scholarly journals Cluster Analysis Identifies Distinct Pathogenetic Patterns in C3 Glomerulopathies/Immune Complex–Mediated Membranoproliferative GN

2017 ◽  
Vol 29 (1) ◽  
pp. 283-294 ◽  
Author(s):  
Paraskevas Iatropoulos ◽  
Erica Daina ◽  
Manuela Curreri ◽  
Rossella Piras ◽  
Elisabetta Valoti ◽  
...  
Keyword(s):  
Immune Complex ◽  
Complement Activation ◽  
Solid Phase ◽  
Alternative Pathway ◽  
Disease Onset ◽  
Simple Algorithm ◽  
Fluid Phase ◽  
Disease Etiology ◽  
High Prevalence ◽  
Distinct Disease

Membranoproliferative GN (MPGN) was recently reclassified as alternative pathway complement–mediated C3 glomerulopathy (C3G) and immune complex–mediated membranoproliferative GN (IC-MPGN). However, genetic and acquired alternative pathway abnormalities are also observed in IC-MPGN. Here, we explored the presence of distinct disease entities characterized by specific pathophysiologic mechanisms. We performed unsupervised hierarchical clustering, a data-driven statistical approach, on histologic, genetic, and clinical data and data regarding serum/plasma complement parameters from 173 patients with C3G/IC-MPGN. This approach divided patients into four clusters, indicating the existence of four different pathogenetic patterns. Specifically, this analysis separated patients with fluid-phase complement activation (clusters 1–3) who had low serum C3 levels and a high prevalence of genetic and acquired alternative pathway abnormalities from patients with solid-phase complement activation (cluster 4) who had normal or mildly altered serum C3, late disease onset, and poor renal survival. In patients with fluid-phase complement activation, those in clusters 1 and 2 had massive activation of the alternative pathway, including activation of the terminal pathway, and the highest prevalence of subendothelial deposits, but those in cluster 2 had additional activation of the classic pathway and the highest prevalence of nephrotic syndrome at disease onset. Patients in cluster 3 had prevalent activation of C3 convertase and highly electron-dense intramembranous deposits. In addition, we provide a simple algorithm to assign patients with C3G/IC-MPGN to specific clusters. These distinct clusters may facilitate clarification of disease etiology, improve risk assessment for ESRD, and pave the way for personalized treatment.

scholarly journals Modulation of complement activation on hemodialysis membranes by immobilized heparin.

1992 ◽  
Vol 2 (8) ◽  
pp. 1328-1337
Author(s):  
A K Cheung ◽  
C J Parker ◽  
J Janatova ◽  
E Brynda
Keyword(s):  
Complement Activation ◽  
Alternative Pathway ◽  
Membrane Surface ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Fluid Phase ◽  
Factor H ◽  
Binding Studies ◽  
Factor B ◽  
Pathway Activity

To determine the effects of surface-associated heparin on the capacity of hemodialysis membranes to activate complement, cellulose acetate (CA) membranes that were untreated and CA membranes that had been coated with heparin (HCA) were incubated with C3-depleted serum repleted with radio-labeled C3. Next, the proteins in the supernatant and those eluted from the membranes were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. C3 activation was quantified by determining the radioactivity of the C3a-containing band in the gel. Total C3a generation (fluid phase C3a plus membrane-associated C3a) was three times greater in the presence of HCA compared with CA. Most (88%) of the C3a generated in the presence of HCA, however, was adsorbed onto the membrane surface. Consequently, there was more C3a in the CA supernatant than in the HCA supernatant. To determine the mechanism by which heparin enhanced alternative pathway activity, binding studies with radiolabeled factor B and factor H were performed. HCA bound 3.4 times more factor B and 20 times more factor H than did CA. The binding of these proteins, however, was not dependent on complement activation. Studies designed to test the functional activity of isolated factor H and factor B that had been adsorbed to the membrane showed that factor H was active on both CA and HCA, whereas factor B was active only on HCA. These data demonstrate that heparin immobilized onto CA hemodialysis membrane enhances C3 activation but produces low levels of C3a in the fluid phase because of high surface adsorption of the anaphylatoxin. Heparin appears to augment alternative pathway activity by favoring the interactions of factor B with other constituents of the amplification C3 convertase of the alternative pathway of complement.

