Figure 1- - uploaded by Samy Samuel Iskandar
Content may be subject to copyright.
Direct immunofluorescence photomicrograph of a glomerulus from a Swiss mouse that received HAF for 14 days and had a predominantly mesangial pattern of immune deposition. (Anti-mouse IgG, x 600) Figure 2-Direct immunofluorescence photomicrograph of a glomerulus from a Swiss mouse that received HAF for 14 days and had predominantly capillary wall immune deposits. (Anti-mouse IgG, x 600) (With a photographic reduction of 4%)
Source publication
Immune-complex-mediated glomerulonephritis (IC-GN) was induced with daily intraperitoneal injections of horse apoferritin (HAF) for varying intervals in Swiss albino and BALB/c mice. Anti-HAF antibody avidity in plasma pools from mice with predominantly mesangial immune deposits was compared with avidity in plasma pools from mice with predominantly...
Context in source publication
Context 1
... Mice (Table 1) Swiss mice with predominantly mesangial localiza- tion of immune deposits (Figure 1) had circulating anti-HAF of higher avidity than Swiss mice with pre- dominantly capillary loop deposits (Figure 2). Swiss mice with predominantly mesangial deposits had almost the same anti-HAF avidity whether given HAF injections for 7 days (7.7 ± 0.7 x 107 L/M) or 14 days (8.7 ± 0.6 x 10' L/M). But Swiss mice given injections for 14 days and displaying predominantly capillary loop immune deposits had anti-HAF avidity of only 5.6 ± 0.3 x 107 L/M. An even lower anti- HAF avidity of 2.4 ± 0.5 x 107 L/M was found in Swiss mice with predominantly capillary wall depos- its after 28 or more days of HAF. By light micros- copy, 12 of the 13 Swiss mice used to form plasma pools had a proliferative GN (Figure 3). One Swiss mouse with mesangial immune deposits had no lesion by light microscopy. No consistent correlation could be discerned between the light-microscopic glomeru- lar morphologic features and the site of immune deposits or anti-HAF avidity, but by electron mi- croscopy the distribution of immune deposits noted by immunofluorescence microscopy corresponded to electron-dense mesangial or subepithelial deposits (Figure 4 and 5). BALB/c Mice (Table 1) BALB/c mice given HAF for 7 days and having exclusively mesangial immune deposits had an anti- HAF avidity of 2.4 x 108 L/M, whereas BALB/c mice injected with HAF for 14 or more days and hav- ing predominantly capillary loop immune deposits had a much lower anti-HAF avidity of 0.6 x 108 L/M. By electron microscopy the former group had only mesangial electron-dense deposits, while the latter had mesangial, subendothelial, and subepi- thelial electron-dense deposits. Even though substan- tial mesangial immune deposition had occurred in the BALB/c mice given HAF for 7 days, no definite light-microscopic lesions were identified. All 7 BALB/c mice that received HAF for 14 or more days had marked proliferative glomerulonephritis, includ- ing one with numerous globally necrotic ...
Similar publications
These studies examined the fate of Factor XIII (fibrin-stabilizing factor) in mice with plasmacytoma (MOPC-300, MOPC-384, MOPC-467, and J-558). Plasma Factor XIII levels in these mice decreased progressively with tumor expansion. No plasma inhibitors of Factor XIII activity could be detected. Factor XIII was found on plasmacytoma cell membranes and...
Citations
... If the antibodies that bind to the antigens have a low affinity, the antigens might pass though the GBM at a time when they are not bound to the antibody. They are trapped in the subepithelial space and then reassociate with the Igs that have also traversed the GBM, thereby reforming the immune complex (Iskandar and Jennette 1983). In addition to the subepithelial immune complexes, secondary membranous GN has immune complexes that are located in mesangial zones, whereas cases of primary membranous GN do not. ...
Glomerulonephritis (GN) is inflammation of glomeruli. The four major categories that cause human GN are mediated by immunoglobulin or complement or both, and they include (1) immune complex–mediated GN, (2) anti-glomerular basement membrane–mediated GN, (3) antineutrophil cytoplasmic autoantibody–mediated GN, and (4) complement factor 3 glomerulopathy mediated by complement dysregulation. Initiating processes include infection, autoimmunity, exogenous antigens, and neoplasia. Often there are predisposing and modulating genetic, epigenetic, and/or environmental factors. Animal models facilitated the recognition and elucidation of the pathogeneses of all four categories of GN, and they continue to be used in preclinical studies to identify and validate therapies for all four types of GN. Advanced diagnostic modalities (e.g., transmission electron microscopy and immunofluorescence) are helpful and sometimes required for the correct categorization of GN in humans and animals. This review provides historical background on the discovery of the different GN pathogeneses, describes some of the animal models used to discover and understand each GN pathogenic category, reviews the diagnostic classification of each category of GN, and compares human GN to spontaneous forms of nonhuman GN.
