IgG subclasses in patients with membranoproliferative glomerulonephritis, membranous nephropathy, and lupus nephritis

Imai, Hirokazu; Hamai, Keiko; Komatsuda, Atsushi; Oda, Hiroshi; Miura, Akira B.

doi:10.1038/ki.1997.32

Cited by 182 publications

(124 citation statements)

References 11 publications

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“…The nature of pathogenic antigen and antibodies in IMN remain yet elusive, and studies at the moment can only be focused on potentially relevant Ig subclasses. In this respect, IgG4 were found to concentrate in the glomerular deposits (25,26), while serum levels were selectively low for IgG2 (27). Identifying the specific antibodies and documenting their disappearance from the circulation after effective B cell inhibition would greatly enhance our understanding of the role of B cell-related mechanisms in IMN.…”

Section: Discussionmentioning

confidence: 99%

Rituximab in Idiopathic Membranous Nephropathy

Ruggenenti

Chiurchiu²,

Brusegan³

et al. 2003

Journal of the American Society of Nephrology

203

171

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Abstract. Currently available monoclonal antibodies against the B cell surface antigen CD20 have been employed to explore whether specific inhibition of B cells may help improve the outcome of idiopathic membranous nephropathy (IMN) and may avoid the side effects of steroids and immunosuppressants. This prospective, observational study evaluated the 1-yr outcome of eight IMN patients with persistent (Ͼ6 mo) urinary protein excretion Ͼ 3.5 g/24 h given four weekly infusions of the anti-CD20 antibody rituximab (375 mg/m 2 ). At 3 and 12 mo, proteinuria significantly decreased from mean (Ϯ SD) 8.6 Ϯ 4.2 to 4.3 Ϯ 3.3 (Ϫ51%, P Ͻ 0.005) and 3.0 Ϯ 2.5 (Ϫ66%, P Ͻ 0.005) g/24 h, albumin fractional clearance from 2.3 Ϯ 2.1 to 1.2 Ϯ 1.7 (Ϫ47%, P Ͻ 0.05) and 0.5 Ϯ 0.6 (Ϫ76%, P Ͻ 0.003), and serum albumin concentration increased from 2.7 Ϯ 0.5 to 3.1 Ϯ 0.3 (ϩ21%, P Ͻ 0.05) and 3.5 Ϯ 0.4 (ϩ41%, P Ͻ 0.05) mg/dl. At 12 mo, proteinuria decreased to Յ0.5 g/24 h or Յ3.5 g/24 h in two and three patients, respectively. Proteinuria decreased in the remaining patients by 74%, 44%, and 41%, respectively. Body weight, diastolic BP, and serum cholesterol progressively decreased in parallel with an improvement of edema in all patients. Renal function stabilized (⌬1/creatinine: ϩ0.002 Ϯ 0.007). CD20 B lymphocytes fell below normal ranges up to study-end. No patient had major drug-related events or major changes in other laboratory parameters. Rituximab thus promotes sustained disease remission in patients otherwise predicted to progress to ESRD, and it is safe. The long-term risk/benefit profile of this novel, diseasespecific approach seems much more favorable to that of commonly employed immunosuppressive drugs.Idiopathic membranous nephropathy (IMN) is an immunemediated disease of deposits of immunoglobulins G and complement components on the subepithelial layer of the glomerular capillary wall (1). Data from studies in animals suggest that the immune deposition resulting from B cell activation promotes injury to the glomerular filtering barrier and consequent proteinuria (2). Thus, agents that limit or prevent B cell production of nephritogenic immunoglobulins should block at an early step the sequence of pathogenic events and eventual progressive renal dysfunction in IMN. So far, however, therapeutic approaches to IMN relied on steroids and immunosuppressant drugs, which are not fully specific and carry the risk of severe toxic effects. This may explain why the outcome of IMN has not substantially improved over the past 30 yr and why up to 40% of patients still progress to end-stage renal failure despite treatment with glucocorticoids and alkylating agents. The long-term effectiveness of cyclosporine is also questionable due to the high relapse rates and associated toxic effects of the drug (3,4).Availability of monoclonal antibodies against the cell surface antigen CD20 of B cells allowed to explore whether more specific B cell inhibition (5) may help improving the outcome of IMN and avoiding the side effects of steroids and immunosup...

