scholarly journals The alternative complement pathway is activated in protoporphyria patients during sun exposure

2020 ◽  
Author(s):  
Francesca Granata ◽  
Lorena Duca ◽  
Valentina Brancaleoni ◽  
Silvia Fustinoni ◽  
Giacomo De Luca ◽  
...  
Keyword(s):  
Light Exposure ◽  
Alternative Pathway ◽  
Global Radiation ◽  
Protoporphyrin Ix ◽  
Sun Exposure ◽  
Factor H ◽  
Factor B ◽  
Alternative Complement ◽  
Differential Involvement ◽  
The Complement System

ABSTRACTThe homeostasis of tissues in chronic disease is an important function of the alternative pathway (AP) of the complement system (CS). However, if not controlled, it may also be detrimental to healthy cells.Protoporphyria (PP) is a rare disease that causes photosensitivity at the visible light due to the accumulation of Protoporphyrin-IX in the dermis. The aim of this study was to deep the knowledge about the involvement of AP in PP photoreaction.Global radiation and UV data were provided from regional agency of environmental protection (ARPA). Properdin, Factor H (FH) and C5 levels were assessed in the serum collected during winter and summer from 19 PP patients and 13 controls..Properdin in winter and summer reflected a positive increase compared to controls. The values in summer were higher than winter. The C5 results were altered only in summer. The outcome was reversed for FH: in the winter, it was higher compared to the summer. A positive correlation was reported between properdin and C3 in summer; a negative tendency between Factor B (FB) and FH was detected.This study substantiated the differential involvement of AP depending on the increase in light exposure during the season, which was demonstrated with ARPA data. The enhanced systemic response could justify the malaise sensation of patients after long light exposure and can be exploited to elucidate the new therapeutic approach.

scholarly journals Alternative Pathway Involvement in Protoporphyria Patients Related to Sun Exposure

2021 ◽  
Vol 12 ◽  
Author(s):  
Francesca Granata ◽  
Lorena Duca ◽  
Valentina Brancaleoni ◽  
Silvia Fustinoni ◽  
Giacomo De Luca ◽  
...  
Keyword(s):  
Chronic Disease ◽  
Light Exposure ◽  
Alternative Pathway ◽  
Global Radiation ◽  
Sun Exposure ◽  
Factor H ◽  
General Malaise ◽  
Local Skin ◽  
Systemic Involvement ◽  
Radiation Data

The homeostasis of tissues in a chronic disease is an essential function of the alternative pathway (AP) of the complement system (CS). However, if not controlled, it may also be detrimental to healthy cells with a consequent aggravation of symptoms. The protoporphyria (PP) is a rare chronic disease that causes phototoxicity in visible light with local skin pain and general malaise. In order to establish if there is a systemic involvement of the CS during sun exposure, we designed a non-invasive method with a serum collection in winter and summer from 19 PP and 13 controls to detect the levels of CS protein: Properdin, Factor H (FH), and C5. Moreover, the global radiation data were collected from the regional agency of environmental protection (ARPA). The results show growing values for every protein in patients with PP, compared to control, in both seasons, in particular in summer compared to winter. To reinforce the evidence, we have estimated the personal exposure of patients based on the global radiation data. The main factors of the AP increased over the season, confirming the involvement of the AP in relation to light exposure. The systemic response could justify the general malaise of patients after long light exposure and can be exploited to elucidate new therapeutic approaches.

scholarly journals Simple Method To Distinguish between Primary and Secondary C3 Deficiencies

2003 ◽  
Vol 10 (2) ◽  
pp. 216-220
Author(s):  
Marlene Pereira de Carvalho Florido ◽  
Patrícia Ferreira de Paula ◽  
Lourdes Isaac
Keyword(s):  
Human Serum ◽  
Complement System ◽  
Factor H ◽  
Normal Human Serum ◽  
Alternative Complement Pathway ◽  
Complement Pathway ◽  
Factor B ◽  
Alternative Complement ◽  
Normal Human ◽  
The Complement System

ABSTRACT Due to the increasing numbers of reported clinical cases of complement deficiency in medical centers, clinicians are now more aware of the role of the complement system in the protection against infections caused by microorganisms. Therefore, clinical laboratories are now prepared to perform a number of diagnostic tests of the complement system other than the standard 50% hemolytic component assay. Deficiencies of alternative complement pathway proteins are related to severe and recurrent infections; and the application of easy, reliable, and low-cost methods for their detection and distinction are always welcome, notably in developing countries. When activation of the alternative complement pathway is evaluated in hemolytic agarose plates, some but not all human sera cross-react to form a late linear lysis. Since the formation of this linear lysis is dependent on C3 and factor B, it is possible to use late linear lysis to routinely screen for the presence of deficiencies of alternative human complement pathway proteins such as factor B. Furthermore, since linear lysis is observed between normal human serum and primary C3-deficient serum but not between normal human serum and secondary C3-deficient serum caused by the lack of factor H or factor I, this assay may also be used to discriminate between primary and secondary C3 deficiencies.

