Alternative Pathway Involvement in Protoporphyria Patients Related to Sun Exposure

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.

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

10.1101/2020.10.12.20210344 ◽

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.

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New functional and structural insights from updated mutational databases for complement factor H, Factor I, membrane cofactor protein and C3

Bioscience Reports ◽

10.1042/bsr20140117 ◽

2014 ◽

Vol 34 (5) ◽

Cited By ~ 41

Author(s):

Elizabeth Rodriguez ◽

Pavithra M. Rallapalli ◽

Amy J. Osborne ◽

Stephen J. Perkins

Keyword(s):

Alternative Pathway ◽

Factor H ◽

Complement Factor H ◽

Complement C3 ◽

Complement Factor ◽

Membrane Cofactor Protein ◽

Complement Alternative Pathway ◽

Factor I ◽

Mutational Hotspots ◽

Structural Insights

A new compilation of 324 mutations in four major proteins from the complement alternative pathway reveals mutational hotspots in factor H and complement C3, and less so in factor I and membrane cofactor protein. Their associations with function are discussed.

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Comparative Study of Ground Measured, Satellite-Derived, and Estimated Global Solar Radiation Data in Nigeria

Journal of Solar Energy ◽

10.1155/2016/8197389 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 7

Author(s):

Boluwaji M. Olomiyesan ◽

Onyedi D. Oyedum

Keyword(s):

Solar Radiation ◽

Comparative Study ◽

Global Radiation ◽

Statistical Error ◽

Global Solar Radiation ◽

Coefficient Of Determination ◽

Mean Bias Error ◽

Percentage Error ◽

Radiation Data ◽

Proposed Model

In this study, the performance of three global solar radiation models and the accuracy of global solar radiation data derived from three sources were compared. Twenty-two years (1984–2005) of surface meteorological data consisting of monthly mean daily sunshine duration, minimum and maximum temperatures, and global solar radiation collected from the Nigerian Meteorological (NIMET) Agency, Oshodi, Lagos, and the National Aeronautics Space Agency (NASA) for three locations in North-Western region of Nigeria were used. A new model incorporating Garcia model into Angstrom-Prescott model was proposed for estimating global radiation in Nigeria. The performances of the models used were determined by using mean bias error (MBE), mean percentage error (MPE), root mean square error (RMSE), and coefficient of determination (R2). Based on the statistical error indices, the proposed model was found to have the best accuracy with the least RMSE values (0.376 for Sokoto, 0.463 for Kaduna, and 0.449 for Kano) and highest coefficient of determination, R2 values of 0.922, 0.938, and 0.961 for Sokoto, Kano, and Kaduna, respectively. Also, the comparative study result indicates that the estimated global radiation from the proposed model has a better error range and fits the ground measured data better than the satellite-derived data.

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Functional Mapping of YadA- and Ail-Mediated Binding of Human Factor H to Yersinia enterocolitica Serotype O:3

Infection and Immunity ◽

10.1128/iai.00314-08 ◽

2008 ◽

Vol 76 (11) ◽

pp. 5016-5027 ◽

Cited By ~ 45

Author(s):

Marta Biedzka-Sarek ◽

Saara Salmenlinna ◽

Markus Gruber ◽

Andrei N. Lupas ◽

Seppo Meri ◽

...

Keyword(s):

Yersinia Enterocolitica ◽

Alternative Pathway ◽

Outer Membrane Proteins ◽

Factor H ◽

Complement Alternative Pathway ◽

Human Host ◽

Serotype O ◽

Complement Resistance ◽

Sense And Respond ◽

Active Complement

ABSTRACT Yersinia enterocolitica is an enteric pathogen that exploits diverse means to survive in the human host. Upon Y. enterocolitica entry into the human host, bacteria sense and respond to variety of signals, one of which is the temperature. Temperature in particular has a profound impact on Y. enterocolitica gene expression, as most of its virulence factors are expressed exclusively at 37°C. These include two outer membrane proteins, YadA and Ail, that function as adhesins and complement resistance (CR) factors. Both YadA and Ail bind the functionally active complement alternative pathway regulator factor H (FH). In this study, we characterized regions on both proteins involved in CR and the interaction with FH. Twenty-eight mutants having short (7 to 41 amino acids) internal deletions within the neck and stalk of YadA and two complement-sensitive site-directed Ail mutants were constructed to map the CR and FH binding regions of YadA and Ail. Functional analysis of the YadA mutants revealed that the stalk of YadA is required for both CR and FH binding and that FH appears to target several conformational and discontinuous sites of the YadA stalk. On the other hand, the complement-sensitive Ail mutants were not affected in FH binding. Our results also suggested that Ail- and YadA-mediated CR does not depend solely on FH binding.