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Section: Discussionmentioning

confidence: 99%

Rituximab in Idiopathic Membranous Nephropathy

Ruggenenti

Chiurchiu²,

Brusegan³

et al. 2003

Journal of the American Society of Nephrology

203

171

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“…One might question the role of complement activation in human MN because the non-complement-fixing IgG4 isotype predominates in the immune deposits (29,53), and the C1qr 2 s 2 complex is quite large (M r ϳ 800 kDa), which undoubtedly impedes its access to the subepithelial space. Still, there is a good deal of circumstantial evidence that complement is activated in subepithelial immune deposits, including the presence of C3 and C5b-9 in many cases (48,99) and C3d in all cases of human MN (28); C3d is the stable C3 product generated from iC3b by factor I, presumably relying on podocyte CR1 as a cofactor.…”

Section: Implications For Human Mnmentioning

confidence: 99%

Experimental membranous nephropathy redux

Cybulsky

Quigg²,

Salant³

2005

American Journal of Physiology-Renal Physiology

116

133

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Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. Active and passive Heymann nephritis (HN) in rats are valuable experimental models because their features so closely resemble human MN. In HN, subepithelial immune deposits form in situ as a result of circulating antibodies. Complement activation leads to assembly of C5b-9 on glomerular epithelial cell (GEC) plasma membranes and is essential for sublethal GEC injury and the onset of proteinuria. This review revisits HN and focuses on areas of substantial progress in recent years. The response of the GEC to sublethal C5b-9 attack is not simply due to disruption of the plasma membrane but is due to the activation of specific signaling pathways. These include activation of protein kinases, phospholipases, cyclooxygenases, transcription factors, growth factors, NADPH oxidase, stress proteins, proteinases, and others. Ultimately, these signals impact on cell metabolic pathways and the structure/function of lipids and key proteins in the cytoskeleton and slit-diaphragm. Some signals affect GEC adversely. Thus C5b-9 induces partial dissolution of the actin cytoskeleton. There is a decline in nephrin expression, reduction in F-actin-bound nephrin, and loss of slit-diaphragm integrity. Other signals, such as endoplasmic reticulum stress, may limit complement-induced injury, or promote recovery. The extent of complement activation and GEC injury is dependent, in part, on complement-regulatory proteins, which act at early or late steps within the complement cascade. Identification of key steps in complement activation, the cellular signaling pathways, and the targets will facilitate therapeutic intervention in reversing GEC injury in human MN.

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“…It is likely that specific types of human glomerulonephritis are associated with a polarization in the T cell response. For example, studies of human crescentic glomerulonephritis have shown that there is a predominant macrophage, T cell, and fibrin deposition that is consistent with a predominant Th1-type immune response (24,25), whereas in membranous nephropathy, there is IgG4 deposition within the glomerulus, an IgG subclass that is associated with a Th2 immune response (26).…”

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confidence: 99%

Toll-Like Receptor 2 Agonists Exacerbate Accelerated Nephrotoxic Nephritis

Brown

Sacks

Robson

2006

Journal of the American Society of Nephrology

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Glomerulonephritis can be exacerbated by infection. This study investigated the effect of N-palmitoyl-S-(2,3-bis(palmitoyloxy)-(2R,S)-propyl)-(R)-cysteinyl-seryl-(lysyl)3-lysine (Pam 3 CysSK 4 ), a synthetic Toll-like receptor 2 (TLR2) ligand, that was given at immunization on disease severity in accelerated nephrotoxic nephritis. Stimulation of TLR by microbial constituents is known to influence the development of the adaptive immunity. It was hypothesized that the TLR2 ligand Pam 3 CysSK 4 can modulate the development of disease in accelerated nephrotoxic nephritis by influencing the development of adaptive immunity. It is shown that Pam 3 CysSK 4 , when given at immunization, can increase profoundly the severity of disease, and with the use of TLR2-deficient mice, it is shown that this disease exacerbation depends on the presence of TLR2. Wild-type mice that were given Pam 3 CysSK 4 at immunization and had more severe disease also had a greater amount of antigen-specific IgG1, IgG2b, and IgG3 in the serum and more IgG2b and IgG3 deposited within the glomerulus. They also had increased numbers of glomerular CD4-positive T cells. Therefore, the more severe disease that was seen in the group that was immunized with lipopeptide can be attributed to an influence on the adaptive immune response.

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IgG subclasses in patients with membranoproliferative glomerulonephritis, membranous nephropathy, and lupus nephritis

Cited by 182 publications

References 11 publications

Rituximab in Idiopathic Membranous Nephropathy

Rituximab in Idiopathic Membranous Nephropathy

Experimental membranous nephropathy redux

Toll-Like Receptor 2 Agonists Exacerbate Accelerated Nephrotoxic Nephritis

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