Overview of complement activation and regulation.

doi:10.1016/J.SEMNEPHROL.2013.08.001

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Overview of complement activation and regulation.

Journal Article•DOI•

Overview of complement activation and regulation.

Marina Noris¹, Giuseppe Remuzzi¹•Institutions (1)

Mario Negri Institute for Pharmacological Research¹

01 Nov 2013-Seminars in Nephrology (Elsevier)-Vol. 33, Iss: 6, pp 479-492

TL;DR: Many kidney disorders have been linked to abnormal complement activation, including immune-complex–mediated glomerulonephritis and rare genetic kidney diseases, but also tubulointerstitial injury associated with progressive proteinuric diseases or ischemia-reperfusion.

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About: This article is published in Seminars in Nephrology.The article was published on 2013-11-01 and is currently open access. It has received 591 citations till now. The article focuses on the topics: Complement receptor & Classical complement pathway.

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Journal Article•DOI•

Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift.

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Yasir N. Jassam, Saef Izzy¹, Saef Izzy², Michael J. Whalen¹, Dorian B. McGavern, Joseph El Khoury¹ - Show less +2 more•Institutions (2)

Harvard University¹, Brigham and Women's Hospital²

13 Sep 2017-Neuron

TL;DR: A new paradigm to study innate immune cells following TBI is proposed that moves away from the existing M1/M2 classification of activation states toward a stimulus- and disease-specific understanding of polarization state based on transcriptomic and proteomic profiling.

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450 citations

Cites background from "Overview of complement activation a..."

...…family of proteins that have diverse roles in inflammatory processes, including pro-inflammatory signaling (anaphylatoxins), marking cells for uptake by other cells (opsonization), and formation of membrane attack complexes that cause direct cellular damage (Chaplin, 2010; Noris and Remuzzi, 2013)....
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...nent of innate immunity is complement, which is a family of proteins that have diverse roles in inflammatory processes, including pro-inflammatory signaling (anaphylatoxins), marking cells for uptake by other cells (opsonization), and formation of membrane attack complexes that cause direct cellular damage (Chaplin, 2010; Noris and Remuzzi, 2013)....
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Journal Article•DOI•

Complement in disease: a defence system turning offensive

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Daniel Ricklin¹, Edimara S. Reis¹, John D. Lambris¹•Institutions (1)

University of Pennsylvania¹

01 Jul 2016-Nature Reviews Nephrology

TL;DR: This Review summarizes the current view of the key activating, regulatory, and effector mechanisms of the complement system, highlighting important crosstalk connections, and discusses the involvement of complement in clinical conditions and promising therapeutic approaches.

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Abstract: Although the complement system is primarily perceived as a host defence system, a more versatile, yet potentially more harmful side of this innate immune pathway as an inflammatory mediator also exists. The activities that define the ability of the complement system to control microbial threats and eliminate cellular debris - such as sensing molecular danger patterns, generating immediate effectors, and extensively coordinating with other defence pathways - can quickly turn complement from a defence system to an aggressor that drives immune and inflammatory diseases. These host-offensive actions become more pronounced with age and are exacerbated by a variety of genetic factors and autoimmune responses. Complement can also be activated inappropriately, for example in response to biomaterials or transplants. A wealth of research over the past two decades has led to an increasingly finely tuned understanding of complement activation, identified tipping points between physiological and pathological behaviour, and revealed avenues for therapeutic intervention. This Review summarizes our current view of the key activating, regulatory, and effector mechanisms of the complement system, highlighting important crosstalk connections, and, with an emphasis on kidney disease and transplantation, discusses the involvement of complement in clinical conditions and promising therapeutic approaches.

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391 citations

Journal Article•DOI•

Systemic AAV Micro-dystrophin Gene Therapy for Duchenne Muscular Dystrophy.

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Dongsheng Duan¹•Institutions (1)

University of Missouri¹

03 Oct 2018-Molecular Therapy

TL;DR: Preclinical data suggests that intravascular AAV micro-dystrophin delivery can significantly ameliorate muscle pathology, enhance muscle force, and attenuate dystrophic cardiomyopathy in animals.

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288 citations

Journal Article•DOI•

The case of complement activation in COVID-19 multiorgan impact.

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Marina Noris¹, Ariela Benigni¹, Giuseppe Remuzzi¹•Institutions (1)

Mario Negri Institute for Pharmacological Research¹

01 Aug 2020-Kidney International

TL;DR: The hypothesis that blockade of the terminal complement pathway may represent a potential therapeutic option for the prevention and treatment of lung and multi-organ damage is proposed.

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261 citations

Cites background from "Overview of complement activation a..."

