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S Batsford

Publications and source records attributed to S Batsford.

At least 37 records · Page 2Linked to original sources
PubMed1992

Glomerular immune deposits in murine lupus models may contain histones.

Two types of lupus mice, NZB/NZW F1 female hybrids and mice with graft-versus-host disease (GVHD), were studied. Histones H3 and H2A were detected by immunofluorescence in glomeruli of 22/22 proteinuric GVHD and 8/12 proteinuric NZB/W F1 female mice; in non-proteinuric animals, 3/5 GVHD and 2/27 NZB/W F1 female were positive. Using antibodies to histone peptides it was shown that mainly the N-terminal regions of histones H3 and H2A were exposed in glomerular deposits. Western blot analysis revealed antibodies to histone subfractions in sera of 33/34 lupus mice that developed proteinuria. This study provides evidence that histones are involved in the pathogenesis of lupus nephritis.

Animals↗
PubMed1991

Handling of cationic antigens in the joint and induction of chronic allergic arthritis. In vivo studies in the rat.

The aims of the present study were to define, under in vivo conditions, factors governing antigen binding and persistence in the rat joint and to establish a chronic arthritis model by means of a natural polycation. The influence of size as well as charge on antigen handling was examined using a range of chemically cationized proteins and natural polycations. Arthritis was induced by intraarticular challenge in preimmunized rats. Immunofluorescence studies revealed that not only pI, which must exceed pH 8-9, but also molecular size was a decisive parameter: only antigens of more than 40 kD were able to persist for significant periods in joint structures. All existing models of antigen induced chronic arthritis in rodents utilize chemically cationized proteins. We extended this system to natural polycations by showing that lysozyme (pI 11.3; MW 14 kD) in tetrameric, charge conserved form (MW 56 kD) as a model-antigen was able to induce chronic arthritis in the rat. After intraarticular challenge of preimmunized animals the course of inflammation was assessed both by 99mTechnetium-pertechnetate (99mTc) scintigram and from the histology. In contrast to monomeric lysozyme, which evoked only a transient inflammatory response (less than two weeks), tetrameric lysozyme induced a chronic arthritis, which still persisted at day 90. Our results show that the ability of cationic antigens to trigger chronic arthritis is vitally size dependent. This is also the first report of a natural polycation acting as an arthritogen, thus providing an experimental basis justifying the search for cationic microbial antigens in human post infectious reactive arthritis.

Animals↗
PubMed1990

The role of cationic proteins in the pathogenesis of immune complex glomerulonephritis.

In spite of intensive endeavours, attempts to identify nephritogenic antigens in cases of immune complex glomerulonephritis have not yielded convincing results. Cationic antigens can have high affinity for the glomerular basement membrane and are prime candidates as nephritogens. They can be expected to play a role in post-infectious and in autoimmune glomerular disease. Histones show great promise in the latter case: we are able to demonstrate (1) a high affinity for the glomerular basement membrane and (2) their ability to promote glomerular deposition of anionic antigens as an additional target. Histones were detectable in glomerular deposits in two murine models of glomerulonephritis: the spontaneous lupus-like disease of NZB/W F1 mice and in graft-versus-host disease. We propose that histones may be responsible for the induction of glomerulonephritis in lupus-like syndromes, as well as other types of autoimmune renal disease. As an analogue, histone-like proteins from micro-organisms may also be responsible for glomerular disease in post-infectious nephritis.

Animals↗
PubMed1989

Ultrastructural studies in passive in situ immune complex glomerulonephritis. A rat model for membranous glomerulonephritis.

Morphologic studies were performed in a passive model of in situ immune complex glomerulonephritis in rats. The formation and fate of subepithelial immune complexes as well as the role of glomerular polyanion in the induction of disease were examined. Unilateral in situ immune complex glomerulonephritis was induced in rats by perfusion of cationised horse spleen ferritin (pI greater than 9.5) (400 micrograms/rat) into the left kidney followed by systemic injection of 0.2 ml (= 400 micrograms precipitating antibody) of sheep anti-ferritin antiserum 2 h later. This schedule induced glomerulonephritis with proteinuria (mean maximum 100 mg/24 h between the 5th and the 12th day). Rats were sacrificed at intervals between 1 h and 42 days after induction of glomerulonephritis, samples of renal tissue were examined by light, immunofluorescence and electron microscopy (including staining of anionic sites by polyethyleneimine). The lesion induced closely resembled that of membranous glomerulonephritis in man as massive subepithelial deposits were seen with very little cellular infiltration or proliferation. The antigen (ferritin) deposits were initially located subepithelially; from 2 weeks onwards intramembranous deposits in the thickened basement membrane were present, the apparent translocation being due to excessive newly synthesised basement membrane material which encloses the deposits. A loss of anionic sites in the lamina rara interna, lamina rara externa and on the epithelial cell surface coat preceded the development of proteinuria.

Animals↗
PubMed1989

[Macromolecular basis of filtration and immune complex pathogenesis in the glomerulus].

