Complement in glomerular diseases

Tan, Ying; Zhao, Ming‐Hui

doi:10.1111/nep.13461

Cited by 11 publications

(9 citation statements)

References 38 publications

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“…The primary efficacy measure of greater than 50% reduction in Birmingham Vasculitis Activity Score by week 12 with no worsening of any organ system was achieved in 86.4% (P ¼ 0.002 for noninferiority) of patients treated with avacopan plus 20 mg prednisone and 81.0% (P ¼ 0.01 for noninferiority) of patients solely treated with avacopan, compared with 70.0% in the control group treated with 60 mg prednisone. These findings support avacopan as an effective substitute in replacing high-dose glucocorticoids in treating vasculitis (Jayne et al, 2017;Tan and Zhao, 2018). A phase II study was recently initiated for avacopan in HS (NCT03852472).…”

Section: Strategies For Anticomplement Therapiessupporting

confidence: 55%

Role of the Complement Pathway in Inflammatory Skin Diseases: A Focus on Hidradenitis Suppurativa

Ghias

Hyde

Tomalin

et al. 2020

Journal of Investigative Dermatology

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Although the role of immune dysregulation in hidradenitis suppurativa (HS) has yet to be elucidated, recent studies identified several complement abnormalities in patients with HS. The complement system serves a critical role in the modulation of immune response and regulation of cutaneous commensal bacteria. Complement is implicated in several inflammatory skin diseases including systemic lupus erythematosus, angioedema, pemphigus, bullous pemphigoid, and HS. A model of HS pathogenesis is proposed, integrating the role of commensal bacteria, cutaneous immune responses, and complement dysregulation. The role of complement in disease pathogenesis has led to the development of novel anticomplement agents and clinical trials investigating the efficacy of such treatments in HS.

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Section: Strategies For Anticomplement Therapiessupporting

confidence: 55%

Role of the Complement Pathway in Inflammatory Skin Diseases: A Focus on Hidradenitis Suppurativa

Ghias

Hyde

Tomalin

et al. 2020

Journal of Investigative Dermatology

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“…We expected this poly-rIgA analog sterically to resemble IgA complexes in its interaction with CD89 for phagocytic clearance [30,35,36]. Furthermore, via an avidity effect [37], the clustered pattern of Fc in poly-rIgA was expected to trigger immune reactivity, including activation of an alternative complement pathway, as seen by IgA immune complexes in human disease [38,39].…”

Section: Construction Of Recombinant Iga-biotin Fusion For Induction Of Oligomers With Streptavidinmentioning

confidence: 99%

Renal deposition and clearance of recombinant poly‐IgA complexes in a model of IgA nephropathy

Xie

Liu

Gao

et al. 2021

The Journal of Pathology

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IgA nephropathy (IgAN) is the most common type of glomerulonephritis worldwide, which follows a chronic but nonetheless highly variable course of progression. IgA immune complexes are the primary source of renal deposits in IgAN. Apart from the presence of granular IgA1 deposits in the glomerular mesangium and mesangial hypercellularity as common features, the detailed process of IgA1 deposition and clearance in the kidney remains unclear. We sought to examine the dynamics of IgA deposition and tissue plasticity in response to deposits including their intrarenal clearance. We followed a synthetic approach to produce a recombinant fusion between IgA Fc (rIgA) and a biotin tag, which was subsequently induced with streptavidin (SA) to form an oligomeric poly‐IgA mimic. Both uninduced rIgA (mono‐rIgA) and polymeric SA‐rIgA (poly‐rIgA) were injected intravenously into Wistar rats. Plasma IgA levels and renal and liver histology were examined in a time series. In contrast to mono‐rIgA, this synthetic poly‐rIgA analog formed renal deposits exclusively in the glomerulus and were mostly cleared in 3 h. However, repeated daily injections for 12 days caused long‐lasting and stronger glomerular IgA deposition together with IgG and complement C3, in association with mesangial cell proliferation, matrix expansion, and variable degrees of albuminuria and hematuria that phenocopied IgAN. Ex vivo, poly‐rIgA bound cultured mesangial cells and elicited cytokine production, in addition to activating plasma C3 that was consistent with the actions of IgA immune complexes in IgAN pathogenesis. Remarkably, the kidneys were able to reverse all pathologic manifestations and restore normal glomerular histology 2 weeks after injections were halted. The synthetic model showed the kinetics between the intricate balance of renal deposition and clearance, as well as glomerular plasticity towards healing. Together, the results revealed a priming effect of existing deposits in promoting stronger and longer‐lasting IgA deposition to cause renal damage. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…The kidney is considered to be particularly vulnerable to damage caused by complement dysfunction ( 10 , 53 ). Although the precise reason thereof is not completely understood, several factors might collude.…”

Section: Inflammatory Kidney Diseases With Complement Involvementmentioning

confidence: 99%

Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway

et al. 2020

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The complement system comprises the frontline of the innate immune system. Triggered by pathogenic surface patterns in different pathways, the cascade concludes with the formation of a membrane attack complex (MAC; complement components C5b to C9) and C5a, a potent anaphylatoxin that elicits various inflammatory signals through binding to C5a receptor 1 (C5aR1). Despite its important role in pathogen elimination, priming and recruitment of myeloid cells from the immune system, as well as crosstalk with other physiological systems, inadvertent activation of the complement system can result in self-attack and overreaction in autoinflammatory diseases. Consequently, it constitutes an interesting target for specialized therapies. The paradigm of safe and efficacious terminal complement pathway inhibition has been demonstrated by the approval of eculizumab in paroxysmal nocturnal hematuria. In addition, complement contribution in rare kidney diseases, such as lupus nephritis, IgA nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, or antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated. This review summarizes the involvement of the terminal effector agents of the complement system in these diseases and provides an overview of inhibitors for complement components C5, C5a, C5aR1, and MAC that are currently in clinical development. Furthermore, a link between increased complement activity and lung damage in severe COVID-19 patients is discussed and the potential for use of complement inhibitors in COVID-19 is presented.

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Complement in glomerular diseases

Cited by 11 publications

References 38 publications

Role of the Complement Pathway in Inflammatory Skin Diseases: A Focus on Hidradenitis Suppurativa

Role of the Complement Pathway in Inflammatory Skin Diseases: A Focus on Hidradenitis Suppurativa

Renal deposition and clearance of recombinant poly‐IgA complexes in a model of IgA nephropathy

Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway

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