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M Mannik

Publications and source records attributed to M Mannik.

At least 55 records · Page 3Linked to original sources
PubMed1988

Hepatic binding of DNA is mediated by a receptor on nonparenchymal cells.

During cell death, nuclear material is released into the cellular environment and into the circulation. Studies in experimental animals have shown that circulating DNA is rapidly removed by the liver and broken down to oligonucleotides. The authors have used a perfused liver system in the mouse to study hepatic binding of single-stranded DNA. DNA binding to the liver was rapid and efficient, and did not require serum factors. Binding was saturable and temperature independent, suggesting a receptor-mediated process. Electron microscope autoradiography demonstrated DNA binding to sinusoidal lining cells, primarily Kupffer cells. In vitro studies with isolated cells confirmed that DNA bound to a trypsin-sensitive receptor on the adherent subset of hepatic nonparenchymal cells. The integrity of the perfused liver was confirmed by the demonstration of appropriate uptake and breakdown of asialoorosomucoid. Despite rapid binding of DNA, however, the perfused liver did not digest DNA or release DNA breakdown products. Infusion of DNAse at intervals after DNA perfusion demonstrated that significant amounts of DNA remained bound to the cell surface, and that serum nucleases were able to cleave this surface bound DNA. It is concluded that DNA binding to the liver is mediated by a receptor on Kupffer cells, but that DNA breakdown may occur at the cell surface or in circulation and may not require cell interiorization.

Animals↗
PubMed1987

Human rheumatoid factors bear the internal image of the Fc binding region of staphylococcal protein A.

The binding specificity of rheumatoid factors (RFs) to human Fc resembles that of some microbial Fc-binding proteins, suggesting conformational similarities in their Fc-binding regions. Using polyclonal chicken antibodies against SPA, we have detected a crossreactive determinant shared by human RFs from different individuals, but not by non-RF IgM and IgG. Chicken anti-SPA was shown to bind to 18 of 19 IgM RFs and 2 of 2 IgG RFs isolated from different individuals. This binding was inhibitable with SPA, fragment D of SPA, human IgG, and Fc fragment of IgG. The binding site for RF was located on the Fab' fragment of chicken anti-SPA. The antigenic mimicry of RFs by a protein of microbial origin suggests that the immune response to infectious agents could induce or modulate RF production through an internal image autoantiidiotype mechanism.

Animals↗
PubMed1987

Immune complexes with cationic antibodies deposit in glomeruli more effectively than cationic antibodies alone.

In previously published studies, highly cationized antibodies alone and in immune complexes bound to glomeruli by charge-charge interaction, but only immune complexes persisted in glomeruli. Because normal IgG does not deposit in glomeruli, studies were conducted to determine whether cationized antibodies can be prepared which deposit in glomeruli when bound to antigen but not when free in circulation. A series of cationized rabbit antiHSA was prepared with the number of added amino groups ranging from 13.3 to 60.2 per antibody molecule. Antibodies alone or in preformed soluble immune complexes, prepared at fivefold or 50-fold antigen excess, were administered to mice. With the injection of a fixed dose of 100 micrograms per mouse, antibodies alone did not deposit in glomeruli with less than 29.6 added amino groups by immunofluorescence microscopy. In contrast, 100 micrograms of antibodies with 23.5 added amino groups in immune complexes, made at fivefold antigen excess, formed immune deposits in glomeruli. With selected preparations of cationized, radiolabeled antibodies, deposition in glomeruli was quantified by isolation of mouse glomeruli. These quantitative data were in good agreement with the results of immunofluorescence microscopy. Immune complexes made at 50-fold antigen excess, containing only small-latticed immune complexes with no more than two antibody molecules per complex, deposited in glomeruli similar to antibodies alone. Selected cationized antibodies alone or in immune complexes were administered to mice in varying doses. In these experiments, glomerular deposition of immune complexes, made at fivefold antigen excess, was detected with five- to 10-fold smaller doses than the deposition of the same antibodies alone. These studies demonstrate that antibody molecules in immune complexes are more likely to deposit in glomeruli by charge-charge interactions than antibodies alone.

Animals↗
PubMed1987

Rheumatoid factors from patients with rheumatoid arthritis possess private repertoires of idiotypes.