Fractional clearance and ultrastructural studies produce results consistent with the idea that the glomerular filtration barrier is a heteroporous membrane. The majority of the pores being small, excluding molecules like serum albumin and larger moieties, while a low number of pores allow the passage of molecules as big as dimeric ferritin, in very restricted quantities. Cationic macromolecules, of a size which should effectively exclude them from the filtration process, readily gain access to all three layers of the GBM. Depending on charge (pI) and size they can in fact exhibit significant affinity for negatively charged structures in both laminae rarae. In addition, polycations can mediate the glomerular deposition of anionic macromolecules, for example DNA-fragments, by diminishing charge repulsion. A prerequisite for the local formation of glomerular immune complexes is that at least one of the reaction partners has an affinity for the GBM. Antigens bound to structures in the laminae rarae are accessible for circulating antibody. Immune complexes formed with cationic antigen in the lamina rara interna are transferred to the subepithelial region with time. Antigen and antibody molecules can penetrate the lamina densa only in dissociated form. The persistence of glomerular immune complexes can be explained by antigen-antibody lattice formation within the network of proteoglycan chains, followed by covalent binding between components of the complex and structures of the GBM.

Animals↗
PubMed1989

Cyclosporin A prevents proteinuria in an active model of membranous nephropathy in rats.

The effect of the immunosuppressant Cyclosporin A on an active model of in situ immune complex glomerulonephritis was evaluated. Wistar rats were preimmunized with human IgG and 2 weeks after the last antigen injection, the left kidney was perfused with cationized human IgG in order to induce unilateral in situ immune complex glomerulonephritis. Three groups of rats were treated orally with Cyclosporin A (15 mg/kg body weight/day) beginning 2 days before induction of disease and continuing for 7 or 14 days afterwards, or alternatively treatment was commenced 5 days after induction of disease and continued until day 14. Cyclosporin A significantly reduced proteinuria (40 +/- 7 mg/day) in rats with immune complex glomerulonephritis when compared with untreated nephritic controls (250 +/- 65 mg/day). This effect was observed when rats were pretreated with Cyclosporin A and even when the drug was given in established disease, 5 days after induction. Proteinuria appeared in rats pretreated with Cyclosporin A when drug administration was stopped at day 7. Cyclosporin A did not alter immune complex formation in glomeruli or serum levels of anti-human-IgG antibody, nor did it reduce inulin clearance (CsA: 234 +/- 31 microliters/minute/100 gm body weight; controls: 119 +/- 27 microliters/minute/100 gm body weight). Morphologic studies did not reveal any differences between controls and the immunosuppressed rats. CsA failed to reduce proteinuria in the nonimmune mediated model of aminonucleoside nephrosis. The data demonstrate that Cyclosporin A can prevent the induction and more importantly ameliorate already established proteinuria in an autologous model of in situ immune complex glomerulonephritis. This latter finding is important since, in general, most treatment schedules have little, if any effect on established experimental glomerular disease.

Animals↗
PubMed1986

Mediator systems in a passive model of in situ immune complex glomerulonephritis. Role for complement, polymorphonuclear granulocytes and monocytes.

The pathogenetic roles of complement, polymorphonuclear granulocytes, and monocytes were studied in a model of in situ immune complex glomerulonephritis employing a cationized antigen. Left kidneys of Wistar rats were perfused with 40 micrograms of cationized human IgG (isoelectric point greater than or equal to 9.5) followed by intravenous injection of rabbit anti-human IgG 1 hour later. This resulted in prominent subepithelial deposit formation in the perfused kidney accompanied by massive proteinuria. Groups examined were: (a) no additional treatment, (b) C3 depleted (cobra venom factor, (c) granulocyte depleted (specific antiserum), (d) monocyte depleted (specific antiserum), and (e) granulocyte depleted and monocyte depleted. The quantity of radiolabeled cationized antigen deposited in the left kidney was not affected by any of the treatment schedules. Proteinuria was abolished in all mediator depleted groups (b to e) for 5 to 7 days, thereafter rising to levels seen in the nondepleted group (a). This late onset of proteinuria is noteworthy since the deposits are then located subepithelially and may be less accessible to circulating mediators. C3 depletion, despite inhibition of proteinuria, did not prevent the intraglomerular accumulation of granulocytes and monocytes thereby suggesting that attraction and activation of these cells may occur independently. Apparently all three mediators are required for full expression of the lesion, a finding not paralleled in other experimental models of glomerulonephritis. The relevance of very low levels of inflammatory cell infiltration for provoking glomerular injury was clearly demonstrated.

Animals↗
PubMed1986

Effect of cyclosporine on in situ immune complex glomerulonephritis.

The influence of Cyclosporine A (CyA) on the development of renal injury in in situ immune complex glomerulonephritis (ICGN) in rats was examined. Left kidneys of male Wistar rats were perfused with cationized human IgG followed by an intravenous injection of rabbit anti-human IgG. CyA was given orally in a dosage of either 2.5, 15 or 25 mg/kg body weight per day in two daily injections. The amount of immune complexes deposited in the left kidney was not affected by CyA application as shown by isotopic studies. There were no differences between the control and CyA groups in respect to immunofluorescence, light and electron microscopy. Proteinuria was significantly inhibited with all treatment schedules, even when rats were first treated five days after inducing nephritis. These results show that CyA inhibits proteinuria without affecting glomerular cell accumulation/proliferation in in situ ICGN, and indicates that cellular activation at glomerular level might be prevented by CyA.