... Moreover, in determining the site of immune complex deposition, antibody avidity is thought to play a significant role. Previous studies have revealed that higher avidity antibodies are associated with mesangial immune deposits, while lower avidity antibodies form capillary wall deposits (7)(8)(9). The same mechanism can be applied to the clinical course: immune deposits of IgG are estimated to localize in the capillary wall, while those of IgA in the mesangium. ...
A 71-year-old woman was admitted with nephrotic syndrome. Light and electron microscopic analyses of renal biopsy tissue showed typical diffuse membranous features. In contrast, granular deposition of immunoglobulin A (IgA), but not IgG, IgM, C3 or C1q, was observed along the capillary walls on immunofluorescence. The patient was pathologically diagnosed with diffuse membranous nephropathy with solitary IgA deposition. Secondary membranous nephropathy was suspected; however, no underlying cause was found. The clinical and pathological findings, except for those of immunofluorescence, were all compatible with a diagnosis of primary membranous nephropathy. This is the first reported case of membranous nephropathy associated with solitary IgA deposition.
... This method of selection, however, may introduce a bias of selecting only B cells expressing membrane-bound Ig that bind TG2 with high affinity, as the low-affinity B cells will bind loosely and will probably not be isolated in this way. An alternative explanation might be that the antibodies with high binding affinity bind TG2 in the gut, whereas the low-affinity anti- bodies do not bind and recirculate in the serum [10,26]. It is known that some patients are serologically negative for TGA, but that these antibodies can be detected in the gut [27,28]. ...
Celiac disease is characterized by intolerance to gliadin and related gluten components present in wheat, barley and rye. Celiac disease patients harbor antibodies directed against allo-antigens, such as gliadin, but also against the autoantigen transglutaminase-2 (TG2). The type and quality of antibody responses provides insight into the underlying immune activation processes. Therefore in this study we have analyzed the avidity of the antibody response directed against the auto-antigen TG2 and compared this to antibody responses against the allo-antigens gliadin and E. coli. We observed that the IgA autoantibody response directed against TG2 is of low avidity as compared to IgA response against the alloantigens gliadin and E. coli in the same patients, the same was true for IgG, both in IgA deficient and in sufficient celiac patients. The observed avidities appear not to be related to disease stage, antibody levels, age or duration of exposure to gluten. In conclusion, in celiac disease there is a clear difference in avidity of the antibody responses directed against the auto- and the allo-antigens, indicating different regulation or site of initiation of these responses.
... TLR-mediated immune activation may play a role in immune complex diseases of the kidney triggered by infections. Horse apoferritin-induced glomerulonephritis (HAF-GN) is a model of immune complex GN that is characterized by circulating HAF-specific antibodies, mesangioproliferative GN, glomerular macrophage accumulation and proteinuria [14]. Single 40-mg doses of CpG DNA administered in the intraperitoneal cavity on days 7 and 8 (HAF-CpG-GN) led to a marked increase in the number of glomerular macrophages, the extent of glomerular damage and proteinuria [15]. ...
... Because potent inhibitory ITAM (iITAM) signalling triggered by monovalent targeting of FcaRI requires an associated FcRg chain [6], we generated a novel transgenic mouse expressing the FcaRIR209L/FcRg chimeric receptor (FcaRIR209L/FcRg Tg). Unexpectedly, this Tg mouse did not show any signs of inflammation in a spontaneous course of at least 12 months (data not shown), whereas FcaRI Tg mice spontaneously developed massive mesangial IgA deposition, glomerular and interstitial macrophage infiltration, mesangial matrix expansion, haematuria and mild proteinuria [14,19]. The molecular mechanism was shown to involve soluble FcaRI released after interaction with IgA, and this release was independent of the FcaRI association with the FcRg chain [21]. ...
