such as occurs in hereditary angioedema or paroxysmal nocturnal hemoglobinuria, are commoner but still are quite rare. As we learn more about complement proteins and their mechanism of action, we will understand more clearly how these proteins function. Polymorphisms of the proteins exists. Learning how these polymorphisms contribute to the development of disease will be the focus of complement studies in the next decade.

Child↗
PubMed1980

Autoimmune hemolytic anemia.

In autoimmune hemolytic anemia, individuals produce antibodies directed against one of their own erythrocyte membrane antigens. The hemolysis in autoimmune hemolytic anemia is most commonly extravascular rather than intravascular, and the liver and spleen play a major role in the clearance of the antibody-coated cells. The importance of complement in the destruction of IgM-coated cells has also been recognized.

Adolescent↗
PubMed1980

Laboratory aspects of immune deficiency in children.

The pediatrician confronted with a patient who may have a host defense abnormality often has at his disposal the tools to properly evaluate such an individual. Utilizing the simple screening tests listed in Table 3, all of the major arms of the immune system can be evaluated. If the history is not a strong one for immune deficiency and the screening tests are normal, then a thorough explanation of the normal patient with recurrent infections should be made and the patient simply observed for the development of more severe problems. Abnormal screening evaluations, or a suggestive history, usually indicates the need for referral to an immunologic center where more complicated tests of immune function can be made. Although curative therapy has not been developed for most immune deficiency diseases, definition of the patient's specific defect with appropriate laboratory tests leads to more informed genetic counselling, more appropriate therapy, and a better overall prognosis. Furthermore, only through the collection and study of such patients will successful therapeutic regimens be developed for severe immune deficiency disease.

Agammaglobulinemia↗
PubMed2003

Dose-dependent inhibition of complement in baboons by vaccinia virus complement control protein: implications in xenotransplantation.

Vaccinia virus complement control protein (VCP) is a potent inhibitor of both the alternative and the classical complement pathways through its binding to activated third and fourth components. In addition to its complement inhibiting abilities, VCP can bind heparan sulfate on cell surfaces, resulting in further functional activities. Altogether, the multiple functions of VCP have been shown to reduce the inflammatory response of the host, helping the vaccinia virus to evade immune destruction. Recently, we reported that VCP is able to block hyperacute xenograft rejection, significantly prolonging graft survival in two separate in vivo heterotopic cervical cardiac xenograft models. Histopathological examination of the transplanted hearts receiving VCP revealed marked VCP deposition on the endothelium, a significant reduction in cardiac tissue damage, and significantly less C3, IgG and IgM deposition in the tissue. It is concluded that VCP may inhibit hyperacute xenorejection by binding to the endothelial surface, blocking complement fixation activation, thereby preventing xenoantibody attachment. In the current study, the level of serum complement inhibition was evaluated following different bolus dosages of VCP in baboons. The results indicated that to achieve a satisfactory level of complement inhibition higher doses of VCP are needed in baboons, than previously observed in rats. The current observations are critical for future assessment of the role of VCP to suppress hyperacute rejection following pig-to-baboon xenotransplantation.

Animals↗
PubMed1989

Complement deficiencies in patients over ten years old with meningococcal disease due to uncommon serogroups.

46 patients in whom meningococcal disease due to serogroups X, Y, Z, W135, or 29E had developed after the age of 10 years were investigated retrospectively for complement deficiency. Complement deficiency was found in half of the patients: properdin deficiency in 9 patients, C3 deficiency syndromes in 5, and homozygous deficiency of a terminal component (C5, C6, C7, or C8) in 9. Meningococcal infections recurred in 5 of the 9 patients with terminal complement component deficiencies but not in the other complement-deficient patients. The findings show that meningococcal disease due to uncommon serogroups is often associated with complement deficiency.

Adolescent↗
PubMedDate not supplied

Echinoderm immunity and the evolution of the complement system.

Our understanding of inflammatory responses in humans has its roots in the comparative approach to immunology. In the late 1900s, research on echinoderms provided the initial evidence for the importance of phagocytic cells in reactions to foreign material. Studies of allograft rejection kinetics have shown that echinoderms have a non-adaptive, activation type of immune response. Coelomocytes mediate the cellular responses to immune challenges through phagocytosis, encapsulation, cytotoxicity, and the production of antimicrobial agents. In addition, a variety of humoral factors found in the coelomic fluid, including lectins, agglutinins, and lysins, are important in host defense against pathogens and other foreign substances. Recently, a simple complement system has been identified in the purple sea urchin that is homologous to the alternative pathway in vertebrates. The sea urchin [corrected] homologue of C3, is inducible by challenge with lipopolysaccharide, which is known to activate coelomocytes. Complement components have been identified in all vertebrate classes, and now have been characterized in protochordates and echinoderms indicating the primordial nature of the complement system. Because it is thought that the complement system evolved from a few primordial genes by gene duplication and divergence, the origin of this system appears to have occurred within the common ancestor of the deuterostomes.

Animals↗
PubMed2001

Origin of bovine IgM structural variants.