Animals↗
PubMed1985

Studies on thromboxane B2 and prostaglandin E2 production in the course of murine autoimmune disease: inhibition by oral histidine and zinc supplementation.

Synthesis of both prostaglandin E2 and thromboxane B2 in liver and kidney tissue of NZB/W F1 hybrid mice was found to increase with advancing age. The rise in prostanoid generation coincided with the appearance and progression of the spontaneous systemic lupus erythematosus (SLE)-like disorders seen in these mice. Substitution of a diet supplemented with histidine (50 g kg-1 dry weight) and/or zinc (160 mg kg-1 dry weight) suppressed the autoimmune disease associated increase in prostanoid generation. The parent NZB and NZW strains also revealed an age-dependent increase in prostanoid synthesis whereas no age-related changes of tissue prostanoid generation were seen in healthy DBA-2 and C57-BL/6 control mice. In a previous study [Schwerdtfeger et al. 1980] a protective effect of histidine and/or zinc on the course of SLE-like disease in NZB/W F1 mice was reported. The current work suggests that this effect may in part have been mediated by the modulation of cellular arachidonic acid metabolism. The proposal that prostanoids are involved in the pathogenesis of autoimmune disease in NZB/W F1 mice is supported by these results.

Administration, Oral↗
PubMed1984

Synthetic amino-acid diet prolongs survival in autoimmune murine disease.

The effect of substituting a fully synthetic diet for standard laboratory pellet feed on the course of spontaneous autoimmune disease in New Zealand Black/White hybrid mice was examined. Delays in the development of anti-nuclear antibody, proteinuria and circulating immune complexes were seen; the survival was markedly prolonged. This type of dietary manipulation has a beneficial effect on the course of murine autoimmune disease.

Amino Acids↗
PubMed1983

Cationic antigens in poststreptococcal glomerulonephritis.

Antigen charge is an important factor in the pathogenesis of experimental immune complex glomerulonephritis. Its potential role in man was investigated in post-streptococcal glomerulonephritis, a disease where the causative agent is known. Cationic, extracellular streptococcal antigens were detected in 8 of 18 renal biopsies from patients with acute poststreptococcal glomerulonephritis (APSGN). The antigen was found mainly in earlier biopsies in which both IgG and IgM were present. Patients' sera taken at the time of biopsy contained antibody to cationic, streptococcal antigens. Cationic moieties are known to have affinity for the glomerular basement membrane and it is possible that the type of antigen described here initiates APSGN via in situ immune complex formation.

Antibodies, Bacterial↗
PubMed1982

Interaction of cationized antigen with rat glomerular basement membrane: in situ immune complex formation.

The influence of charge and size on antigen binding to the rat glomerular basement membrane (GBM) was investigated. Chemically cationized ovalbumin, human serum albumin (HSA), human immunoglobulin G (Hu IgG), horse spleen ferritin and human immunoglobulin M (Hu IgM) were injected into rats intravenously. By immunofluorescence significant glomerular binding occurred when the pI exceeded a threshold value of 8.5 to 9.5. At a given pI antigen binding increased with molecular size. Cationized Hu IgM bound only weakly to the glomerular capillary wall, presumably excluded due to size. Subepithelial immune deposits were formed only when antibody was injected subsequently. Detailed electron microscopic studies on in situ formation of immune complexes were performed using cationized horse spleen ferritin. Early on subendothelial deposits were very marked, giving way to subepithelial deposits with time. Under the conditions employed, it appears that deposits can be formed directly at the subepithelial locus but that complexes are also formed subendothelially, dissociating into free molecules or small complexes and then migrating through the lamina densa and reforming.

Animals↗
PubMed1982

[Double blind study of the influence of aristolochic acid on granulocyte phagocytic activity].

In two double blind studies, separated by a time interval, the influence on phagocytic activity of peripheral granulocytes was investigated by aid of 3H-labelled staphylococci following administration of therapeutic doses of aristolochic acid, a nitrophenanthrene carboxylic acid derivative, to 12 healthy test subjects. Both double blind studies showed that aristolochic acid in a dosage of 0.9 mg/d produced a definite increase in phagocytic activity in healthy test persons after the third day of treatment; this increase reached a maximum within a 10-day treatment period between the seventh and tenth days; following discontinuation of treatment normal values were recorded again within a week. Other laboratory parameters investigated were not influenced.

Adult↗
PubMed1980

Anionic binding sites in the glomerular basement membrane: possible role in the pathogenesis of immune complex glomerulonephritis.

This paper details the ways in which the anionic sites of the GBM could be involved in immune complex deposition. Experiments were performed with chemically cationised proteins to test the hypotheses proposed. The most detailed investigations were concerned with the role of basic (cationic) antigen as a planted antigen, leading to in situ immune complex formation. A model was developed where it was possible to induce marked proteinuria following a single injection of small quantities of cationised human IgG or ferritin.

Animals↗