Considerable interest has focused on idiotypic cross-reactivity among antibody molecules. Cross-reactive idiotypes (Id) on monoclonal and polyclonal rheumatoid factors (RF) have been found frequently. Sufficient attention has not been directed, however, to the proportion of RF exhibiting the cross-reactivity, leaving the impression of extensive RF cross-reactivity when, in fact, this might represent a small minority of total RF molecules in a given individual. We have examined the polyclonal RF from patients with rheumatoid arthritis (RA) for cross-reactive Id in three different assays and with different Id-anti-Id systems. First, a sensitive liquid-phase radioimmunoassay was used in which panels of sera were tested for inhibition of different, idiotypically unrelated, Id-anti-Id interactions. When compared with normal sera, some of the sera from patients with RA caused minimal inhibition of Id-anti-Id interactions. None, however, caused marked inhibition of any Id-anti-Id system. Secondly, the panels of sera were also tested in a direct binding ELISA to detect partially cross-reactive Id that may not have been identified in the inhibition radioimmunoassay without differing results. Finally, results similar to the autologous Id-anti-Id inhibition assay were also found when the panels of RA sera were tested in two nonautologous Id-anti-Id systems, in which the anti-Id reacted with other than their own Id. These studies indicate that although cross-reactivity with some RF of an individual's total RF population may be seen frequently, an individual's repertoire of RF is itself private, quite diverse, and unique to that individual.

Antibodies, Anti-Idiotypic↗
PubMed1987

Charge-charge interactions between articular cartilage and cationic antibodies, antigens, and immune complexes.

Bovine articular cartilage was used to examine the binding of cationized antibodies, antigens, and immune complexes to articular cartilage by charge-charge interactions. Rabbit antibodies to human serum albumin (anti-HSA) and HSA were cationized to various degrees by the addition of amino groups. When approximately 20 or more new amino groups were added to HSA and approximately 25 or more amino groups were added to anti-HSA, the proteins readily bound to cartilage and penetrated into the matrix. Soluble immune complexes made with the cationic antibodies, including small-latticed complexes, bound only to the surface of the cartilage. When cationic HSA was bound to the matrix of the cartilage, unaltered antibodies bound only to the antigen at the surface and did not penetrate the matrix. This model system defines the manner in which cationic antigens and antibodies bind to and penetrate into the articular cartilage.

Animals↗
PubMed1987

Removal of subepithelial immune complexes with excess unaltered or cationic antigen.

Since cationic molecules are known to pass through the lamina densa of the glomerular basement membrane at higher rates than anionic molecules, the ability of cationic antigen to disperse subepithelial glomerular immune deposits was investigated in rats. Subepithelial glomerular immune deposits were formed in rats by the sequential administration of cationized human serum albumin (HSAED) and purified rabbit antibodies to human serum albumin (HSA). In vitro the addition of fifty-fold excess HSA or HSAED to immune precipitates formed with HSAED and antibodies to human serum albumin (antiHSA) solubilized the precipitates to comparable degree. Excess HSA or HSAED was given intravenously to rats which already had HSAED-antiHSA immune deposits in glomeruli. Serial renal biopsies were obtained and examined. Control animals received saline or nonspecific cationic molecules, protamine sulfate or cationized rabbit serum albumin, without any effect on the persistence of immune deposits in glomeruli. The injection of 10 mg of HSAED caused complete disappearance of glomerular immune deposits by 48 hours. In contrast, 100 mg of HSA was required to achieve the same effect. Thus, cationic antigens are more efficient than anionic antigens in the removal of subepithelial glomerular immune deposits.

Animals↗
PubMed1987

Relationship between renal pathology and the size of circulating immune complexes in patients with systemic lupus erythematosus.