scholarly journals Case Report: Lipoprotein Glomerulopathy Complicated by Atypical Hemolytic Uremic Syndrome

2021 ◽  
Vol 8 ◽  
Author(s):  
Lara Kollbrunner ◽  
Patricia Hirt-Minkowski ◽  
Javier Sanz ◽  
Elena Bresin ◽  
Thomas J. Neuhaus ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Complement Factor ◽  
Inherited Disease ◽  
Lipoprotein Glomerulopathy ◽  
Gene Encoding ◽  
Alternative Complement ◽  
Uremic Syndrome ◽  
The Complement System

Lipoprotein glomerulopathy (LPG) is a rare inherited disease caused by mutations in the APOE gene, encoding apolipoprotein E (apoE). Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) characterized by overactivation of the alternative complement pathway. Here we report the case of a 21-year-old man with LPG who developed aHUS. A functional complement assay demonstrated an overactivation of the complement system. Complementary genetic analysis revealed a homozygous aHUS risk allele for complement factor-H related 1 (CFHR1), CFHR1*B. To the best of our knowledge, this is the first report of an aHUS in a patient with LPG.

Interaction of C3b2–IgG complexes with complement proteins properdin, factor B and factor H: implications for amplification

2000 ◽  
Vol 349 (1) ◽  
pp. 217-223
Author(s):  
Emiliana JELEZAROVA ◽  
Anna VOGT ◽  
Hans U. LUTZ
Keyword(s):  
Present Report ◽  
Alternative Pathway ◽  
Fluid Phase ◽  
Factor H ◽  
Complement Protein ◽  
Factor B ◽  
Physiological Conditions ◽  
Amplification Loop ◽  
Target Molecules ◽  
Properdin Factor B

Nascent C3b can form ester bonds with various target molecules on the cell surface and in the fluid phase. Previously, we showed that C3b2-IgG complexes represent the major covalent product of C3 activation in serum [Lutz, Stammler, Jelezarova, Nater and Späth (1996) Blood 88, 184-193]. In the present report, binding of alternative pathway proteins to purified C3b2-IgG complexes was studied in the fluid phase by using biotinylated IgG for C3b2-IgG generation and avidin-coated plates to capture complexes. Up to seven moles of properdin ‘monomer’ bound per mole of C3b2-IgG at physiological conditions in the absence of any other complement protein. At low properdin/C3b2-IgG ratios bivalent binding was preferred. Neither factor H nor factor B affected properdin binding. On the other hand, properdin strongly stimulated factor B binding. Interactions of all three proteins with C3b2-IgG exhibited pH optima. An ionic strength optimum was most pronounced for properdin, while factor B binding was largely independent of the salt concentration. C3b2-IgG complexes were powerful precursors of the alternative pathway C3 convertase. In the presence of properdin, C3 convertase generated from C3b2-IgG cleaved about sevenfold more C3 than the enzyme generated on C3b. C3b2-IgG complexes could therefore maintain the amplification loop of complement longer than free C3b.

Schistosoma mansoni: complement activation in human and rodent sera by living parasites of various developmental stages

Parasitology ◽  
1983 ◽  
Vol 87 (1) ◽  
pp. 75-86 ◽  
Author(s):  
A. Ruppel ◽  
U. Rother ◽  
H. Vongerichten ◽  
H. J. Diesfeld
Keyword(s):  
Schistosoma Mansoni ◽  
Complement System ◽  
Developmental Stages ◽  
Alternative Pathway ◽  
Classical Pathway ◽  
Factor B ◽  
The Complement System ◽  
Dose Dependent ◽  
Living Adult

SUMMARYLiving Schistosoma mansoni of various developmental stages were studied with respect to their ability to activate the complement system in sera of humans, mice and rats. Immunofluorescence assays demonstrated that binding of human C3 occurred on fresh schistosomula as well as on schistosomula prepared from mouse lymph-nodes or lungs and on adult schistosomes. However, rodent C3 was deposited only on fresh schistosomula. Deposition of human C3 on the worms' surface required activation of the complement system. The alternative pathway was shown to be involved in deposition of human C3 on schistosomes of all ages, whereas activation of the classical pathway was demonstrable only with fresh schistosomula. Immunoelectrophoretic studies demonstrated a dose-dependent cleavage of human C3 and conversion of factor B by living adult schistosomes. The results demonstrate that the ability of living schistosomes to activate complement in vitro is dependent not only on their developmental stage but also on the species of the serum.

