Henry Gewurz
Rush Medical College
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Current Opinion in Immunology | 1995
Henry Gewurz; Xiao-Hui Zhang; Thomas F. Lint
Over the past two years, the three-dimensional structure of the serum amyloid P component was defined by X-ray diffraction, the first such visualization of a pentraxin. Binding sites for calcium, ligands and complement were identified. New fusion proteins with amino acid sequence homology to the pentraxins were described, and new insights were gained into pentraxin phylogeny, biosynthesis, ligands, complement activation, leukocyte reactivity and biological functions in vivo.
Immunopharmacology | 1999
Carolyn Mold; Henry Gewurz; Terry W. Du Clos
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.
Molecular Immunology | 1987
Lawrence A. Potempa; Joan N. Siegel; Barry A. Fedel; Rita T. Potempa; Henry Gewurz
It has previously been reported that human C-reactive protein (CRP) can exist in at least two molecular conformations distinguished by antigenic, electrophoretic and ligand-binding reactivities. In the present study we describe the formation, detection and distinctiveness of a conformation expressing a CRP neoantigen (neo-CRP), and report that this form is characteristic in vitro of a free CRP subunit. Soluble native-CRP was found to express neo-CRP antigenicity upon treatment with acid; upon urea-chelation or heating in the absence of calcium; and upon adsorption onto uncoated polystyrene plates. Native-CRP bound by capture ELISA to phosphorylcholine-containing ligand or anti-native-CRP did not express neo-CRP antigenicity, suggesting that PC ligand- or antibody binding is not sufficient to induce expression of the neoantigen. Human CRP which expressed neo-CRP antigenicity had limited solubility and tended to aggregate in buffers of ionic strength 0.15, but remained soluble when the ionic strength was reduced to 0.015. Soluble urea-chelated or acid-treated CRP molecules expressing neo-CRP antigenicity chromatographed and electrophoresed as a single protein with a Mr of approx. 22,000, indicating that the CRP neoantigen can be expressed on free CRP subunits and this expression need not require proteolysis. Further, molecules expressing neo-CRP antigenicity were detected in the plasma of patients with rheumatoid arthritis. The identification and characterization of this CRP neoantigen should serve as a useful marker in studies of CRP subunits and biologically relevant forms of CRP, and should contribute to the elucidation of the role of CRP in the acute inflammatory response.
Molecular Immunology | 1983
Lawrence A. Potempa; Brian A. Maldonado; Philippe Laurent; Edward S. Zemel; Henry Gewurz
C-Reactive protein (CRP) is a trace component of normal human serum which has a mol. wt of 105,000 and is composed of five apparently identical subunits arranged in cyclic symmetry. The serum concentration of this protein is known to increase dramatically in response to acute inflammatory or necrotic processes. We report here that in the presence of high concentrations of urea significant antigenic, electrophoretic and binding site modifications of CRP occur selectively in the absence of calcium. CRP treated in this way (designated F-CRP) had a pI of 5.4 and alpha-electrophoretic mobility in contrast to the native molecule which had a pI of 6.4 and gamma-mobility. F-CRP retained a partial antigenic identity to native CRP, displayed decreased intrinsic tryptophan fluorescence, and expressed a new antigenic reactivity. A similar neoantigen was expressed by heating CRP selectively in the absence if calcium (63 degrees C, 5 min). Treatment with guanidinium-HCl or deliberate carbamylation did not produce F-CRP or the expression of the F-antigen. The formation of F-CRP in urea or by heat was prevented by the presence of 0.7 mM or more calcium. CRP treated in this way retained identical characteristics to native CRP. F-CRP chromatographed through Sephadex G-150 in the presence or absence of 6M urea as a protein of apparent mol. wt 75, 000 with no evidence for free CRP subunits. The formation of F-CRP from native CRP resulted in a loss of capacity for calcium-dependent binding to the C-polysaccharide despite the persistence of calcium-independent binding reactivity for polycations. These data suggest that in the presence of sufficient calcium CRP can resist urea- or heat-induced structural denaturation, maintaining antigenic, electrophoretic and binding identity to the native molecule. In the absence of calcium, exposure to urea led to increased electrophoretic mobility and exposure of a new antigenic reactivity, and to alterations in the phosphocholine- but not the polycation-binding sites of the native CRP molecule; this new antigenic reactivity may be of value in further studies on the CRP molecule.
Journal of Immunology | 1976
Richard F. Mortensen; Alexander P. Osmand; Thomas F. Lint; Henry Gewurz
The serum constituent C-reactive protein (CRP), which activates the classical complement (C) pathway when reacting with its substrates, was examined for its ability to mediate reactions of opsonic adherence and phagocytosis. Erythrocytes coated with C-polysaccharide (CPS) and reacted with CRP (E. CPS-CRP) failed to adhere to B cells and displayed only minimal adherence to monocytes. However, upon the addition of absorbed C or purified C components these cells were found to possess the cleavage products C4b and C3b, which in turn resulted in attachment of these cells to both human B lymphocytes and peripheral blood monocytes. E. CPS-CRP treated with C in the absence of antibody were readily phagocytosized by glass-adherent human monocytes. The phagocytosis of E. CPS-CRP-C was not only mediated by CRP but also required the presence of CRP on the surface of the red cells. The extent of ingestion was proportional to the amount of CRP on the red cell intermediate and was reduced by blocking monocyte receptors with aggregated human gamma-globulin (HGG) at concentrations which did not impair the uptake of other particles. The mediation by CRP of reactions of opsonic adherence and phagocytosis as outlined in these studies points to a significant role for CRP in reactions of host defense and inflammation.
