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M Mannik

Publications and source records attributed to M Mannik.

At least 73 records · Page 4Linked to original sources
PubMed1985

Cutaneous deposition of immune complexes in chronic serum sickness of mice induced with cationized or unaltered antigen.

We have previously shown that cationic proteins localize to the dermal-epidermal junction (DEJ) after i.v. injection in experimental animals. In the present studies, cationized rabbit IgG was used as antigen for induction of chronic serum sickness in C57BL/6J mice over a period of 4 weeks. The formation of immune deposits was examined by immunofluorescence microscopy at weekly intervals during chronic antigen administration and at 7 weeks from the initiation of studies. Chronic administration of the cationized antigen led to immune complex deposits at the DEJ, while administration of the same antigen in native form did not lead to these deposits. Junctional immune deposits increased with higher doses of cationized antigen and paralleled renal extraglomular deposition in intensity, persistence, and morphology. Mice given cationized antigen also demonstrated vascular immune complex deposits without complement, while mice given native antigen had complement deposits and developed perivascular inflammation. No inflammation or complement deposition was detected at the DEJ in either group. Charge properties of circulating antigens are important in determining tissue sites of immune complex deposition and inflammation. Circulating cationic antigens can lead to immune deposits at the DEJ.

Animals↗
PubMed1985

IgG rheumatoid factors and self-association of these antibodies.

IgG RFs are unique antibodies since they form immune complexes by self-association without the presence of separate antigen molecules. These immune complexes can drive inflammation by complement activation and by interaction with monocytes. Plasma cells in the synovial tissues of patients with RA synthesize IgG RFs and other rheumatoid factors. The reason for the accumulation of these cells in the synovium has not been elucidated. The detection and quantitation of IgG RFs has been difficult owing to the unique nature of these antibodies. The methods for this purpose, however, have improved. In patients with RA the presence of high levels of IgG RFs in serum is associated with clinical evidence of vasculitis. The quantitation of IgG RFs in serum of patients has not yet been established as a diagnostic or prognostic tool. Available evidence, however, suggests that these antibodies have a significant role in the pathogenesis of rheumatoid arthritis.

Animals↗
PubMed1985

Antibody localization in the glomerular basement membrane may precede in situ immune deposit formation in rat glomeruli.

The administration of cationized antibodies, specific to human serum albumin, into the renal artery of rats caused transient presence of IgG in glomeruli by immunofluorescence microscopy. Intravenous infusion of appropriate doses of antigen after the injection of cationized antibodies resulted in immune deposit formation in glomeruli that persisted through 96 hr. By electron microscopy, these deposits were located in the subepithelial area. The injection of large doses of antigen produced immune deposits which were present in glomeruli for only a few hours, presumably due to formation of only small-latticed immune complexes. The presented data indicate that cationic antibodies bound to the fixed negative charges of the glomerular basement membrane can interact with circulating antigen to form immune deposits in glomeruli. This mechanism may be important because anionic antigens have been shown to induce the synthesis of cationic antibodies.

Animals↗
PubMed1985

Competition between antigen and anti-idiotypes for rheumatoid factors.

Many idiotypic determinants on antibody molecules are thought to be located at the antigen binding site, and therefore the interaction between idiotype (Id) and anti-idiotype (anti-Id) is expected to be inhibited by the antigen. We describe two IgG and one IgM rheumatoid factors whose interactions with their respective anti-Id could only be partially inhibited by very large amounts of antigen, i.e., normal IgG. The anti-Id, however, readily inhibited the binding of their respective rheumatoid factors to IgG. The differences in interaction energies resulted in failure of antigen to readily block the Id-anti-Id interaction, and did not mean that the Id was not at the antigen combining site. The association constants for the Id-anti-Id interactions varied from 1.3 to 14.8 X 10(7) M-1, whereas the strength of the rheumatoid factor antigen bond is on the order of 10(5) M-1 for interaction with monomeric IgG. In addition, the anti-Id were able to remove rheumatoid factors that were bound to solid phase IgG, indicating that anti-Id have the potential for disrupting the immune complexes formed by antigen and antibody.