Sera from 35 patients with biopsy-proven diffuse proliferative (WHO class IV) or membranous (WHO class V) lupus nephritis were analyzed for the presence and size of circulating immune complexes. Elevations of the C1q solid-phase assay (C1qSP) for immune complexes were found in sera from all patients with diffuse proliferative nephritis, with a mean +/- 1 SEM of 166.8 +/- 42.0 micrograms/AHG-equivalents/ml serum, and in 71.4% of the patients with membranous nephritis (83.1 +/- 26.7, p = 0.06). Using the WHO criteria for subclasses of membranous lupus nephritis, we also designated renal biopsies as nonproliferative (WHO classes Va and Vb) or proliferative (WHO classes IV and Vc). Employing the latter groupings, we observed significant differences between C1qSP results of patients with nonproliferative (30.3 +/- 8.8) and proliferative (172.8 +/- 36.8, p less than 0.001) lupus nephritis. These data suggest that the presence of C1q-binding material in serum is pathophysiologically related to proliferative glomerular lesions, and that levels of C1qSP binding reflect renal lesions in SLE patients. Sucrose density gradient ultracentrifugation was performed on each serum, and gradient fractions analyzed for C1qSP-binding and total IgG, using techniques to minimize losses of immune complexes. The predominant peak of C1qSP activity sedimented with the 6.6S monomeric IgG. The 6.6S C1q-binding IgG was increased only in 1 of 10 patients with membranous lupus nephritis without proliferative changes, and was elevated in 16 of 25 patients with proliferative lesions (WHO classes IV and Vc). A significant negative correlation was found between the presence of this C1q-binding material and subepithelial electron-dense deposits, suggesting that the presence of this material contributed to the absence of subepithelial immune deposits. Large-molecular-weight C1qSP-binding material was also present, mainly in sera from patients with proliferative lesions. Furthermore, highly positive correlations were found between immune deposits in interstitial blood vessels and peritubular areas, and the concentrations of C1qSP-binding IgG and rapidly sedimenting IgG in density gradient analysis. Overall, these findings are consistent with the hypotheses that circulating immune complexes contribute to the pathogenesis of glomerulonephritis and interstitial nephritis in patients with SLE, and that 6.6S C1q-binding IgG plays a role in the proliferative lesions of lupus glomerulonephritis.

Antigen-Antibody Complex↗
PubMed1987

Mechanisms of tissue deposition of immune complexes.

Immune deposits in renal glomeruli can arise by deposition of circulating immune complexes or by local formation of antigen-antibody complexes. Circulating immune complexes tend to form deposits in the mesangial and subendothelial areas and their size limits their passage through the lamina densa of the glomerular basement membrane. In local immune complex formation endogenous or planted molecules serve as antigens. Subepithelial immune deposits arise mainly by local formation of immune deposits. Charge-charge interactions contribute to planting of antigens in glomeruli or to initial binding of immune complexes to glomeruli. Precipitating antigen-antibody systems are required for retention of immune deposits in glomeruli.

Antigen-Antibody Complex↗
PubMed1987

Identification of the site on IgG Fc for interaction with streptococci of groups A, C and G.

The interaction between living groups A, C and G streptococci and IgG Fc was studied using human IgG, IgG Fc and IgG Fc-intermediate (Fci) fragments, chemically modified human IgG and fragment D of staphylococcal protein A (SPA). Diethylpyrocarbonate modification of His or N-acetylimidazole modification of Tyr of human IgG resulted in the loss of its capacity to inhibit the binding of radiolabelled human IgG Fc to the group A streptococci types M1 and M55, and to the group C strain SC-1, indicating that the amino acids His and Tyr are involved in the binding. Lys seems not to participate in the binding of IgG to these bacteria, however, since reductive methylation of Lys did not reduce its inhibitory capacity. Fragment D of SPA also inhibited the binding of radiolabelled human IgG Fc to strains M1, M55 and SC-1. We have previously shown that these bacteria do not bind to IgG fragments consisting of only the C gamma 2 or C gamma 3 domains. On the basis of these results, and the known relative positions in space of the His and Tyr residues on IgG Fc, it is speculated whether streptococci with IgG Fc receptors, like SPA and rheumatoid factors, interact with IgG in the interface between the C gamma 2 and C gamma 3 domains and involve His 435 and one or more of Tyr 436, His 433 and His 310. The similarities in binding sites on IgG for RFs and these bacterial Fc binding proteins suggest structural similarities between them that may be relevant to the production of rheumatoid factors in rheumatoid arthritis.

Antigen-Antibody Reactions↗
PubMed1987

Clearance kinetics and organ uptake of complement-solubilized immune complexes in mice.

C3-bearing immune complexes were prepared by in vitro solubilization of BSA-anti-BSA complexes at equivalence. Sucrose density gradient analyses showed a size-heterogeneous population of solubilized complexes with a range of 7S to greater than 29S and a peak at around 19S. The presence of C3bi was demonstrated by precipitation with antibodies to C3c and to C3d and by binding to conglutinin. Immune complexes solubilized in two and three times antigen excess were selected as controls due to their size similarities with complement-solubilized complexes. Blood clearance curves were very similar for C3-bearing complexes and controls. At 1 hr, the percentage of injected material remaining in the circulation for complement-solubilized and two and three times antigen excess complexes were 29.5 +/- 1.3, 30.9 +/- 1.7 and 26.1 +/- 2.7, respectively. Uptake by liver accounted for the majority of complement- and antigen-solubilized immune complexes removed from circulation. Although the uptake by the spleen was no more than one-tenth of the liver uptake, more complement-solubilized complexes than antigen-solubilized complexes were removed by this organ. The present data indicate that soluble immune complexes bearing C3 components and soluble immune complexes without C3 components, but of comparable size, are cleared from the circulation of mice at comparable rates. The mechanisms of clearance of these two populations of complexes, however, may differ.

