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V Montinaro

Publications and source records attributed to V Montinaro.

10 recordsLinked to original sources
PubMed1992

Extrarenal cytokines modulate the glomerular response to IgA immune complexes.

Clinical episodes of IgA nephropathy coincide recurrently with microbial infections. Cytokines produced during such infections may play a role in the pathogenesis of IgA-associated glomerulonephritis. To test this hypothesis, we examined the influence of passively administered proinflammatory cytokines (IL-1, IFN-gamma and IL-6) on the development of glomerulonephritis in an experimental model of IgA nephropathy. Glomerular IgA immune deposits were induced in mice by administration of IgA anti-phosphorylcholine (PC) with either a PC-containing carbohydrate antigen of Pneumococcal C polysaccharide (PnC) or a protein antigen of PC-conjugated bovine serum albumin (PC-BSA). The effect of IL-1 on the IgA-PC-BSA induced glomerular changes resulted in an increase of mesangial hypercellularity that was associated with mild proteinuria and hematuria. Mice treated with IL-1 and IgA-PnC developed diffuse proliferative glomerulonephritis with proteinuria and hematuria. In contrast, IL-6 treatment with IgA-PC-BSA of IgA-PnC failed to exert any significant renal effect. The combination of IL-6 and IL-1, however, intensified the mesangial hypercellularity of the IgA-PC-BSA, and induced severe proliferative glomerulonephritis with inflammatory monocytes and neutrophils infiltrates in the IgA-PnC treated mice. These glomerular changes were also accompanied by increased proteinuria and hematuria. Similarly, the combination of IFN with IL-1 produced histologic changes and compromised renal function more than IFN or IL-1 exerted independently. These results suggest that extrarenal cytokines influence the renal response to IgA immune deposits. We also conclude that a synergy of multiple cytokines and nephritogenic antigens immobilized in glomerular IgA immune deposits may lead to rapid progression of IgA-associated glomerulonephritis.

Animals↗
PubMed1992

Primary IgA nephropathy: the relevance of experimental models in the understanding of human disease.

IgA nephropathy is the most common form of primary glomerulonephritis worldwide. About one quarter of patients progress to terminal renal failure 10 years after the apparent clinical onset. Therefore, the disease represents a social problem in terms of number of patients requiring maintenance hemodialysis. Despite the intense research effort devolved to clarify the pathogenesis of IgA nephropathy, the exact relationship linking the several factors involved is still unknown. In this review we analyze the experimental works reported since 1979, when the first animal model of IgA nephropathy was published by Rifai et al. We also discuss the interplay between experimental data and clinical observations to maximize the information gathered from the different animal models. Finally, we report the new insights into the role played by cytokines, growth factors and autacoids.

Animals↗
PubMed1992

Immunopathological aspects of immunoglobulin A nephropathy and other mesangial proliferative glomerulonephritides.

Immunoglobulin A nephropathy (IgAN) is an immune complex (IC) glomerulonephritis (GN) that represents one of the most common forms of primary glomerular disease. Proliferation of mesangial cells and the increase of mesangial matrix are histological hallmarks of mesangioproliferative GN. Increased serum levels of IgA, polymeric IgA, IgA rheumatoid factor, IgA-IC, and spontaneous or pokeweed mitogen-induced production of IgA by peripheral blood mononuclear cells are major humoral immune alterations reported in IgAN. Recently, we focused on the role of cytokines and growth factors in the mediation of glomerular injury. Platelet-derived growth factor, transforming growth factor beta, interleukin (IL)-1 and IL-6 are expressed by and act on mesangial cells. Increased expression of platelet-derived growth factor was found in both an active model of IgAN and in renal biopsies of patients with proliferative GN. A strict correlation between increased expression of B-chain mRNA and mesangial proliferation was found. Cytokines such as IL-1, interferon gamma, and IL-6, released by infiltrating mononuclear cells or produced locally by mesangial cells, affect the glomerular response to IgA-IC. In a passive murine experimental model of IgAN, IL-1 and interferon gamma increased mesangial hypercellularity, whereas IL-6 was highly pathogenic when associated to IL-1. In conclusion, classical immunological mechanisms in mesangial GN could interact with other pathways involving cytokines and growth factors in the progression of glomerular injury.

