Altered glomerular permeability induced by F(ab′)2 and Fab′ antibodies to rat renal tubular epithelial antigen

Altered glomerular permeability induced by F(ab′)2 and Fab′ antibodies to rat renal tubular epithelial antigen. Rats injected with F(ab′)2 and Fab′ antibody fragments directed against an antigen in the rat proximal tubular epithelial brushborder (Fx1A) developed immediate proteinuria [F(ab′)2 43.2 ± 6.7, N = 6; Fab′ 9.5 ± 2.8, N = 5; normal 1.6 ± 0.9 mg/day, N = 20]), that subsided after 3 to 5 days' duration. This reaction is in contrast to one exhibited by rats given intact IgG anti-Fx1A; the rats that did not develop immediate proteinuria (2.2 ± 0.3 mg/day, N = 5), and the glomerular binding of125I-antibody fragments was significantly less than that of intact IgG [F(ab′)2 0.11 ± 0.01; Fab′ 0.03 ± 0.01; IgG 0.17 ± 0.01% administered equimolar dose] at 24 hr. No proteinuria resulted from equimolar doses of nonantibody F(ab′)2 and Fab′. Less than 8% of the proteinuria induced by antibody fragments represented injected material, and 30 to 38% was albumin. Immunofluorescence revealed faint and diffuse glomerular capillary wall deposits of F(ab′)2 and Fab′ and tubular brushborder staining. Subepithelial, electrondense deposits and focal, podocyte effacement were seen by electron microscopy in rats given the F(ab′)2 antibody. Light microscopy and colloidal iron-staining were normal. In our study antibody fragments appear to interact directly with components of the outer, glomerular capillary wall to alter permeability in the absence of recognized mediators such as complement and inflammatory cells.Modification de la perméabilité glomérulaire déterminée par anticorps chez des rats anti-épithélium tubulaire F(ab′)2 et Fab′. Les rats été injectés avec des fragments F(ab′)2 et Fab′ contra anticorps de la bordure en brosse de l'épithélium tubulaire proximal de rat (Fx1A) ont immédiatement une protéinurie [F(ab′)2 43,2 ± 6,7, N = 6; Fab′ 9,5 ± 2,8, N = 5; normaux 1,6 ± 0,9 mg/d, N = 20] qui persiste pendant 3 à 5 jours. Cela réaction est différent de ce qui est observé chez les rats qui reçoivent l'IgG anti-Fx1A intacte; les rats quelles n'ont pas de protéinurie immédiate (2,2 ± 0,3 mg/d, N = 5) quoiqu'à 24 heures la liaison glomérulaire de fragments125I de l'anticorps soit significativement plus faible que celle de I'IgG intacte [F(ab′)2 0,11 ± 0,01; Fab′ 0,03 ± 0,01; IgG 0,17 ± 0,01 en % de la dose équimolaire administrée]. Aucune protéinurie n'a été la conséquence de l'administration équimolaire de F(ab′)2 et Fab′ non-anticorps. Moins de 8% de la protéinurie déterminée par les fragments d'anticorps représentent du matériel injecté et 30 à 38% est de l'albumine. L'immunofluorescence a montré des dépôts faibles et diffus, sur les parois des capillaires giomérulaires, de F(ab′)2 et Fab′ et le marquage de la bordure en brosse. En électronique, des dépôts denses sous-épithéliaux et l'effacement local des podocytes ont été observés chez les rats qui avaient reçu l'anticorps F(ab′)2. La microscopie optique et la coloration par le fer colloïdal n'ont pas montré d'anomalies. Dans notre étude les fragments d'anticorps semblent avoir paroi externe du capillaire glomérulaire et avoir modifié la perméabilité en l'absence de médiateurs connus tels le complément ou les cellules inflammatoires

Lupus autoantibodies interact directly with distinct glomerular and vascular cell surface antigens

Lupus autoantibodies interact directly with distinct glomerular and vascular cell surface antigens. We have identified monoclonal anti-DNA antibodies derived from lupus prone MRL-lpr/lpr mice that produce glomerular immune deposits and nephritis after passive transfer to normal mice. Particularly noteworthy is that the location of immune deposition varied among nephritogenic Ig, and this was associated with distinctive histologies and clinical disease profiles. Although their autoantigen binding properties differed, they were highly cross-reactive, in a manner similar to Ig deposited in glomeruli of lupus mice. This antigen binding profile was also typical of other previously described nephritogenic autoantibodies that bound directly to glomerular antigens to initiate immune deposit formation. In this study, we questioned whether ligation of different glomerular antigens by individual autoantibodies could contribute to the observed differences in the location of immune deposits. To examine this possibility, monoclonal anti-DNA antibodies (IgG2a) that produced glomerular immune deposits in different locations were evaluated. H221 produced mesangial, intracapillary (that is, intraluminal or within the capillary lumen) and subendothelial deposits associated with heavy proteinuria, whereas H147 produced mesangial, subendothelial and linear basement membrane deposits associated with proliferative glomerulonephritis. Initially, the capacity of H221 and H147 to bind directly to glomerular and vascular cell surfaces was evaluated. As demonstrated by FACS, H221 bound preferentially to mesangial cells whereas H147 bound preferentially to endothelial cells. To identify possible target cell surface antigens, Western blots, immunoprecipitation of surface labeled cells, and 2D gel electrophoresis were employed. H221 reacted with a 108kDa protein on mesangial cells not identified by H147, whereas H147 reacted with a 45kDa protein on endothelial cells not identified by H221. These results support the hypothesis that some nephritogenic lupus autoantibodies initiate immune deposit formation through direct interaction with glomerular antigens. Furthermore, they suggest that the site of immune deposition is determined by both antigen binding properties of the relevant antibody and the location of its target ligand within the glomerulus. In a given individual, therefore, the predominant autoantibody-glomerular antigen interaction may influence the morphologic and clinical phenotype expressed. Variation in the predominant interaction may also contribute to variations in disease expression among individuals with lupus nephritis