Animals↗
PubMed1986

Only the initial binding of cationic immune complexes to glomerular anionic sites is mediated by charge-charge interactions.

The role of charge-charge interactions between cationic immune complexes and the anionic sites on the glomerular basement membrane was examined. For this purpose, soluble immune complexes at fivefold antigen excess were prepared with human serum albumin and cationized rabbit antibodies to this protein. When unrelated cationic proteins, protamine sulfate or cationized rabbit serum albumin, were given 1 min before the cationized immune complexes, glomerular immune deposits did not form. Cationic immune complexes allowed to deposit in glomeruli could readily be displaced by protamine sulfate or cationized rabbit serum albumin injected 1 min after the immune complexes. If the same cationic molecules were injected 1 hr after the immune complexes, the complexes could not be displaced from glomeruli. In contrast, cationic complexes that were deposited in glomeruli in the presence of a very high degree of antigen excess in circulation to prevent their condensation into larger complexes in glomeruli were readily displaced at 1 min and 1 hr with protamine sulfate or with cationized rabbit serum albumin. On the basis of these results, we concluded that the initial binding of cationic immune complexes to glomeruli occurs by charge-charge interactions. Once the immune complexes in glomeruli condense to larger deposits, forces other than charge-charge interactions are responsible for their retention in glomeruli.

Animals↗
PubMed1986

Interaction between herpes simplex type 1-induced Fc receptor and human and rabbit immunoglobulin G (IgG) domains.

Cells infected with herpes simplex virus type 1 (HSV-1) express a cell surface receptor able to bind to the Fc region of immunoglobulin G (IgG). The ability of HSV-1-infected cells to bind 125I-labelled human and rabbit IgG and IgG fragments was studied to localize the site of interaction to the C gamma 2 or C gamma 3 domains of IgG. 125I-labelled IgG and IgG Fc fragments consisting of C gamma 2 and C gamma 3 domains bound strongly to HSV-infected cells and did not bind to uninfected cells. In contrast, 125I-labelled F(ab')2, Facb [consisting of F(ab')2 and C gamma 2 domains] and pFc' (consisting of C gamma 3 domains) fragments did not bind to any of these cells. Unlabelled IgG and IgG Fc fragments inhibited the interaction between 125I-labelled rabbit IgG Fc and the HSV Fc receptor, whereas F(ab')2, Facb and pFc' fragments failed to inhibit this interaction. These data indicate that the HSV Fc receptor requires both the C gamma 2 and C gamma 3 domains for interaction with the IgG molecule analogous to the known interaction of protein A of Staphylococcus aureus, the Fc binding proteins of Group A, C and G streptococci, and certain human rheumatoid factors.

Animals↗
PubMed1986

Interaction between streptococcal IgG Fc receptors and human and rabbit IgG domains.

Groups A, C and G streptococci were tested for their ability to bind 125I-labelled fragments of human and rabbit IgG in order to localize their sites of interaction with IgG domains. Among the Group A streptococci, strains with IgG Fc receptors bound 85% of the added IgG Fc fragments in the test systems, whereas these strains showed practically no reactivity with F(ab')2, Facb (F(ab')2 + C gamma 2 domains) or pFc' (C gamma 3 domains). The Group C and Group G strains bound 48-100% of IgG Fc, but could also bind up to 36% of the added F(ab')2 in accordance with a previously described 'alternative' Fab reactivity. However, unlabelled IgG F(ab')2 or Facb showed no, or only slight, inhibitory capacity for the binding of 125I-labelled IgG Fc to the C and G strains. Collectively, these results indicate that Groups A, C and G streptococci require both the C gamma 2 and C gamma 3 domains for interaction with IgG, and most probably also bind in the interface region between the C gamma 2 and C gamma 3 domains as has been shown for staphylococcal protein A.

Animals↗
PubMed1985

IgG rheumatoid factors and staphylococcal protein A bind to a common molecular site on IgG.

