Autoantibodies in haemolytic uraemic syndrome (HUS)

2009 ◽  
Vol 101 (02) ◽  
pp. 227-232 ◽  
Author(s):  
Mihály Józsi ◽  
Peter Zipfel ◽  
Marie-Agnes Dragon-Durey ◽  
Veronique Fremeaux-Bacchi ◽  
Christine Skerka
Keyword(s):  
Haemolytic Uraemic Syndrome ◽  
Alternative Pathway ◽  
Severe Disease ◽  
Gene Mutations ◽  
Factor H ◽  
Host Cells ◽  
The Novel ◽  
Enterohaemorrhagic Escherichia Coli ◽  
Microangiopathic Anemia ◽  
The Complement System

SummaryHaemolytic uraemic syndrome (HUS) is a severe disease with renal failure, microangiopathic anemia and thrombocytopenia. Several mechanisms leading to HUS have been identified, like infections with enterohaemorrhagic Escherichia coli, as well as genetic mutations of complement genes, which result in defective complement control on the surface of host cells. The complement system forms the first defense line of innate immunity and mediates the attack against foreign microorganisms. Defective regulation of this cascade results in attack of self cells and in autoimmune disease. Apparently, the alternative pathway convertase C3bBb is central for the pathophysiology of HUS as gene mutations of the components (C3 and Factor B) or of regulators (Factor H, Factor I and MCP/CD46) are observed in the genetic form of HUS. Recently, a novel mechanism leading to atypical HUS (aHUS) was identified, in form of autoantibodies that bind the complement inhibitor Factor H. Here we summarize the current concept of HUS and focus in particular on the novel subgroup of aHUS patients with IgG autoantibodies to Factor H which develop on the genetic background of CFHR1/CFHR3 deficiency, and which define a new subform termed DEAP-HUS (deficient for CFHR proteins and Factor H autoantibody positive).

scholarly journals Hijacking Factor H for Complement Immune Evasion

2021 ◽  
Vol 12 ◽  
Author(s):  
Sara R. Moore ◽  
Smrithi S. Menon ◽  
Claudio Cortes ◽  
Viviana P. Ferreira
Keyword(s):  
Host Cell ◽  
Complement System ◽  
Alternative Pathway ◽  
Expression Patterns ◽  
Fluid Phase ◽  
Factor H ◽  
Host Cells ◽  
Complement C3 ◽  
Complement Regulators ◽  
The Complement System

The complement system is an essential player in innate and adaptive immunity. It consists of three pathways (alternative, classical, and lectin) that initiate either spontaneously (alternative) or in response to danger (all pathways). Complement leads to numerous outcomes detrimental to invaders, including direct killing by formation of the pore-forming membrane attack complex, recruitment of immune cells to sites of invasion, facilitation of phagocytosis, and enhancement of cellular immune responses. Pathogens must overcome the complement system to survive in the host. A common strategy used by pathogens to evade complement is hijacking host complement regulators. Complement regulators prevent attack of host cells and include a collection of membrane-bound and fluid phase proteins. Factor H (FH), a fluid phase complement regulatory protein, controls the alternative pathway (AP) both in the fluid phase of the human body and on cell surfaces. In order to prevent complement activation and amplification on host cells and tissues, FH recognizes host cell-specific polyanionic markers in combination with complement C3 fragments. FH suppresses AP complement-mediated attack by accelerating decay of convertases and by helping to inactivate C3 fragments on host cells. Pathogens, most of which do not have polyanionic markers, are not recognized by FH. Numerous pathogens, including certain bacteria, viruses, protozoa, helminths, and fungi, can recruit FH to protect themselves against host-mediated complement attack, using either specific receptors and/or molecular mimicry to appear more like a host cell. This review will explore pathogen complement evasion mechanisms involving FH recruitment with an emphasis on: (a) characterizing the structural properties and expression patterns of pathogen FH binding proteins, as well as other strategies used by pathogens to capture FH; (b) classifying domains of FH important in pathogen interaction; and (c) discussing existing and potential treatment strategies that target FH interactions with pathogens. Overall, many pathogens use FH to avoid complement attack and appreciating the commonalities across these diverse microorganisms deepens the understanding of complement in microbiology.

MOLECULAR GENETIC CHARACTERISTICS OF COMPONENTS OF THE COMPLEMENT SYSTEM IN SEVERE ACNE

2021 ◽  
Vol 100 (2) ◽  
pp. 40-48
Author(s):  
A.G. Rumyantsev ◽  
◽  
A.G. Rumyantsev ◽  
O.M. Demina ◽  
◽  
...  
Keyword(s):  
Nucleotide Sequence ◽  
Complement System ◽  
Molecular Genetic ◽  
Factor H ◽  
Host Cells ◽  
Pathophysiological Mechanism ◽  
Genetic Characteristics ◽  
Severe Acne ◽  
C3 Gene ◽  
The Complement System