The structure of IgM determined from two cDNAs isolated from a Holstein (BLV7G1) and an Angus x Hereford cross-bred (B5D8) cow reveals high sequence similarity both at nucleotide (98.7%) and amino acid (97.9%) level and is closest to sheep (89.4%). Three bovine IgM allotypes, designated as IgMa, IgMb and IgMc, are classified based on nucleotide substitutions in all the Cmu exons resulting in amino acid replacements. Further, insertion of three in-frame codons at Cmu1 and Cmu2 junction of B5D8 IgM from the intervening intron, via cleavage of pre-mRNA at an alternate cryptic 5' splice donor site, leads to generation of additional bovine IgM variants. The C1q-binding site, involved in classical complement pathway, is identified in bovine IgM where ten amino acids are conserved across species. Interestingly, bovine IgM has the lowest number of proline residues (5) in the Cmu2 domain in comparison to other species (7-9) and this is likely to impose structural constraints on mobility of Fab arms of the bovine IgM during antigen recognition. The rigidity in the bovine IgM Cmu2 domain may, however, facilitate exposure of C1q-binding site subsequent to antigen binding and enhance its complement fixing ability. The restricted mobility of bovine IgM Fab arms may possibly favor generation of an antigen-combining site requiring an unusually long third complementarity determining region of the heavy chain (CDR3H), apart from antigen selection of variable domains. This is consistent with the fact that an exceptionally long CDR3H has not been observed in bovine IgG which bears a long and more flexible hinge region. Additional hydrophilic threonine and serine residues in the Cmu2 domain of bovine IgM, as compared to other species, however, enhance its ability to extend into the solvent. Finally, restricted fragment length polymorphism analysis of genomic DNA from four cattle breeds reveals the presence of; at least, four allelic variants of bovine Cmu gene.

Amino Acid Sequence↗
PubMed1997

Binding of complement component Clq to myelin oligodendrocyte glycoprotein: a novel mechanism for regulating CNS inflammation.

Myelin oligodendrocyte glycoprotein (MOG) is a myelin-specific protein restricted to the central nervous system (CNS). While MOG is considered a putative autoantigen in MS, its function(s) in myelin is unknown. As CNS myelin is able to activate the classical complement pathway, it must contain a Clq-binding/activating protein but the identity of this protein has not been reported. The data in this paper clearly demonstrate that MOG specifically binds Clq in a dose-dependent and saturating manner. This calcium-dependent interaction is mediated by the extracellular immunoglobulin-like domain of MOG. This MOG domain contains an amino acid motif similar to the core Clq-binding sequence previously identified in IgG antibodies. Purified MOG also inhibited the antibody-dependent lysis of RBC by complement. Taken together, these results demonstrate that MOG binds Clq near the IgG binding site and may be the protein responsible for complement activation in myelin. This direct interaction between a myelin-specific protein and Clq has significant implications for CNS inflammation and could be particularly important in demyelinating diseases such as multiple sclerosis.

Animals↗
PubMed2000

C3 activation is inhibited by analogs of compstatin but not by serine protease inhibitors or peptidyl alpha-ketoheterocycles.

C3 convertase is a key enzyme in the complement cascade and is an attractive therapeutic target for drug design. Recent studies have demonstrated that this enzyme is inhibited by compstatin (Morikis, D. , Assa-Munt, N., Sahu, A., Lambris, J.D., 1998. Solution structure of Compstatin, a potent complement inhibitor. Protein Sci. (7) 619-627; Sahu, A., Kay, B.K., Lambris, J.D., 1996. Inhibition of human complement by a C3-binding peptide isolated from a phage-displayed random peptide library. J. Immunol. (157) 884-891), a 13 amino acid cyclic peptide that binds to C3. Since the enzyme exhibits some homology to serine proteases, substrate-based design could be another avenue for drug design. In this study, we confirm the activity of compstatin using different sources of enzyme and different assay systems. We also tested the activity of substituted compstatin analogs and compared the selectivity and toxicity of these compounds to peptidyl alpha-ketoheterocyclic compounds. Our work confirms the activity of compstatin in both alternative and classical complement pathways, describes 11 new active analogs of this cyclic peptide, and provides evidence for key segments of the peptide for activity. Compstatin and related active analogs showed little or no inhibition of clotting or key enzymes in the clotting cascade nor did they appear to have significant cytotoxicity. The characteristics of compstatin suggest that this peptide and its analogs could be attractive candidates for further clinical development. By contrast, known serine protease inhibitors, including peptidyl alpha-ketoheterocycles, did not inhibit C3 convertase illustrating the atypical nature of this enzyme.

Complement Activation↗
PubMed1999

Regulation of complement activation by C-reactive protein.

C-reactive protein (CRP) is an acute-phase serum protein and a mediator of innate immunity. CRP binds to microbial polysaccharides and to ligands exposed on damaged cells. Binding of CRP to these substrates activates the classical complement pathway leading to their uptake by phagocytic cells. Complement activation by CRP is restricted to C1, C4, C2 and C3 with little consumption of C5-9. Surface bound CRP reduces deposition of and generation of C5b-9 by the alternative pathway and deposition of C3b and lysis by the lectin pathway. These activities of CRP are the result of recruitment of factor H resulting in regulation of C3b on bacteria or erythrocytes. Evidence is presented for direct binding of H to CRP. H binding to CRP or C3b immobilized on microtiter wells was demonstrated by ELISA. Attachment of CRP to a surface was required for H binding. H binding to CRP was not inhibited by EDTA or phosphocholine, which inhibit ligand binding, but was inhibited by a 13 amino acid CRP peptide. The peptide sequence was identical to the region of CRP that showed the best alignment to H binding peptides from Streptococcus pyogenes (M6) and Neisseria gonorrhoeae (Por1A). The results suggest that CRP bound to a surface provides secondary binding sites for H resulting in greater regulation of alternative pathway amplification and C5 convertases. Complement activation by CRP may help limit the inflammatory response by providing opsonization with minimal generation of C5a and C5b-9.

Amino Acid Sequence↗