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De Novo Atypical Haemolytic Uremic Syndrome after Kidney Transplantation

Case Reports in Nephrology ◽

10.1155/2018/1727986 ◽

2018 ◽

Vol 2018 ◽

pp. 1-4

Author(s):

Arnaud Devresse ◽

Martine de Meyer ◽

Selda Aydin ◽

Karin Dahan ◽

Nada Kanaan

Keyword(s):

Kidney Transplantation ◽

De Novo ◽

Alternative Pathway ◽

Factor H ◽

Complement Factor ◽

Haemolytic Uremic Syndrome ◽

Hinman Syndrome ◽

Uremic Syndrome ◽

Stage Renal Disease ◽

End Stage

De novo thrombotic microangiopathy (TMA) can occur after kidney transplantation. An abnormality of the alternative pathway of complement must be suspected and searched for, even in presence of a secondary cause. We report the case of a 23-year-old female patient who was transplanted with a kidney from her mother for end-stage renal disease secondary to Hinman syndrome. Early after transplantation, she presented with 2 episodes of severe pyelonephritis, associated with acute kidney dysfunction and biological and histological features of TMA. Investigations of the alternative pathway of the complement system revealed atypical haemolytic uremic syndrome secondary to complement factor I mutation, associated with mutations in CD46 and complement factor H related protein genes. Plasma exchanges followed by eculizumab injections allowed improvement of kidney function without, however, normalization of creatinine.

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A Dimerization Site at SCR-17/18 in Factor H Clarifies a New Mechanism for Complement Regulatory Control

Frontiers in Immunology ◽

10.3389/fimmu.2020.601895 ◽

2021 ◽

Vol 11 ◽

Author(s):

Orla M. Dunne ◽

Xin Gao ◽

Ruodan Nan ◽

Jayesh Gor ◽

Penelope J. Adamson ◽

...

Keyword(s):

Host Cell ◽

Analytical Ultracentrifugation ◽

Dissociation Constants ◽

Alternative Pathway ◽

Factor H ◽

Regulatory Control ◽

Size Exclusion ◽

Complement Factor ◽

Dimer Formation ◽

Self Association

Complement Factor H (CFH), with 20 short complement regulator (SCR) domains, regulates the alternative pathway of complement in part through the interaction of its C-terminal SCR-19 and SCR-20 domains with host cell-bound C3b and anionic oligosaccharides. In solution, CFH forms small amounts of oligomers, with one of its self-association sites being in the SCR-16/20 domains. In order to correlate CFH function with dimer formation and the occurrence of rare disease-associated variants in SCR-16/20, we identified the dimerization site in SCR-16/20. For this, we expressed, in Pichia pastoris, the five domains in SCR-16/20 and six fragments of this with one-three domains (SCR-19/20, SCR-18/20, SCR-17/18, SCR-16/18, SCR-17 and SCR-18). Size-exclusion chromatography suggested that SCR dimer formation occurred in several fragments. Dimer formation was clarified using analytical ultracentrifugation, where quantitative c(s) size distribution analyses showed that SCR-19/20 was monomeric, SCR-18/20 was slightly dimeric, SCR-16/20, SCR-16/18 and SCR-18 showed more dimer formation, and SCR-17 and SCR-17/18 were primarily dimeric with dissociation constants of ~5 µM. The combination of these results located the SCR-16/20 dimerization site at SCR-17 and SCR-18. X-ray solution scattering experiments and molecular modelling fits confirmed the dimer site to be at SCR-17/18, this dimer being a side-by-side association of the two domains. We propose that the self-association of CFH at SCR-17/18 enables higher concentrations of CFH to be achieved when SCR-19/20 are bound to host cell surfaces in order to protect these better during inflammation. Dimer formation at SCR-17/18 clarified the association of genetic variants throughout SCR-16/20 with renal disease.

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The Opportunistic Human Pathogenic Fungus Aspergillus fumigatus Evades the Host Complement System

Infection and Immunity ◽

10.1128/iai.01037-07 ◽

2007 ◽

Vol 76 (2) ◽

pp. 820-827 ◽

Cited By ~ 80

Author(s):

Judith Behnsen ◽

Andrea Hartmann ◽

Jeannette Schmaler ◽

Alexander Gehrke ◽

Axel A. Brakhage ◽

...