scholarly journals C4b-binding protein (C4BP) inhibits development of experimental arthritis in mice

2008 ◽  
Vol 68 (1) ◽  
pp. 136-142 ◽  
Author(s):  
A M Blom ◽  
K S Nandakumar ◽  
R Holmdahl
Keyword(s):  
Binding Protein ◽  
Alternative Pathway ◽  
Disease Onset ◽  
Fluid Phase ◽  
Collagen Induced Arthritis ◽  
Complement Activity ◽  
Therapeutic Value ◽  
Before And After ◽  
Severity Of The Disease ◽  
The Complement System

Objectives:To assess the human complement inhibitor C4b-binding protein (C4BP) for treatment of arthritis.Methods:We have used two mouse models of rheumatoid arthritis (RA) to assess the therapeutic effect of C4BP on different phases of arthritis, the collagen antibody-induced arthritis (CAIA), an acute antibody-induced disease and the collagen-induced arthritis (CIA), which carries the full complexity of arthritis.Results:Purified human C4BP injected intraperitoneally alleviated CAIA significantly in a manner similar to cobra venom factor that depletes complement due to massive activation. Furthermore, C4BP was injected before and after the disease development into CIA mice. In the former case, the disease onset was delayed and in the latter, the severity of the disease was reduced in animals treated with C4BP. However, C4BP did not affect the anti-CII antibody synthesis. C4BP present in mouse sera decreased activity of the classical but not the alternative pathway of the complement system when these were assessed in a fluid phase. However, C4BP was efficiently inhibiting the alternative pathway when present on the activating surface. Taken together, the disease ameliorating effect of C4BP appears to be related to inhibition of both pathways of complement.Conclusions:Although human C4BP was cleared relatively fast from the circulation and was only moderately affecting complement activity, its effect on the disease severity was substantial, suggesting that minor alterations in complement activity can have significant therapeutic value in RA.

scholarly journals Mechanisms of Host-Pathogen Protein Complex Formation and Bacterial Immune Evasion of Streptococcus suis Protein Fhb

2016 ◽  
Vol 291 (33) ◽  
pp. 17122-17132 ◽  
Author(s):  
Xueqin Li ◽  
Peng Liu ◽  
Shuzhen Gan ◽  
Chunmao Zhang ◽  
Yuling Zheng ◽  
...  
Keyword(s):  
Immune Complex ◽  
Complement Activation ◽  
Hydrophobic Interactions ◽  
Cell Envelope ◽  
Alternative Pathway ◽  
Streptococcus Suis ◽  
Factor H ◽  
Immune Recognition ◽  
Bacterial Surface ◽  
Pathogen Protein

Streptococcus suis serotype 2 (S. suis 2)-induced sepsis and meningitis are often accompanied by bacteremia. The evasion of polymorphonuclear leukocyte-mediated phagocytic clearance is central to the establishment of bacteremia caused by S. suis 2 and is facilitated by the ability of factor H (FH)-binding protein (Fhb) to bind FH on the bacterial surface, thereby impeding alternative pathway complement activation and phagocytic clearance. Here, C3b/C3d was found to bind to Fhb, along with FH, forming a large immune complex. The formation of this immune complex was mediated by domain II of Fhb via electrostatic and hydrophobic interactions, which, to our knowledge, is a new type of interaction. Interestingly, Fhb was found to be associated with the cell envelope and also present in the culture supernatant, where secreted Fhb inhibited complement activation via interactions with domain II, thereby enhancing antiphagocytic clearance by polymorphonuclear leukocytes. Thus, Fhb is a multifunctional bacterial protein, which binds host complement component C3 as well as FH and interferes with innate immune recognition in a secret protein manner. S. suis 2 therefore appears to have developed a new strategy to combat host innate immunity and enhance survival in host blood.