Animals↗
PubMed1984

Clearance of circulating IgA immune complexes is mediated by a specific receptor on Kupffer cells in mice.

To characterize the physiology of circulating IgA immune complexes (IgA-IC), the dynamics of IgA-IC removal by the liver were examined. After intravenous injection, covalently cross-linked IgA antibodies to the dinitrophenyl determinant were rapidly removed from the circulation by the liver. Immunofluorescence microscopy and light and electron microscope autoradiography showed that the IgA-IC were associated with Kupffer cells. With increasing doses of injected IgA-IC the clearance velocity approached a maximum, thus prolonging the circulation of IgA-IC. All these observations indicated a receptor-mediated process. Saturating doses of various potential receptor-blocking agents, heat-aggregated mouse IgG, microaggregated human serum albumin, and purified dimeric IgA did not influence the clearance pattern and hepatic uptake of radiolabeled IgA-IC. Mouse livers were also perfused via the portal vein with 1 microgram of IgA-IC. In the presence or absence of serum proteins, 43% of the perfused IgA-IC were removed in a single passage. This liver uptake was not reduced with simultaneous perfusion of large doses of aggregated mouse IgG, aggregated human serum albumin, or purified free dimeric mouse IgA. In contrast, the liver uptake of radiolabeled IgA-IC was decreased by 88% with the addition of 1 mg unlabeled IgA-IC. These observations support the conclusion that removal of IgA-IC from circulation is mediated by a specific IgA receptor on Kupffer cells.

Animals↗
PubMed1984

Self-associating IgG rheumatoid factors in MRL/l autoimmune mice.

Previous work has shown that the intermediate complexes isolated from the plasma of patients with rheumatoid arthritis are composed of self-associating IgG rheumatoid factors. Mice of the MRL/l strain develop spontaneous autoimmune disease with arthritis that is pathologically similar to human rheumatoid arthritis. Also, the sera of MRL/l mice contain autoantibodies to nuclear antigens as well as IgM and IgG rheumatoid factors. The present studies were done to determine if the IgG rheumatoid factors isolated from these mice undergo self-association. MRL/l mouse sera were categorized into groups A and B based on serum-serum precipitin interactions. Thirteen of 13 MRL/l mice sera examined contained intermediate complexes sedimenting between the 6.6S and 19S components of normal serum by sedimentation velocity ultracentrifugation. There were no differences in the level of intermediate complexes between groups A and B. IgG rheumatoid factors were isolated from the sera of 9 other mice. Upon sedimentation equilibrium ultracentrifugation, these rheumatoid factors underwent concentration-dependent self-association similar to that described for human self-associating IgG rheumatoid factors, although the precise stoichiometry of self-association could not be determined. The IgG rheumatoid factors from group B had higher energies of self-interaction than those from group A. These studies provide additional evidence that MRL/l mice may be the best available animal model for the study of human rheumatoid arthritis.

Animals↗
PubMed1984

In situ formation of immune complexes in the choroid plexus of rats by sequential injection of a cationized antigen and unaltered antibodies.

The deposition of cationized human serum albumin (HSAED) in the choroid plexus of rats was compared to deposition in renal glomeruli. Initial deposition in the choroid plexus required a higher dose of antigen than deposition in glomeruli. The optimal dose for deposition in the choroid plexus was 50 mg/kg of HSAED. With this dose the antigen was still present in the choroid plexus at eight days after injection, whereas the glomeruli became largely negative by one day. Immune complex formation and persistence was examined in the choroid plexus by injecting rabbit antibodies to HSA at varying times after the injection of HSAED. When a limited amount of antibody was injected, it localized preferentially to glomeruli as compared to the choroid plexus. When sufficient antibodies were injected, the antigen and antibodies persisted in a comparable manner in the choroid plexus and glomeruli. By the eighth day after injection of foreign proteins, rat IgG deposited in both organs, indicating an endogenous immune response. The formed deposits were still present at 28 days, containing HSA, rabbit IgG, and rat IgG, but not rat C3. These results indicate that immune deposits readily form in the choroid plexus after injecting a cationized antigen. Differences, however, exist in the formation of immune deposit in the choroid plexus and the glomeruli.