Myeloid FcαRI, a receptor for immunoglobulin (Ig)A, mediates cell activation or inhibition depending on the type of ligand interaction, which can be either multivalent or monovalent. Anti-inflammatory signalling is triggered by monomeric targeting using anti-FcαRI Fab or IgA ligand binding, which inhibits immune and non-immune-mediated renal inflammation. The participation of Toll-like receptors (TLRs) in kidney pathology in experimental models and various forms of human glomerular nephritis has been discussed. However, little is known about negative regulation of innate-immune activation. In the present study, we generated new transgenic mice that express FcαRI(R209L) /FcRγ chimeric protein and showed that the monovalent targeting of FcαRI exhibited inhibitory effects in an in vivo model of TLR-9 signalling-accelerated nephritis. Mouse monoclonal anti-FcαRI MIP8a Fab improved urinary protein levels and reduced the number of macrophages and immunoglobulin deposition in the glomeruli. Monovalent targeting using MIP8a Fab attenuates the TLR-9 signalling pathway and is associated with phosphorylation of extracellular signal-related protein kinases [extracellular signal-regulated kinase (ERK), P38, c-Jun N-terminal kinase (JNK)] and the activation of nuclear factor (NF)-κB. The inhibitory mechanism involves recruitment of tyrosine phosphatase Src homology 2 domain-containing phosphatase-1 (SHP-1) to FcαRI. Furthermore, cell transfer studies with macrophages pretreated with MIP8a Fab showed that blockade of FcαRI signalling in macrophages prevents the development of TLR-9 signalling-accelerated nephritis. These results suggest a role of anti-FcαRI Fab as a negative regulator in controlling the magnitude of the innate immune response and a new type of anti-inflammatory drug for treatment of kidney disease.
... It has been hypothesized that MGN arises when IgG4 ICs formed between self Ags and low avidity/affinity Abs in the glomerular capillaries accumulate and are deposited in the outer aspect of the glomerular basement membrane (26,(33)(34)(35). Indeed, it has been shown that ICs formed from IgG4 and autoantibodies are relatively small and tend to localize in the subepithelial space (36). We observed such subepithelial deposits of ICs in WSX-1 Ϫ/Ϫ MRL/lpr mice. ...
MRL/lpr mice develop spontaneous glomerulonephritis that is essentially identical with diffuse proliferative glomerulonephritis (World Health Organization class IV) in human lupus nephritis. Lupus nephritis is one of the most serious complications of systemic lupus erythematosus. Diffuse proliferative glomerulonephritis is associated with autoimmune responses dominated by Th1 cells producing high levels of IFN-gamma. The initial mounting of Th1 responses depends on the function of the WSX-1 gene, which encodes a subunit of the IL-27R with homology to IL-12R. In mice deficient for the WSX-1 gene, proper Th1 differentiation was impaired and abnormal Th2 skewing was observed during infection with some intracellular pathogens. Disruption of the WSX-1 gene dramatically changed the pathophysiology of glomerulonephritis developing in MRL/lpr mice. WSX-1-/- MRL/lpr mice developed disease resembling human membranous glomerulonephritis (World Health Organization class V) with a predominance of IgG1 in glomerular deposits, accompanied by increased IgG1 and IgE in the sera. T cells in WSX-1-/- MRL/lpr mice displayed significantly reduced IFN-gamma production along with elevated IL-4 expression. Loss of WSX-1 thus favors Th2-type autoimmune responses, suggesting that the Th1/Th2 balance may be a pivotal determinant of human lupus nephritis development.
... The model is characterized by a mesangioproliferative and necrotizing glomerulonephritis with leukocyte infiltration, tuft thrombosis, and moderate proteinuria within 10-14 days and can progress to glomerulosclerosis [29]. Interstrain variations of apoferritin susceptibility are not related to the major histocompatibility complex, but depend on the production of high-avidity antibodies [30][31][32]. The susceptibility of Balb/c but not of C57BL/6 mice and the relation to antibody production indicates that the apoferritin model depends on a Th-2-type immune response. ...
The elucidation of the pathogenesis of human renal disease at the molecular level has been facilitated by the growing field of gene targeting and the development of mouse strains with single-gene deletions - the 'knock-out' mice. Experimental nephrology, therefore, requires well-characterized and reliable models of human renal disease that can be induced reproducibly in mice. Today surgical procedures for the induction of renal ischemia, chronic renal failure, and ureter obstruction are feasible in mice. Models of mesangioproliferative or crescentic glomerulonephritis, glomerulosclerosis, and tubulointerstitial disease are readily available; however, these depend heavily on the mouse genetic background. Attention to the genetic background and appropriate backcrossing are, therefore, of great importance in the design and interpretation of experimental studies, especially in transgenic mice. Simple murine models displaying the clinical features of other human renal diseases such as IgA nephropathy, membranous glomerulonephritis, and renal vasculitis are still lacking. Mouse strains that spontaneously develop distinct renal pathologies similar to lupus nephritis and focal-segmental glomerulosclerosis can be intercrossed with transgenic mice to study the impact of single-gene deletions on the renal phenotype. The present review provides a survey about currently available spontaneous and inducible murine models of renal disease with special attention to problems and future perspectives for their use in transgenic animals.