scholarly journals Complement Activation via Alternative Pathway Is Critical in the Development of Laser-Induced Choroidal Neovascularization: Role of Factor B and Factor H

2006 ◽  
Vol 177 (3) ◽  
pp. 1872-1878 ◽  
Author(s):  
Nalini S. Bora ◽  
Sankaranarayanan Kaliappan ◽  
Purushottam Jha ◽  
Qin Xu ◽  
Jeong-Hyeon Sohn ◽  
...  
Keyword(s):  
Choroidal Neovascularization ◽  
Complement Activation ◽  
Alternative Pathway ◽  
Factor H ◽  
Factor B

Inherited complement deficiencies

1984 ◽  
Vol 306 (1129) ◽  
pp. 419-430 ◽  
Keyword(s):  
Immune Complex ◽  
Complement System ◽  
Lupus Erythematosus ◽  
Alternative Pathway ◽  
Strong Association ◽  
Factor H ◽  
Complement Deficiency ◽  
Classical Pathway ◽  
The Complement System

Isolated genetic deficiencies of individual components of the complement system have been described in man for all the components of the classical pathway and the membrane attack complex as well as for Factor I, Factor H and properdin. It is only for Factor B and Factor D of the alternative pathway that homozygous deficiency states are not so far known. Complement deficiency states provide the most direct way of looking at the role of the complement system in vivo and emphasize the importance of complement in resistance to bacterial infection and in particular to infection with Neisseria . This association is not unexpected since in vitro studies have shown complement to be an efficient enhancer of phagocytosis and inflammation. The particularly frequent occurrence of neisserial infection may be ascribed to the ability of these organisms to survive in phagocytic cells so that the plasma cytolytic activity provided by complement is needed to kill them. On the other hand the strong association between complement deficiencies and immune-complex diseases - especially systemic lupus erythematosus — was unexpected and seems paradoxical in view of the large part played by complement in the pathogenesis of immune complex mediated tissue damage. The paradox can be explained in part by the necessity for an intact complement system in the solubilization and the proper handling of immune complexes. It is also likely that complement deficiency can allow the persistence of low virulence organisms that produce disease solely by an immune complex mechanism. Recently described deficiencies of complement receptors and their effects in vivo are described.

TT30, a Novel Human Protein Therapeutic, Selectively Modulates the Complement Alternative Pathway by Targeted Supplementation of Local Factor H Activity.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3021-3021 ◽  
Author(s):  
V. Michael Holers ◽  
Istvan Mazsaroff ◽  
Hillary Akana ◽  
Christopher G. Smith ◽  
J. Woodruff Emlen ◽  
...  
Keyword(s):  
Cell Surface ◽  
Potent Inhibitor ◽  
Ex Vivo ◽  
Alternative Pathway ◽  
Factor H ◽  
Employment Equity ◽  
Complement Alternative Pathway ◽  
Equity Ownership ◽  
The Complement System