Animals↗
PubMed1984

Localization of preformed, circulating immune complexes in murine skin.

The cutaneous localization of intravenously injected preformed immune complexes was examined in C57B1/6J mice and the importance of complex size and antibody charge was assessed for deposition and persistence in cutaneous structures. After a single intravenous bolus, large-latticed complexes deposited transiently in an interstitial extravasated pattern, and persisted longer in a vascular pattern. Small-latticed complexes, prepared at 50 times antigen excess, did not deposit. When large-latticed complexes were prepared with reduced and alkylated antibodies, their vascular deposition was similar, but they did not localize in the interstitium due to decreased extravasation. Large-latticed complexes prepared with cationized antibodies deposited in a vascular and interstitial pattern as well as at the dermal-epidermal junction. Complexes prepared with anionized antibodies deposited comparable to unaltered complexes. Cutaneous deposition of circulating immune complexes in mice requires a large lattice. Circulating immune complexes formed with cationic antibodies deposit at the dermal-epidermal junction.

Animals↗
PubMed1984

Glomerular localization of preformed immune complexes prepared with anionic antibodies or with cationic antigens.

The glomerular basement membrane presents a highly anionic surface to circulation. The effects of anionic antibody and cationic antigen in preformed immune complexes prepared at 5-fold antigen excess were investigated in separate experiments in mice. Anionized antibodies (isoelectric point 4 to 6) to human serum albumin were prepared by acetylation and immune complexes produced in vitro. Blood clearance kinetics and glomerular immunofluorescence patterns of these immune complexes were not affected by anionization . Electron microscopy revealed mesangial deposits, indicating that the deposition of immune complexes in the mesangium occurs with highly anionic immune complexes. Cationic human serum albumin (AgED, isoelectric point 7.5 to 9.0) alone or as performed immune complexes ( AgEDAb ) showed rapid blood clearance (less than 1% remaining by 18 hours) and localized in renal glomeruli by immunofluorescence microscopy. AgED injected alone was present in glomeruli at 1 minute after injection but was absent at 12 hours. After injection of AgEDAb , both antigen and antibodies were present in glomeruli from 1 minute through 72 hours by immunofluorescence microscopy. Electron-dense deposits were seen at the anionic sites in the lamina rara interna and lamina rara externa at 1 minute and 1 hour after injection of AgED and AgEDAb containing free AgED. After AgEDAb injection electron-dense deposits were evident at 12 to 48 hours in the mesangium and in the subendothelial area, especially adjacent to the mesangium. By 72 hours after AgEDAb injections mesangial deposits predominated, although small subepithelial deposits were also present. An inflammatory reaction was noted in the glomeruli after administration of AgEDAb . Thus, preformed immune complexes containing cationized antigen show glomerular deposition, primarily in the subendothelial and mesangial regions and at later time points also in the subepithelial area.

Animals↗
PubMed1984

Effect of DNA size and strandedness on the in vivo clearance and organ localization of DNA.