Keyword(s):

Aspergillus Fumigatus ◽

Complement System ◽

Developmental Stages ◽

Fungal Infections ◽

Alternative Pathway ◽

Pathogenic Fungus ◽

Factor H ◽

Human Sera ◽

Human Pathogenic Fungus ◽

Complement Regulators

ABSTRACT The opportunistic human pathogenic fungus Aspergillus fumigatus causes severe systemic infections and is a major cause of fungal infections in immunocompromised patients. A. fumigatus conidia activate the alternative pathway of the complement system. In order to assess the mechanisms by which A. fumigatus evades the activated complement system, we analyzed the binding of host complement regulators to A. fumigatus. The binding of factor H and factor H-like protein 1 (FHL-1) from human sera to A. fumigatus conidia was shown by adsorption assays and immunostaining. In addition, factor H-related protein 1 (FHR-1) bound to conidia. Adsorption assays with recombinant factor H mutants were used to localize the binding domains. One binding region was identified within N-terminal short consensus repeats (SCRs) 1 to 7 and a second one within C-terminal SCR 20. Plasminogen was identified as the fourth host regulatory molecule that binds to A. fumigatus conidia. In contrast to conidia, other developmental stages of A. fumigatus, like swollen conidia or hyphae, did not bind to factor H, FHR-1, FHL-1, and plasminogen, thus indicating the developmentally regulated expression of A. fumigatus surface ligands. Both factor H and plasminogen maintained regulating activity when they were bound to the conidial surface. Bound factor H acted as a cofactor to the factor I-mediated cleavage of C3b. Plasminogen showed proteolytic activity when activated to plasmin by urokinase-type plasminogen activator. These data show that A. fumigatus conidia bind to complement regulators, and these bound host regulators may contribute to evasion of a host complement attack.

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Alternative Pathway Inhibition by Exogenous Factor H Fails to Attenuate Inflammation and Vascular Leakage in Experimental Pneumococcal Sepsis in Mice

PLoS ONE ◽

10.1371/journal.pone.0149307 ◽

2016 ◽

Vol 11 (2) ◽

pp. e0149307 ◽

Cited By ~ 2

Author(s):

Erika van der Maten ◽

Saskia van Selm ◽

Jeroen D. Langereis ◽

Hester J. Bootsma ◽

Fred J. H. van Opzeeland ◽

...

Keyword(s):

Alternative Pathway ◽

Factor H ◽

Vascular Leakage ◽

Exogenous Factor ◽

Pneumococcal Sepsis ◽

Pathway Inhibition

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Pathological aspects of membranoproliferative glomerulonephritis (MPGN) and haemolytic uraemic syndrome (HUS) / thrombocytic thrombopenic purpura (TTP)

Thrombosis and Haemostasis ◽

10.1160/th07-12-0761 ◽

2009 ◽

Vol 101 (02) ◽

pp. 265-270 ◽

Cited By ~ 33

Author(s):

Kerstin Benz ◽

Kerstin Amann

Keyword(s):

Membranoproliferative Glomerulonephritis ◽

Haemolytic Uraemic Syndrome ◽

Alternative Pathway ◽

Regulatory Protein ◽

Factor H ◽

Morphological Alteration ◽

Vascular Morphology ◽

Electron Microscopical Level ◽

Electron Microscopical ◽

Von Willebrand

SummaryIn this paper, epidemiology, pathogenesis and typical morphological aspects of all three types of membranoproliferative glomerulonephritis (MPGN), of the haemolytic uraemic syndrome (HUS) as well as of thrombotic thrombopenic purpura (TTP) will be reviewed on the light microscopical, immunohistological or immunofluorescence and electron microscopical level. In particular, differences in the pathogenesis of these diseases are discussed. Important recent molecular and genetic insights into the pathogenesis of the three types of MPGN, of typical and atypical HUS and of TTP, i.e. dysregulation of the complement system, distinct molecular defects in C3 and factor H, the major regulatory protein of the alternative pathway of complement activation, and deficiency of a von Willebrand factor (VWF) -cleaving protease, i.e. ADAMTS13, are highlighted. Finally, particular emphasis will be put on differences in glomerular and vascular morphology in the three types of MPGN and in thrombotic microangiopathy (TMA), which is the characteristic morphological alteration of the kidney in HUS and TTP, respectively.

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

Biochemical Journal ◽

10.1042/bj3490217 ◽

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.

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