The antigenic determinant on the Fc region of human IgG for two IgG rheumatoid factors (IgG-RF) from patients with rheumatoid arthritis were investigated in detail. The RF did not interact with IgG fragments that contained the C gamma 2 or C gamma 3 region alone, but required the presence of both regions for binding. The RF binding to solid-phase IgG were poorly inhibited by the IgG3 subclass and strongly inhibited by staphylococcal protein A (SPA) (42 kD), and fragment D of SPA (7 kD), indicating that the binding site is most likely the same as the Ga antigenic determinant described for IgM-RF, and is in the same location as the site on IgG that binds SPA. pH titration studies of the RF binding to IgG indicated the involvement of histidine and lysine or tyrosine side chains. Chemical modification studies showed the histidines were involved on the Fc side of the interactions, and tyrosines were involved on both the antigenic and antibody sides of the interactions. Lysines were not involved. The above information, and the knowledge of the number and position in space of the amino acid residues involved in the C gamma 2-C gamma 3 interface region of IgG, the binding site for SPA, and the amino acid substitutions in IgG3 that account for its inability to bind protein A, allowed the identification of the site on IgG that bind IgG-RF. This binding site involves some of the same amino acid side chains, His 435, Tyr 436, and one or both His 433 and 310, and is in the same location as the site that binds SPA. The same site is likely to be a common antigenic determinant for other RF. Furthermore, the described molecular mimicry suggests a biological relationship between bacterial Fc-binding proteins and the production of RF in rheumatoid arthritis.

Arthritis, Rheumatoid↗
PubMed1985

Selective losses of large immune complexes during density gradient ultracentrifugation and an approach for prevention of these losses.

Substantial amounts (12.3-40.0%) of model immune complexes became nonspecifically adsorbed to centrifuge tubes during sucrose density gradient ultracentrifugation, and the adsorbed complexes were therefore unavailable for subsequent detection by the C1q solid-phase assay. The adsorption was greater for heavier immune complexes; thus detection of large-latticed complexes was impaired more than detection of small-latticed complexes. Loss of complexes could be prevented by incorporation of 0.05% polyoxyethylene (20) sorbitan monolaurate (Tween 20) into sucrose density gradient solutions and precoating tubes with gelatin. Tween 20 did not alter the immune complex lattice and did not prevent detection of immune complexes by the C1q solid-phase assay. Similar selective losses of immune complexes occurred when serum specimens from 2 patients with circulating immune complexes were analyzed by sucrose density gradient ultracentrifugation; the nonspecific adsorption of serum immune complexes which occurred during ultracentrifugation could be prevented by precoating centrifuge tubes with gelatin and incorporating 0.05% Tween 20 into sucrose gradients.

Adsorption↗
PubMed1985

Cyanogen bromide cleaves Fc fragments of pooled human IgG at both methionine and tryptophan residues.

An attempt was made to obtain fragments containing the C gamma 2 region by selectively cleaving human Fc fragments prepared from pooled IgG at Met residues using cyanogen bromide. Based on the known locations of Met residues in the Fc regions of human IgG subclasses, fragments between Met 252 and 358, comprising the C gamma 2 domains, were expected from IgGl Gm -1, IgG2, IgG3 and IgG4. Greater fragmentation of the Fc fragments occurred, however, than was predicted. Automated N-terminal sequencing identified five major points (Trp 381, 313 and 277, and Met 397 and 252) and two minor points of cleavage (Met 428 and Trp 417). The majority of cleavage points occurred at Trp rather than Met. Furthermore, cleavage at Met 358, necessary to produce C gamma 2 domains, was not detected. Control experiments verified the integrity of the Fc fragments handled in exactly the same manner without cyanogen bromide exposure and the ability of the same cyanogen bromide preparation to produce the expected cleavages at Met of sperm whale apomyoglobin without fragmentation at Trp. Cleavage at Met 358 did not occur presumably because of the difficulty associated with cyanogen bromide cleavage at Met-Thr peptide bonds. Cleavage at Trp probably occurred by way of halogen promoted oxidation of the indole nucleus with resultant peptide bond fissure. These observations show that cyanogen bromide cleavage of pooled human Fc fragments is not selective for Met, but also cleaves at Trp residues. The resultant fragmentation of the C gamma 2 region coupled with the inability to make the required cleavage at the 358-359 Met-Thr bond resulted in the inability to produce fragments comprising the C gamma 2 domains. The reasons for the selective cleavage at Met in some proteins and the cleavage at both Trp and Met in others are not known.

Chemical Phenomena↗