DNA-anti-DNA immune complexes play a major role in the pathogenesis of SLE. Evidence suggests that the DNA contained within these complexes, as well as free circulating DNA, is of small molecular weight and predominantly double stranded. Previous studies have shown that large DNA is cleared from circulation rapidly and efficiently. To examine if variations in the configuration of DNA itself affected its ability to persist in the circulation, we studied the clearance and organ uptake of single stranded DNA(ssDNA) and double stranded DNA(dsDNA) of different sizes in normal mice. Clearance of DNA from the circulation was described by two exponential components. The first component represented organ uptake, and was much more rapid for ssDNA than for dsDNA. The second component represented the excretion of breakdown products from the total body pool, and was the same for all DNA preparations. Regardless of its initial size, DNA larger than 15 bases did not persist in the circulation longer than 20 min for ssDNA, and longer than 40 min for dsDNA. Organ distribution studies showed that ssDNA was removed by the liver, but that dsDNA bound poorly to the liver and was distributed like oligonucleotide breakdown products. Our results suggest that dsDNA and ssDNA are removed from the circulation by different mechanisms. Although dsDNA remains in the circulation slightly longer than ssDNA, all DNA, regardless of its size or strandedness, is cleared from the circulation and broken down rapidly and efficiently.

Animals↗
PubMed1983

Precipitating antigen-antibody systems are required for the formation of subepithelial electron-dense immune deposits in rat glomeruli.

This study was conducted to determine whether multivalent, precipitating antigens are required for formation of subepithelial electron-dense immune deposits in glomeruli. 2-nitro-4-azidophenyl (NAP) was conjugated with variable density to human serum albumin (HSA) to yield nonprecipitating (NAP3.1 X HSA and NAP11.4 X HSA) and precipitating (NAP19.7 X HSA) antigens with antibodies to the hapten. These antigen preparations were cationized with ethylene diamine to enhance deposition in renal glomeruli due to interaction with the fixed negative charges in the glomerular capillary wall. Following injection into the left renal artery of rats these antigens alone persisted in the glomeruli for a relatively short time by immunofluorescence microscopy. When antibodies to NAP were injected intravenously after the antigen injection, the nonprecipitating antigens and antibodies were detectable in the glomeruli by immunofluorescence microscopy up to 8 h, comparable to antigen alone. Electron-dense deposits were not formed in these glomeruli. In contrast, when the precipitating antigen was injected and followed by antibodies to the hapten, antigen and antibody were detected by immunofluorescence microscopy through 96 h. In these specimens electron-dense deposits were present from 40 min through 96 h and after 24 h the deposits were present only in the subepithelial area. The same results were obtained when the nonprecipitating hapten-carrier conjugates were followed with antibodies to the carrier molecule. These data indicate that the persistence of immune deposits by immunofluorescence microscopy and the formation of electron-dense deposits in the subepithelial area require a precipitating antigen-antibody system.

Animals↗
PubMed1983

Rearrangement of immune complexes in glomeruli leads to persistence and development of electron-dense deposits.

Covalently, cross-linked immune complexes were prepared with multivalent 2-nitro-4-azidophenyl X human serum albumin (NAP X HSA) and antibodies to NAP at five times antigen excess. After purification with gel filtration, affinity chromatography with antigen-agarose column, and addition of the hapten, 9.5% of the antibodies dissociated from the complexes by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis. After injection of these cross-linked immune complexes into mice, glomeruli stained for the complexes by immunofluorescence microscopy for only a few hours and electron-dense deposits were not detected. In contrast, when the same immune complexes with comparable lattice but without covalent cross-linking were administered to a second group of mice, the initial deposition by immunofluorescence was comparable and then increased to extensive deposits that persisted to 96 h. In this second group of mice extensive electron-dense deposits evolved. These observations supported the conclusion that the immune complexes initially deposited from circulation must undergo rearrangement to persist and to form electron-dense deposits in glomeruli. The covalently cross-linked immune complexes existed in glomeruli only for a short period of time since these complexes could not rearrange.

Animals↗
PubMed1983

Self-associating IgG rheumatoid factors stimulate monocytes to release prostaglandins and mononuclear cell factor that stimulates collagenase and prostaglandin production by synovial cells.

Self-associating IgG rheumatoid factors isolated from three patients with rheumatoid arthritis activated human monocytes to release prostaglandin E2 as well as a previously described mononuclear cell factor, which stimulates human synovial cells to release additional prostaglandin E2 and collagenase. Thus, the immune complexes composed of self-associating IgG rheumatoid factors can contribute to the processes that destroy cartilage and bone in patients with rheumatoid arthritis.