The Journal of Pediatrics | 1976
Diasdado Lim; Anita T. Gewurz; Thomas F. Lint; Mohammed Ghaze; Bahram Sepheri; Henry Gewurz
A previously healthy 6-year-old boy who presented with meningococcal meningitis responded favorably to ampicillin, but suffered two and possibly three repeat attacks in the ensuing month. No abnormality of the otolarynx, skin, or neuroskeleton was found. The infecting strain, Neisseria meningitidis, Group Y, Type IV, was sensitive to the therapeutic agents used, and antibiotic levels were adequate. Serum bactericidal antibody titers against autologous meningococci were high. Serum complement hemolytic bactericidal activities, however, were entirely lacking, and this was attributable to a complete deficiency of C6. Measurements of the remaining complement components, C-dependent chemotaxis and opsonization, neutrophil function, specific immunity, and the coagulation system, were normal. The parents had half-normal C6 levels. Recurrence of meningitis in this patient supports the concept that complement plays a role in resistance to certain microorganisms and emphasizes the need for complete evaluation of the complement system in individuals with unexplained repeated infections.
The Journal of Pediatrics | 1977
Stephen G. Osofsky; Barry H. Thompson; Thomas F. Lint; Henry Gewurz
A previously well 34-month-old male presenting with fever, skin rash, and arthralgias was found to lack C3 by immunochemical (undetectable) and hemolytic (1% normal) assays. No infectious agent could be demonstrated. Protein levels of Clq. C4, C5, properdin, and C3b-INA and hemolytic activities of complement components C1 to C9 except C3 were normal or elevated; total hemolytic complement activity was 13% of normal and was reconstituted by purified C3. Properdin factor B was 702 (normal 175 to 275) mug/ml, and was not cleaver upon addition of zymosan or cobra venom factor. The serum had normal immune adherence activity, but was deficient in ability to opsonize Candida albicans for uptake and Escherichia coli for killing by neurophils, generate neutrophil chemotactic factors and inhibit the growth of E. coli; these activities were restored by purified C3. A transfusion of 320 ml 1-hour-old normal whole blood on the fifty-second day resulted in transitory elevation of the C3 level to 25 mg/dl with a fall-off (approximately 2 1/2% per hour) to undetectable levels by 69 hours; it was followed by disappearance of the skin rash and arthralgias and return to normal of the previously elevated temperature and CRP levels. C3 levels in family members (seven of 24 half-normal), lack of anti-C3 activity, normal C3b-INA levels and a normal rate of catabolism of transfused C3 indicated that the deficiency was inherited with autosomal codominance and involved decreased synthesis of C3. Thus, this child is a unique individual with inherited C3 deficiency presenting with absence of repeated infections, whose symptoms of fever, skin rash, and arthralgia were abated by whole blood transfusion.
Annals of the New York Academy of Sciences | 1982
C Mold; Terry W. Du Clos; Shuei Nakayama; Kathryn M. Edwards; Henry Gewurz
In the studies described here we have attempted to evaluate the hypothesis that CRP may function in host defense using two systems in which CRP in the presence of C appears to have opsonic properties. In the first, CRP and C were found to stimulate ingestion of erythrocytes by human monocyte or mouse macrophages in vitro, and to alter clearance patterns in vivo. In the second, we have studied opsonization of S. pneumoniae by CRP and C. Experiments with human neutrophils indicate that although CRP and C can enhance opsonization of S. pneumoniae, this effect is more pronounced in the absence of antibody. In vivo CRP was found to protect mice against intravenous infection with S. pneumoniae.
Hospital Practice | 1982
Henry Gewurz
In the nearly half century since its discovery, interest in CRP has waxed and waned. That interest has now been intensified, both because of recognition that CRP is prototypical of a family of acute phase proteins, including serum amyloid, and because it can now be seen as one of a unique class of proteins that may represent a host defense system that parallels but is distinct from immunologic response.
Clinical and Experimental Immunology | 1998
Chusana Suankratay; Mold C; Yonghong Zhang; Potempa La; Thomas F. Lint; Henry Gewurz
Mannan‐binding lectin (MBL) is an acute‐phase protein which activates complement at the level of C4 and C2. We recently reported that the alternative pathway also is required for haemolysis via this ‘lectin pathway’ in human serum. CRP is another acute‐phase reactant which activates the classical pathway, but CRP also inhibits the alternative pathway on surfaces to which it binds. Since serum levels of both proteins generally increase with inflammation and tissue necrosis, it was of interest to determine the effect of CRP on cytolysis via the lectin pathway. We report here that although CRP increases binding of C4 to MBL‐sensitized erythrocytes, which in turn enhances lectin pathway haemolysis, it inhibits MBL‐initiated cytolysis by its ability to inhibit the alternative pathway. This inhibition is characterized by increased binding of complement control protein H and decreased binding of C3 and C5 to the indicator cells, which in turn is attributable to the presence of CRP. Immunodepletion of H leads to greatly enhanced cytolysis via the lectin pathway, and this cytolysis is no longer inhibited by CRP. These results indicate that CRP regulates MBL‐initiated cytolysis on surfaces to which both proteins bind by modulating alternative pathway recruitment through H, pointing to CRP as a complement regulatory protein, and suggesting a co‐ordinated role for these proteins in complement activation in innate immunity and the acute‐phase response.