scholarly journals Infections of People with Complement Deficiencies and Patients Who Have Undergone Splenectomy

2010 ◽  
Vol 23 (4) ◽  
pp. 740-780 ◽  
Author(s):  
Sanjay Ram ◽  
Lisa A. Lewis ◽  
Peter A. Rice
Keyword(s):  
Complement Activation ◽  
Antigen Processing ◽  
Respiratory Infections ◽  
Alternative Pathway ◽  
Fluid Phase ◽  
Host Cells ◽  
Medical Attention ◽  
Classical Pathway ◽  
Complement Components ◽  
Complement Pathways

SUMMARY The complement system comprises several fluid-phase and membrane-associated proteins. Under physiological conditions, activation of the fluid-phase components of complement is maintained under tight control and complement activation occurs primarily on surfaces recognized as “nonself” in an attempt to minimize damage to bystander host cells. Membrane complement components act to limit complement activation on host cells or to facilitate uptake of antigens or microbes “tagged” with complement fragments. While this review focuses on the role of complement in infectious diseases, work over the past couple of decades has defined several important functions of complement distinct from that of combating infections. Activation of complement in the fluid phase can occur through the classical, lectin, or alternative pathway. Deficiencies of components of the classical pathway lead to the development of autoimmune disorders and predispose individuals to recurrent respiratory infections and infections caused by encapsulated organisms, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. While no individual with complete mannan-binding lectin (MBL) deficiency has been identified, low MBL levels have been linked to predisposition to, or severity of, several diseases. It appears that MBL may play an important role in children, who have a relatively immature adaptive immune response. C3 is the point at which all complement pathways converge, and complete deficiency of C3 invariably leads to severe infections, including those caused by meningococci and pneumococci. Deficiencies of the alternative and terminal complement pathways result in an almost exclusive predisposition to invasive meningococcal disease. The spleen plays an important role in antigen processing and the production of antibodies. Splenic macrophages are critical in clearing opsonized encapsulated bacteria (such as pneumococci, meningococci, and Escherichia coli) and intraerythrocytic parasites such as those causing malaria and babesiosis, which explains the fulminant nature of these infections in persons with anatomic or functional asplenia. Paramount to the management of patients with complement deficiencies and asplenia is educating patients about their predisposition to infection and the importance of preventive immunizations and seeking prompt medical attention.

scholarly journals Solid-phase classical complement activation by C-reactive protein (CRP) is inhibited by fluid-phase CRP–C1q interaction

2007 ◽  
Vol 352 (1) ◽  
pp. 251-258 ◽  
Author(s):  
Christopher Sjöwall ◽  
Jonas Wetterö ◽  
Torbjörn Bengtsson ◽  
Agneta Askendal ◽  
Gunnel Almroth ◽  
...  
Keyword(s):  
Complement Activation ◽  
Solid Phase ◽  
Fluid Phase ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Classical Complement

scholarly journals The complement system in age-related macular degeneration

2021 ◽  
Author(s):  
Angela Armento ◽  
Marius Ueffing ◽  
Simon J. Clark
Keyword(s):  
Risk Factors ◽  
Macular Degeneration ◽  
Complement System ◽  
Complement Activation ◽  
Molecular Mechanisms ◽  
Alternative Pathway ◽  
Disease Onset ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
The Complement System