Abstract Abstract 3021 Poster Board II-997 The complement system is activated through three pathways: classical, lectin/mannose and alternative. Polymorphisms and mutations that promote Complement Alternative Pathway (CAP) activity are associated with human diseases including atypical hemolytic uremic syndrome (aHUS) and age-related macular degeneration (AMD). The complement system is also centrally involved in many hemolytic disorders, including paroxysmal nocturnal hemoglobinuria (PNH) where the CAP initiates complement activation resulting in intravascular hemolysis (IVH) after engagement of C5 and formation of the membrane attack complex (MAC). Systemic neutralization of C5 with the anti-C5 monoclonal antibody, eculizumab, abrogates IVH when plasma concentrations are maintained above the minimal efficacious concentration (Cmin = 35 μg/mL). However, because eculizumab does not inhibit CAP activity prior to C5, C3 fragments (C3frag) continue to covalently bind to and accumulate on PNH red blood cells (RBCs). Clearance by the reticuloendothelial system of PNH RBCs that are C3frag-coated is a putative cause of extravascular hemolysis (EVH) in eculizumab-treated patients. In order to selectively modulate CAP activity, we developed TT30, a novel therapeutic 65kD fusion protein linking the first four short consensus repeat (SCR) domains of human complement receptor type 2 (CR2/CD21) with the first five SCR of human factor H (fH). CR2 SCR1-4 encompasses the antigen-fixed C3frag (iC3b, C3dg and C3d) binding domain. Factor H is the primary soluble phase, negative regulator of CAP activity functioning via the SCR1-5 domains. The unique mechanism of TT30 utilizes CR2 SCR1-4 to recognize and bind to C3frag on cells in which complement activation is occurring, thus delivering cell surface-targeted inhibition of CAP activity via fH SCR 1-5. TT30 both prevents CAP-dependent hemolysis of rabbit RBCs in human serum and blocks accumulation of C3frag on the RBC surface. By design, TT30 should also be a potent inhibitor of the CAP, but with minimal inhibition of the complement classical (CCP) and mannose (lectin; CMP) pathways. To test this hypothesis, we utilized sensitive pharmacodynamic assays that allow in vitro or ex vivo assessment in an ELISA format of individual complement pathway activity present in human serum. In this format, TT30 is a potent and selective inhibitor of CAP activity in normal human complement-preserved serum, with EC50 and EC100 values of ∼0.1 and 1 μg/mL serum. As predicted by the use of fH in its construction, TT30 is a much less potent inhibitor of the CCP and CMP, with EC100 values of ∼65 μg/mL. By contrast, in these assays a monoclonal and polyclonal anti-C5 antibody each demonstrate non-selective inhibition of CAP and CCP activity at all effective concentrations. TT30 activity is dependent upon CR2 binding to C3frag, as an anti-CR2 monoclonal antibody reverses the surface inhibition of CAP activity. This surface-targeting approach to delivering fH SCR1-5 results in a molecule with a 10-fold potency gain in CAP inhibition relative to added purified fH and an ∼30-fold potency gain relative to the total fH present in the serum used in the assay. TT30 administered as a single IV injection at 20 mg/kg to rats, rabbits and monkeys results in Cmax values of ∼400, 500 and 300 μg/mL and concentration-dependent inhibition of CAP activity. At serum concentrations of TT30 that induced maximal (100%) inhibition of systemic CAP activity for up to 12 hours, CCP activity is modestly (∼35-60%) inhibited for only 2 hours. CAP activity returns to baseline levels in a predictable fashion. Pharmacokinetic analysis indicates no gender-related differences and the expected scaling of parameters across species. TT30 is pharmacologically active in monkeys, rabbits and mice. TT30 administered as a single subcutaneous injection at 20 mg/kg to monkeys results in Cmax values of ∼25 μg/mL, and EC100 values identical to those observed with IV administration, but with a 3-fold prolongation of the maximal pharmacodynamic effect. The novel therapeutic TT30 has been shown in vitro and ex vivo to deliver cell surface-targeted control of CAP activation with minimal CCP and CMP inhibition and effective blockade of C3frag accumulation and MAC formation. As a result, TT30 has potential utility for the treatment of complement-mediated diseases such as PNH, AMD and aHUS, in which cell surface-targeted control of CAP activation may be clinically beneficial. Disclosures Holers: Taligen Therapeutics: Employment, Equity Ownership, Patents & Royalties, Research Funding. Mazsaroff:Taligen Therapeutics: Employment. Akana:Taligen Therapeutics: Employment. Smith:Taligen Therapeutics: Employment. Emlen:Taligen Therapeutics: Employment, Equity Ownership. Marians:Taligen Therapeutics: Employment. Horvath:Taligen Therapeutics: Employment.

Complement levels and activity in the normal and LPS-injured lung

2007 ◽  
Vol 292 (3) ◽  
pp. L748-L759 ◽  
Author(s):  
Molly S. Bolger ◽  
DeAndre S. Ross ◽  
Haixiang Jiang ◽  
Michael M. Frank ◽  
Andrew J. Ghio ◽  
...  
Keyword(s):  
Factor H ◽  
Mouse Lung ◽  
Rat Lung ◽  
Rt Pcr ◽  
Factor B ◽  
Complex Protein ◽  
Injured Lung ◽  
And Function ◽  
The Complement System ◽  
Stimulation Of

Complement, a complex protein system, plays an essential role in host defense through bacterial lysis, stimulation of phagocytosis, recruitment of immune cells to infected tissue, and promotion of the inflammatory response. Although complement is most well-characterized in serum, complement activity is also present in the lung. Here we further characterize the complement system in the normal and inflamed lung. By Western blot, C5, C6, and factor I were detected in bronchoalveolar lavage (BAL) at lower levels than in serum, whereas C2 was detected at similar levels in BAL and serum. C4 binding protein (C4BP) was not detectable in BAL. Exposure to lipopolysaccharide (LPS) elevated levels of C1q, factor B, C2, C4, C5, C6, and C3 in human BAL and C3, C5, and factor B in mouse and rat BAL. Message for C1q-B, C1r, C1s, C2, C4, C3, C5, C6, factor B, and factor H, but not C9 or C4BP, was readily detectable by RT-PCR in normal mouse lung. Exposure to LPS enhanced factor B expression, decreased C5 expression, and did not affect C1q-B expression in mouse and rat lung. BAL from rats exposed to LPS had a greater ability to deposit C3b onto bacteria through complement activation than did BAL from control rats. In summary, these data demonstrate that complement levels, expression, and function are altered in acute lung injury and suggest that complement within the lung is regulated to promote opsonization of pathogens and limit potentially harmful inflammation.

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.

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