A Realist Perspective on AI-era Public Management

Recent years have witnessed a number of significant ideas and approaches to addressing the shortcomings of the New Public Management paradigm. Three of these recent ideas, which include Digital Era Governance, Public Value Management, and New Public Governance, emphasise partnerships collaboration and engagement of citizens; performance governance and innovation and recognize the transformational potentials of digital technologies. Artificial Intelligence (AI) is one of the digital technologies attracting the greatest interest in public administration in terms of its potential impact. There are already a number of reports on how AI is being deployed in the public sector with good outcomes. By employing a realist review approach, this study investigates the specific mechanisms across post-NPM, organisational, individual and innovation contexts which are associated with positive outcomes from AI initiatives in the public sector. The study further examined the specific applications of AI initiatives within Post-NPM agendas. Our findings provide some empirical evidence for a better understanding of the conditions and where to target AI-based solutions in post-NPM context for positive outcomes

Glomerular Autoimmune Multicomponents of Human Lupus Nephritis In Vivo (2): Planted Antigens.

Glomerular planted antigens (histones,DNA,andC1q) arepotential targets of autoimmunity in lupus nephritis (LN). However, the characterization of these antigens in human glomeruli in vivo remains inconsistent. We eluted glomerular autoantibodies recognizing planted antigens from laser-microdissected renal biopsy samples of 20 patientswith LN. Prevalent antibody isotypes were defined, levelswere determined, and glomerular colocalization was investigated. Renal and circulating antibodieswerematched, and serum levelswere compared in 104 patients with LN, 84 patients with SLE without LN, and 50 patients with rheumatoid arthritis (RA). Autoantibodies against podocyte antigens (antia-enolase/antiannexin AI) were also investigated. IgG2 autoantibodies against DNA, histones (H2A, H3, and H4), and C1q were detected in 50%, 55%, and 70% of biopsy samples, respectively. Anti-DNA IgG3 was the unique non-IgG2 anti-DNA deposit, and anti-C1q IgG4 was mainly detected in subepithelial membranous deposits. Anti-H3, anti-DNA, and anti-C1q IgG2 autoantibodies were also prevalent in LN serum, which also contained IgG3 against the antigen panel and anti-C1q IgG4. Serum and glomerular levels of autoantibodies were not strictly associated. High serum levels of all autoantibodies detected, including anti a-enolase and antiannexin AI, identified LN versus SLE and RA. Anti-H3 and antia-enolase IgG2 levels had the most remarkable increase in LN serum and represented a discriminating feature of LN in principal component analysis. The highest levels of these two autoantibodies were also associated with proteinuria.3.5 g/24 hours and creatinine>1.2 mg/dl. Our findings suggest that timely autoantibody characterization might allow outcome prediction and targeted therapies for patients with nephritis

Glomerular autoimmune multicomponents of human lupus nephritis in vivo: α-enolase and annexin AI

Renal targets of autoimmunity in human lupus nephritis (LN) are unknown. We sought to identify autoantibodies and glomerular target antigens in renal biopsy samples from patients with LN and determine whether the same autoantibodies can be detected in circulation. Glomeruli were microdissected from biopsy samples of 20 patients with LN and characterized by proteomic techniques. Serum samples from large cohorts of patients with systemic lupus erythematosus (SLE) with and without LN and other glomerulonephritides were tested. Glomerular IgGs recognized 11 podocyte antigens, with reactivity varying by LN pathology. Notably, IgG2 autoantibodies against \u3b1-enolase and annexin AI were detected in 11 and 10 of the biopsy samples, respectively, and predominated over other autoantibodies. Immunohistochemistry revealed colocalization of \u3b1-enolase or annexin AI with IgG2 in glomeruli. High levels of serum anti-\u3b1-enolase (>15 mg/L) IgG2 and/or anti-annexin AI (>2.7 mg/L) IgG2 were detected in most patients with LN but not patients with other glomerulonephritides, and they identified two cohorts: patients with high anti-\u3b1-enolase/low anti-annexin AI IgG2 and patients with low anti-\u3b1-enolase/high anti-annexin AI IgG2. Serum levels of both autoantibodies decreased significantly after 12months of therapy for LN. Anti-\u3b1-enolase IgG2 recognized specific epitopes of \u3b1-enolase and did not cross-react with dsDNA. Furthermore, nephritogenic monoclonal IgG2 (clone H147) derived from lupus-prone MRL-lpr/lpr mice recognized human \u3b1-enolase, suggesting homology between animal models and human LN. These data show a multiantibody composition in LN, where IgG2 autoantibodies against \u3b1-enolase and annexin AI predominate in the glomerulus and can be detected in serum

What is damaging the kidney in lupus nephritis?

Despite marked improvements in the survival of patients with severe lupus nephritis over the past 50 years, the rate of complete clinical remission after immune suppression therapy i