Animals↗
PubMed1991

Antigen as mediator of glomerular injury in experimental IgA nephropathy.

IgA immune complexes (IgA-IC) are considered the primary cause of IgA nephropathy. Despite the consistent findings of IgA and frequently C3 glomerular deposits in most patients, the renal histopathologic lesion may vary from mild mesangial involvement to severe sclerosis. In the IgA immune deposits, IgA and C3 are considered to be relatively constant, whereas the composition of the antigen is expected to vary according to its origin. This report explored th possibility that the histopathologic lesion is a function of the antigen in an IgA immune deposit. To test this hypothesis we developed a passive model of IgA nephropathy whereby glomerular IgA deposits can capture, in situ, circulating antigens. In this model, glomerular IgA deposits (IgA/IgA-IC) were induced by administration of a constant amount of IgA anti-dinitrophenyl (antibody) and dinitrophenyl-conjugated IgA anti-phosphorylcholine (PC) as an antigen. The latter also served as antibody to capture, in situ, circulating PC-containing antigens. Mice that received only IgA/IgA-IC developed glomerular IgA and C3 deposits and a focal increase in mesangial cells and matrix, but no evidence of renal damage. A diffuse increase in mesangial cells and matrix developed in mice treated with IgA/IgA-IC and either PC-Ficoll (carbohydrate antigen) or PC conjugate of bovine serum albumin (protein antigen). In contrast, mice that received IgA/IgA-IC and pneumococcal C polysaccharide, a PC-containing antigen, developed severe diffuse mesangial hypercellularity with segmental necrosis and thrombosis. These mice also developed proteinuria and hematuria. Our results demonstrate that the antigen plays a critical role in development of glomerulonephritis associated with IgA-IC.

Animals↗
PubMed1989

Increased serum levels of IgA1-IgG immune complexes and anti-F(ab')2 antibodies in patients with primary IgA nephropathy.

A solid-phase ELISA was used to detect IgA1 immune complexes (IgA1 ICs) containing IgG and IgM in 38 serum samples from 30 patients with primary IgA nephropathy (IgAN) and 14 subjects with non-IgA chronic glomerulonephritis. A jackfruit lectin, jacalin, was used as the substrate for the selective binding of human IgA1 ICs in serum PEG precipitate (7%). The presence of IgG, A and M antibodies against the F(ab')2 region of IgG was also investigated by the solid-phase ELISA. Six patients were studied during remission and relapse (fever, upper respiratory tract infection and macroheamaturia). The results showed significant increases in serum levels of IgA1 ICs (P less than 0.001) in 39.4% of the IgAN patients, IgA1-IgG ICs (P less than 0.001) in 68.4%, and IgA1-IgM ICs (P less than 0.002) in 10.5% of the patients. A significant increase in IgA1-IgG ICs was observed during relapse (P less than 0.02). Significantly high values of IgG (P less than 0.003) and IgA (P less than 0.001) antibodies directed at the F(ab')2 region of IgG were found. A significant increase in anti F(ab')2 antibodies (class IgA and IgM) was seen in the acute phase of the disease. The data suggest that an increased production of IgA1 ICs occurs in IgAN patients; ICs are mainly IgA1-IgG ICs during relapse. The presence of high serum levels of IgG and IgA antibodies against the F(ab')2 region of IgG indicates that in addition to the multiple anomalies of IgA regulation described in IgAN patients there may be further aberrances.

Adolescent↗
PubMed1989

Clearance kinetics and fate of macromolecular IgA in patients with IgA nephropathy.