Humans↗
PubMed1983

Influence of immune complex lattice on the C1q solid phase assay as determined with covalently cross-linked immune complexes.

The influence of the lattice of immune complexes on the C1q solid phase assay was examined using covalently cross-linked 125I-labelled immune complexes, separated into pools of varying and stable lattice. The C1q binding of antibodies alone, of Ag1Ab1, and of Ag2Ab2 could not be distinguished from each other statistically; but with increasing, higher lattices, immune complexes bound more efficiently to C1q. The binding of these immune complexes to C1q was also measured with 131I-labelled antibodies to IgG in the immune complexes. The detection of bound immune complexes by this indirect method showed the same order of binding efficiency as that observed by the direct measurement of immune complex binding. Up to a critical level, the binding of 131I-antibodies to IgG was proportional to the 125I-IgG in the bound complexes, and was independent of the lattice of complexes. This proportionality, however, was lost at higher levels of binding. The presence of serum diminished the binding of both large latticed and small latticed immune complexes, but serum did not alter the order of binding efficiency and the order of detection of binding using 131I-antibodies to IgG. The conclusion was reached that no single ideal standard for this assay can be currently designed to permit accurate quantitation of the concentration of immune complexes of varying lattice.

Antigen-Antibody Complex↗
PubMed1983

Hepatic uptake of small-latticed immune complexes does not alter mononuclear phagocyte system function.

The hepatic and splenic uptake of circulating, small-latticed immune complexes and the effect of these complexes on the hepatic mononuclear phagocyte system (MPS) were examined in mice. The small-latticed immune complexes were prepared at fifty-fold antigen excess. The clearance from circulation and uptake by the liver and spleen of two probes of MPS function, aggregated human IgG and aggregated mouse albumin, were quantified. The hepatic uptake of a dose of small-latticed complexes, containing 5 mg of antibodies, at 1 hr was comparable with the uptake of a similar dose of complexes that contained large-latticed complexes. At later time points, the hepatic uptake of the small complexes was significantly less than that of the larger complexes. The splenic uptake of the small-latticed complexes was less at all time points. Doses of the small-latticed complexes, ranging from 1 to 5 mg antibody in the complexes, produced no significant inhibition of the clearance or organ uptake of the MPS probes when administered 1 hr after the preload injections. In contrast, large-latticed complexes produced a dose-dependent delay in clearance due to a decreased hepatic uptake of the probes. These observations showed that small-latticed immune complexes were ineffectively removed by the hepatic MPS and that the presence of large quantities of small-latticed complexes in circulation did not alter MPS function.

Animals↗
PubMed1983

Clearance kinetics and fate of mouse IgA immune complexes prepared with monomeric or dimeric IgA.

To determine the pathophysiologic mechanism(s) involved in experimental IgA nephropathy, the clearance kinetics and tissue distribution of soluble IgA immune complexes in mice were investigated. Purified radiolabeled dimeric (dIgA) and monomeric (mIgA) IgA antidinitrophenyl, obtained from MOPC-315, were covalently cross-linked with a bivalent affinity-labeling antigen, bis-2,4-dinitrophenyl pimelic ester. After i.v. injection, heavy polymers (greater than 1.2 X 10(6) m.w.) were rapidly removed from circulation. Analysis of circulating intermediate-latticed complexes by gradient polyacrylamide gel electrophoresis indicated that polymers with a minimal composition of four dIgA or eight mIgA were required for rapid elimination. The dIgA and mIgA complexes with lattices smaller than this critical size were removed at slower rates (yielding a t1/2 of 35 min for complexes with dIgA and a t1/2 of 60 min for complexes with mIgA). Tissue distribution of both dIgA and mIgA immune complexes was similar. The liver was the major organ involved in uptake of IgA immune complexes with an insignificant amount in the bile. Heavy polymers of dIgA or mIgA were predominantly localized in the hepatic nonparenchymal cells.

Animals↗