...In patients with COVID-19, eculizumab, by preventing the cleavage of C5, could exert a favorable effect by blocking the proinflammatory and prothrombotic actions of the terminal products of the complement cascade activated by SARS-CoV2, while preserving the activity of early complement components that are important for viral clearance and activation of the adaptive immune response.(13,22) We hypothesize that C5 blockade could also have beneficial effects in countering AKI by preventing C5b-9 accumulation in tubuli....
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...SARS-CoV interacts with MBL,(20) a C-type lectin that activates the mannose-binding protein–associated serine protease 2 to cleave C4 and C2 and initiate the complement lectin pathway (Figure 2).(13)...
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...However, unrestrained complement activation contributes to acute and chronic inflammation, intravascular coagulation, and cell injury, and it ultimately leads to multiple organ failure and death.(13) In a preprint article recently published online,(14) an immunohistochemistry analysis of lung tissue from patients who died of COVID-19 revealed strong staining for the...
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...The complement system is made up of over 30 proteins organized in the 3 activation pathways—the classical, the lectin, and the alternative (Figure 2)—that converge on the cleavage of central component C3 by enzyme complexes—the classical/lectin and the alternative C3 convertases—that generate activation products (C3a, C4a, C3b, and C4b) that function to eliminate pathogens through opsonization, attract and activate neutrophils and macrophages, and enhance humoral immunity and T-cell response.(13)...
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Journal Article•DOI•

Cellular and molecular mechanisms of kidney fibrosis.

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Sonja Djudjaj¹, Peter Boor¹•Institutions (1)

RWTH Aachen University¹

01 Feb 2019-Molecular Aspects of Medicine

TL;DR: This review summarized the different appearance, cellular origin and major emerging processes and mediators of fibrosis in each compartment of kidney's histological structure, and depicted and discussed the challenges in translation of anti-fibrotic treatment to clinical practice.

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247 citations

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Journal Article•DOI•

Complement: a key system for immune surveillance and homeostasis

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Daniel Ricklin¹, George Hajishengallis², Kun Yang¹, John D. Lambris¹•Institutions (2)

University of Pennsylvania¹, University of Louisville²

01 Sep 2010-Nature Immunology

TL;DR: An updated view of the function, structure and dynamics of the complement network is described, its interconnection with immunity at large and with other endogenous pathways is highlighted, and its multiple roles in homeostasis and disease are illustrated.

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Abstract: Nearly a century after the significance of the human complement system was recognized, we have come to realize that its functions extend far beyond the elimination of microbes. Complement acts as a rapid and efficient immune surveillance system that has distinct effects on healthy and altered host cells and foreign intruders. By eliminating cellular debris and infectious microbes, orchestrating immune responses and sending 'danger' signals, complement contributes substantially to homeostasis, but it can also take action against healthy cells if not properly controlled. This review describes our updated view of the function, structure and dynamics of the complement network, highlights its interconnection with immunity at large and with other endogenous pathways, and illustrates its multiple roles in homeostasis and disease.

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2,986 citations

Journal Article•DOI•

Complement. First of two parts.

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Mark Walport¹•Institutions (1)

Imperial College London¹

05 Apr 2001-The New England Journal of Medicine

2,773 citations

Journal Article•DOI•

Anesthesiology. First of two parts.

[...]

Wiklund Ra¹, Rosenbaum Sh•Institutions (1)

Yale University¹

16 Oct 1997-The New England Journal of Medicine

2,232 citations

Journal Article•DOI•

M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.

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Laurence H. Beck¹, Ramon G. Bonegio¹, Gérard Lambeau, David M. Beck¹, David W. Powell, Timothy D. Cummins, Jon B. Klein, David J. Salant¹ - Show less +4 more•Institutions (1)

Boston University¹

02 Jul 2009-The New England Journal of Medicine

TL;DR: A majority of patients with idiopathic membranous nephropathy have antibodies against a conformation-dependent epitope in PLA(2)R, indicating that PLA( 2)R is a major antigen in this disease.

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Abstract: BACKGROUND Idiopathic membranous nephropathy, a common form of the nephrotic syndrome, is an antibody-mediated autoimmune glomerular disease. Serologic diagnosis has been elusive because the target antigen is unknown. METHODS We performed Western blotting of protein extracts from normal human glomeruli with serum samples from patients with idiopathic or secondary membranous nephropathy or other proteinuric or autoimmune diseases and from normal controls. We used mass spectrometry to analyze the reactive protein bands and confirmed the identity and location of the target antigen with a monospecific antibody. RESULTS Serum samples from 26 of 37 patients (70%) with idiopathic but not secondary membranous nephropathy specifically identified a 185-kD glycoprotein in nonreduced glomerular extract. Mass spectrometry of the reactive protein band detected the M-type phospholipase A 2 receptor (PLA 2 R). Reactive serum specimens recognized recombinant PLA 2 R and bound the same 185-kD glomerular protein as did the monospecific anti-PLA 2 R antibody. Anti-PLA 2 R autoantibodies in serum samples from patients with membranous nephropathy were mainly IgG4, the predominant immunoglobulin subclass in glomerular deposits. PLA 2 R was expressed in podocytes in normal human glomeruli and colocalized with IgG4 in immune deposits in glomeruli of patients with membranous nephropathy. IgG eluted from such deposits in patients with idiopathic membranous nephropathy, but not in those with lupus membranous or IgA nephropathy, recognized PLA 2 R. CONCLUSIONS A majority of patients with idiopathic membranous nephropathy have antibodies against a conformation-dependent epitope in PLA 2 R. PLA 2 R is present in normal podocytes and in immune deposits in patients with idiopathic membranous nephropathy, indicating that PLA 2 R is a major antigen in this disease.

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1,643 citations

Journal Article•DOI•

Complement. Second of two parts.

[...]

Mark Walport¹•Institutions (1)

Imperial College London¹

12 Apr 2001-The New England Journal of Medicine

1,447 citations