... In addition, Balb/c mice did not develop proteinuria or azotemia, suggesting that pathologic abnormalities are a more sensitive indicator of glomerular pathology in this disease model. Previous work with Balb/c has shown similar findings [5,15,16] although the degree of pathologic abnormalities was somewhat different. ...
... In addition, DBA/2J mice had normal physi- ological parameters and developed only a modest antibody response compared to the other three strains studied. Interestingly, B10.BR (H-2") mice, which develop mesangial proliferation in response to apoferritin [6], actually have antibody levels somewhat lower than the levels in the DBA/2J mice, suggesting that other factors such as antibody avidity [16] or isotype may be playing a role. It is clear from this data that the H2d genotype is not sufficient for the development of severe Apo-ICGN. ...
These experiments examined the effects of genes outside of the H-2 region on disease susceptibility and pathogenesis. Four strains of mice with the susceptible H-2 type, H-2d, but different non-H-2 genes were studied. B10, D2, Balb/c, NZB, and DBA/2J mice were injected with 4 mg of apoferritin i.p. q.d. for 28 days. B10, D2 and Balb/c mice developed proliferative and crescentic glomerulonephritis. NZB mice developed proliferative and crescentic glomerulonephritis with wire loop lesions suggestive of lupus. DBA/2J mice developed only minimal mesangial proliferation without crescents or necrosis. Electron microscopy showed subepithelial and mesangial deposits in B10, D2, moderate subepithelial and mesangial deposits in Balb/c, and marked mesangial, subendothelial and subepithelial deposits in NZB. Immunofluorescence demonstrated the presence of IgG, IgM, C3 and apoferritin in these deposits. The DBA/2J mice had only minimal mesangial deposits by immunofluorescence and electron microscopy. These experiments demonstrate that non-H-2 genes alter the H-2d determined disease susceptibility seen in H-2 congenic mice. NZB genes can alter the disease so that lupus-like lesions develop and DBA/2J genes can substantially ameliorate the disease.
We examined the role of antigenic charge on the deposition of immune complexes (IC) in murine gloerulia Acute serum sickens nephritis was induced by injecting chemically modified cationic bovine serum albumin (cationic BSA). Controls were immunized with unmodified native BSA (native BSA), All mice were given a primary intraperitoneal immunization with 500 pg of the respective antigens plus Freund's complete adjuvant. After 14 days, we divided the mice into following three groups. The first group was bled and killed for the characterization of antisera and histologic studyo Second group was injected intravenously with 200 μg of ¹²⁵I-labeled each BSA and bled at 5 minutes for measuring the size of IC. Third group was killed at 15 minutes after the second injection for histologic study. In the former renal specimens, neither IC nor antigen was detected in all animals. After the challenge, mice immunized with cationic BSA showed capillary wall deposits of IgG, whereas those immunized with native BSA developed mesangial depositions of IgG. Antibody avidity values in cationic BSA group were significantly lower than those in native BSA group (P<0, 005). The sucrose density gradient ultracentrif ugation study showed that the size of IC in cationic BSA group was slightly larger than 7S. From the above results, we speculated that : 1) The IC depositions on the glomerular capillary walls result from circulating IC formation. 2) The IC composed of cationic BSA effectively binds to the polyanion layer of the glomerular basement membrane. 3) Chemically modified cationization alters the characteristics of BSA, thereby causing the formation of small sized IC.
The kidneys of mice with glomerulonephritis vary in appearance depending on the stage of the dis- ease, but both kidneys are usually equally affect ed. In strain NZB and in (NZB × NZW) F1 hybrids in the acute phase of systemic lupus, the kidneys are café au lait or dusky pink and enlarged; the surfaces are smooth and shiny, and the capsule is nonadherent. Later in the course of the disease, the kidneys may be shrunken and the capsule adherent, revealing a granular pitted surface and small cysts or petechiae on the cut surface.