AbstractAge-related macular degeneration (AMD) is a chronic and progressive degenerative disease of the retina, which culminates in blindness and affects mainly the elderly population. AMD pathogenesis and pathophysiology are incredibly complex due to the structural and cellular complexity of the retina, and the variety of risk factors and molecular mechanisms that contribute to disease onset and progression. AMD is driven by a combination of genetic predisposition, natural ageing changes and lifestyle factors, such as smoking or nutritional intake. The mechanism by which these risk factors interact and converge towards AMD are not fully understood and therefore drug discovery is challenging, where no therapeutic attempt has been fully effective thus far. Genetic and molecular studies have identified the complement system as an important player in AMD. Indeed, many of the genetic risk variants cluster in genes of the alternative pathway of the complement system and complement activation products are elevated in AMD patients. Nevertheless, attempts in treating AMD via complement regulators have not yet been successful, suggesting a level of complexity that could not be predicted only from a genetic point of view. In this review, we will explore the role of complement system in AMD development and in the main molecular and cellular features of AMD, including complement activation itself, inflammation, ECM stability, energy metabolism and oxidative stress.

scholarly journals Complement Activation and Formation of the Membrane Attack Complex on Serogroup B Neisseria meningitidis in the Presence or Absence of Serum Bactericidal Activity

2002 ◽  
Vol 70 (7) ◽  
pp. 3752-3758 ◽  
Author(s):  
M. Drogari-Apiranthitou ◽  
E. J. Kuijper ◽  
N. Dekker ◽  
J. Dankert
Keyword(s):  
Bactericidal Activity ◽  
Complement Activation ◽  
Alternative Pathway ◽  
Membrane Attack Complex ◽  
Fluid Phase ◽  
Normal Serum ◽  
Chimeric Antibody ◽  
Classical Pathway ◽  
Bacterial Surface ◽  
Serum Bactericidal Activity

ABSTRACT Encapsulated meningococci are complement sensitive only in the presence of bactericidal antibodies by yet-unexplored mechanisms. The objective of this study was to investigate the involvement of major bacterial surface constituents on complement activation and membrane attack complex (MAC) formation on serogroup B meningococci in the presence or absence of antibody-dependent serum bactericidal activity (SBA). The strains used were the encapsulated H44/76, five of its variants differing in capsulation and expression of the class 1 porin (PorA), and its lipopolysaccharide (LPS)-deficient isogenic mutant (LPS−) pLAK33. Two normal sera, one with high SBA (SBA+) and one with no bactericidal activity (SBA−) against H44/76 as well as an a-γ-globulinemic serum were used for sensibilization of the bacteria. C3b and iC3b deposition on H44/76, its unencapsulated variant v24, and pLAK33 was similar in SBA+ and SBA− serum, and no difference was present between the strains. MAC deposition on H44/76 was higher in SBA+ serum than in SBA− serum and the a-γ-globulinemic serum. The amounts of C3b on H44/76, v24, and pLAK33 in the a-γ-globulinemic serum were also not different, indicating immunoglobulin G (IgG)- and LPS-independent complement activation. H44/76 PorA(+) and its PorA(−) variant and the v24 PorA(+) and its PorA(−) variant incubated in SBA− serum induced comparable amounts of MAC, despite their different serum sensitivities. Complement formation on the surface of the bacteria occurred almost exclusively via the classical pathway, but the considerable amounts of Bb measured in the serum indicated alternative pathway activation in the fluid phase. We conclude that complement deposition on meningococci is, for the most part, independent of classical pathway IgG and is not influenced by the presence of PorA or LPS on the meningococcal surface. Addition of an anti-PorA chimeric antibody to the nonbactericidal normal serum, while promoting a dose-related bacterial lysis, did not influence the amounts of C3b, iC3b, and MAC formed on the bacterial surface. These findings support the hypothesis that proper MAC insertion rather than the quantity of MAC formed on the bacterial surface is of importance for efficient lysis of meningococci.

scholarly journals Alternative pathway of complement: demonstration and characterization of initiating factor and its properdin-independent function.