IgA glomerulonephritis is associated with macromolecules of polymeric IgA in the circulation and mesangial deposits. An impairment in the reticulophagocytic function of patients with IgA nephropathy has been postulated as the potential cause for persistence of IgA immune complexes in the circulation and their eventual glomerular deposition. Since the fate and removal mechanisms of circulating macromolecular IgA are unknown in humans, we examined the blood clearance and organ uptake of purified IgA polymers and macromolecules in patients with IgA nephropathy and normal controls. The IgA macromolecules were prepared by covalent cross-linking of purified human polymeric IgA with a heterobifunctional reagent, N-succinimidyl 3-(2-pyridyldithio) propionate. After intravenous injection, large IgA molecules were removed rapidly from the circulation of patients (t1/2 = 3.8 +/- 1.0 minutes) and controls (t1/2 = 4.9 +/- 1.5 minutes). Dynamic gamma camera scintigraphy revealed the liver as the major organ that mediated the removal of the macromolecular IgA with no significant difference in the rate of hepatic uptake for patients (t1/2 = 3.4 +/- 0.6 minutes) and controls (t1/2 = 3.3 +/- 0.9 minutes). No significant amount of radioactivity could be detected in the lungs, kidneys, and spleen. The small polymers had a slower and similar clearance rates for patients (t1/2 = 29.3 +/- 7.9 h) and controls (t1/2 = 29.0 +/- 8.6 h). These findings have general significance in showing the liver as a major organ for removal of macromolecular IgA. In addition, the results have specific importance in showing that patients with IgA nephropathy do not suffer from an IgA removal dysfunction.

Adolescent↗
PubMed1988

Polymeric IgA and IgA rheumatoid factor decrease the capacity of serum to solubilize circulating immune complexes in patients with primary IgA nephropathy.

Primary IgA nephropathy (IgAN) is characterized by the presence of immune complexes (IC), high levels of polymeric IgA (pIgA), and IgA rheumatoid factor (RF) in the blood. The impaired capacity of serum to solubilize IC in the presence of normal values of C hemolytic activity as well as high serum levels of C3, C4, and properdin factor B have led us to analyze whether pIgA and IgA RF from patients with IgAN where capable of inhibiting the capacity of normal human serum to solubilize immune precipitates (BSA-anti-BSA) preformed at equivalence. The results showed a significant reduced mean capacity of serum from patients with IgAN to solubilize "in vitro" immune precipitates (p less than 0.001) and significant high mean levels of pIgA (p less than 0.001) and IgA RF (p less than 0.005) in the blood. Increasing amounts of pIgA inhibited solubilization of IC in the fluid phase, and inhibitory activity was also shown by the IgA RF. There were inverse correlations between pIgA and the capacity of serum to solubilize IC (r = -0.36; p less than 0.05), and between IgA RF and the complement-mediated solubilization (r = -0.57; p less than 0.001). It is suggested that pIgA and IgA RF may be responsible for the impaired complement-mediated solubilization of serum and the persistence of insoluble nephritogenic IC in the blood of patients with primary IgAN.

Adolescent↗
PubMed1988

The role of polymeric IgA in complement-mediated solubilization of IgG and IgA immune complexes.

Sera from patients with IgA nephropathy (IgAN) have a reduced capacity to solubilize immune complexes. The in vitro complement-mediated solubilization of immune complexes containing IgG (bovine serum albumin [BSA]-anti-BSA) or IgA (DNP29-BSA-anti-DNP) was decreased, despite normal serum levels of complement. The close correlation between low values for complement-mediated solubilization and high serum levels of polymeric IgA and/or IgA rheumatoid factor indicates that these macromolecules interfere with the process. These findings suggest that polymeric IgA produced during stimulation of mucosae specifically interferes with immune complex solubilization. Further studies are necessary to elucidate the mechanisms. The decreased complement-mediated solubilization in patients with IgAN could be responsible for persistently high levels of immune complexes containing IgA or IgG in the circulation and their continual deposition in the mesangium.

Antigen-Antibody Complex↗