1976 ◽  
Vol 144 (4) ◽  
pp. 1062-1075 ◽  
Author(s):  
R D Schreiber ◽  
O Götze ◽  
H J Müller-Eberhard
Keyword(s):  
Disulfide Bonds ◽  
Solid Phase ◽  
Alternative Pathway ◽  
Fluid Phase ◽  
Cytolytic Activity ◽  
Initial Reaction ◽  
Heat Stable ◽  
Human Serum Protein ◽  
Alternative Pathway Of Complement

A novel component of the properdin system has been discribed which represents a heretofore unrecognized human serum protein. The protein has been tentatively termed the initiating factor (IF) because it functions in the initial reaction of the properdin pathway. IF is a 170,000 dalton beta-pseudoglobulin which is composed of two presumably identical 85,000 dalton chains linked by disulfide bonds. The protein reacts with antibody to nephritic factor, which is defined by its activity and is found in the serum of patients with certain nephritides. The activity of IF is heat stable. Upon treatment of serum with activators of the alternative pathway, the initial C3 convertase is assembled from IF, Factors D and C, C3, and magnesium without participation of properdin. It is the function of the enzyme to deposit C3b on the surface of the activator particles, thereby affording generation of the solid phase enzymes of the pathway, a process that is a prerequisite for properdin activation. By exposure to low pH, IF assumed the electrophoretic mobility of psi-globulin and acquired the ability to generate without activators a fluid phase C3 convertase in serum. Serum depleted of IF did not allow activation of the properdin pathway. Serum depleted of properdin did permit activation of the pathway and expression of cytolytic activity. These results raise the possibility that IF represents the recognition unit of the pathway.

Turbulent Double-Diffusive Free Convection in a Porous Square Cavity Simulated With the Two Temperature Approach

2016 ◽  
Author(s):  
Marcelo J. S. de Lemos ◽  
Paulo H. S. Carvalho
Keyword(s):  
Solid Phase ◽  
Control Volume ◽  
Chemical Species ◽  
Simple Algorithm ◽  
Fluid Phase ◽  
Solid Matrix ◽  
Thermal Conductivity Ratio ◽  
Algebraic Equations ◽  
Square Cavity ◽  
Volume Method

This work investigates the influence of thermal conductivity ratio on energy and mass transport across a porous square cavity. Modeling of heat transfer from side to side of the enclosure assumed the hypothesis of thermal non-equilibrium between the solid matrix and the fluid phase. Transport equations were discretized using the control-volume method and the system of algebraic equations obtained was relaxed via the SIMPLE algorithm. Results showed that Shw, mass flux of chemical species and heat flux in the solid phase are strongly dependent of ks/kf, significantly increasing their values as such ratio increases.

Kinematic and Dynamic Parameters of a Liquid-Solid Pipe Flow Using DPIV∕Accelerometry

2007 ◽  
Vol 129 (11) ◽  
pp. 1415-1421 ◽  
Author(s):  
Joseph Borowsky ◽  
Timothy Wei
Keyword(s):  
Pipe Flow ◽  
Solid Phase ◽  
Fluid Phase ◽  
Central Moment ◽  
Steady Flows ◽  
Dynamic Parameters ◽  
Two Phase ◽  
Turbulence Structures ◽  
Two Phases ◽  
Flat Profile

An experimental investigation of a two-phase pipe flow was undertaken to study kinematic and dynamic parameters of the fluid and solid phases. To accomplish this, a two-color digital particle image velocimetry and accelerometry (DPIV∕DPIA) methodology was used to measure velocity and acceleration fields of the fluid phase and solid phase simultaneously. The simultaneous, two-color DPIV∕DPIA measurements provided information on the changing characteristics of two-phase flow kinematic and dynamic quantities. Analysis of kinematic terms indicated that turbulence was suppressed due to the presence of the solid phase. Dynamic considerations focused on the second and third central moments of temporal acceleration for both phases. For the condition studied, the distribution across the tube of the second central moment of acceleration indicated a higher value for the solid phase than the fluid phase; both phases had increased values near the wall. The third central moment statistic of acceleration showed a variation between the two phases with the fluid phase having an oscillatory-type profile across the tube and the solid phase having a fairly flat profile. The differences in second and third central moment profiles between the two phases are attributed to the inertia of each particle type and its response to turbulence structures. Analysis of acceleration statistics provides another approach to characterize flow fields and gives some insight into the flow structures, even for steady flows.

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