It has been shown that the inflammatory response in acne develops at the early subclinical stages of the disease, sometimes before the formation of comedones. It is known that an important component of the innate immune system is the complement system, which includes more than 60 components, including 9 basic proteins (C1-C9), a variety of activation products (C3a, C3b, iC3b, C3d and C3dg), regulatory and inhibitory molecules [factor H, fH-like protein 1 (FHL1), CR1 (CD35), C4b-binding protein (C4BP), C1inh and vitronectin], proteases and secreted enzymes (factor B, factor D, C3bBb and C4bC2b), as well as receptors for effector molecules [C3aR, C5aR, C5L2 and C1q receptor (C1qR)]. The compliment is the central part of innate immunity, which is the first line of protection against alien and altered host cells. The objectives of this study were to determine and analyze the variants of the nucleotide sequence of the genes of the complement system C1QA, C1S, C2, C3, C5, C6, C7, C8A, C8B, C8G, C9 in patients with severe acne. Materials and methods of research: To achieve the target a prospective open non-randomized one-center study was carried out in 2017–2020. Under our supervision in the clinical setting at the Department of Skin Diseases and Cosmetology of the Pirogov Russian National Research Medical University, there were 50 patients in the main group and 20 participants in the comparison group (70 people in total) (42/60% men and 28/40% women) aged 15 to 46 years (median – 22,1 years). Molecular genetic diagnostics was performed in all 70 patients of the main and control groups by the method of high-throughput DNA sequencing – next-generation sequencing (NGS). Results: when analyzing the nucleotide sequence variants of the complement system genes identified in our study, it is shown that the severe form of acne probably has an association (4 SNPs of the C8A gene, 1 SNPs of the C8B gene, 2 SNPs of the C1S gene, 3 SNPs of the C3 gene, 2 SNPs of the C9 gene, 1 SNPs of the C7 gene, 1 SNPs of the C6 gene, 1 SNPs of the C2 gene, 2 SNPs of the C5 gene, 2 SNPs of the C8G gene), 13 SNPs of the complement system genes in introns (1 SNPs of the C8A gene, 1 SNPs of the C8B gene, 2 SNPs of the C1S gene, 1 SNPs of the C3 gene, 1 SNPs of the C7 gene, 2 SNPs of the C6 gene, 4 SNPs of the C5 gene, 1 SNPs of C8G gene), 6 SNPs of the complement system genes (2 SNPs of the C8B gene: one SNPs each in the 3'UTR and 5'UTR zones; 3 SNPs of the C3 gene in the 5'UTR zone, 1 SNPs of the C7 gene in the 3'UTR zone). Two mutations of the frame shift of the C2 gene (frameshift deletion) and the C9 gene (rs748464075, frameshift insertion) seem to have a protective effect in the development of acne. Conclusion: the obtained variants of the nucleotide sequence of the genes of the complement system C1QA, C1S, C2, C3, C5, C6, C7, C8A, C8B, C8G, C9, apparently, are associated with the formation of severe acne and cause an imbalance of the components of the complement system. It can cause a defect in chemotactic and phagocytic reactions, and as a result a disturbance of the regulation of the inflammatory reaction with chronization of the skin process occures. Thus, results of studies carried out, revealed – for the first time – polymorphic loci of genes of components of the complement system, the imbalance of which is the pathophysiological mechanism of acne.

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.

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

2009 ◽  
Vol 101 (02) ◽  
pp. 265-270 ◽  
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.

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.

scholarly journals Humanized C3 Mouse: A Novel Accelerated Model of C3 Glomerulopathy

2020 ◽  
Vol 32 (1) ◽  
pp. 99-114
Author(s):  
Kishor Devalaraja-Narashimha ◽  
Karoline Meagher ◽  
Yifan Luo ◽  
Cong Huang ◽  
Theodore Kaplan ◽  
...  
Keyword(s):  
Alternative Pathway ◽  
Gene Mutations ◽  
Factor H ◽  
Complement Factor ◽  
C3 Glomerulopathy ◽  
Wild Type ◽  
Therapeutic Approaches ◽  
Pathologic Features ◽  
Complement Gene ◽  
Extended Survival

BackgroundC3 glomerulopathy (C3G) is characterized by the alternative-pathway (AP) hyperactivation induced by nephritic factors or complement gene mutations. Mice deficient in complement factor H (CFH) are a classic C3G model, with kidney disease that requires several months to progress to renal failure. Novel C3G models can further contribute to understanding the mechanism behind this disease and developing therapeutic approaches.MethodsA novel, rapidly progressing, severe, murine model of C3G was developed by replacing the mouse C3 gene with the human C3 homolog using VelociGene technology. Functional, histologic, molecular, and pharmacologic assays characterize the presentation of renal disease and enable useful pharmacologic interventions in the humanized C3 (C3hu/hu) mice.ResultsThe C3hu/hu mice exhibit increased morbidity early in life and die by about 5–6 months of age. The C3hu/hu mice display elevated biomarkers of kidney dysfunction, glomerulosclerosis, C3/C5b-9 deposition, and reduced circulating C3 compared with wild-type mice. Administration of a C5-blocking mAb improved survival rate and offered functional and histopathologic benefits. Blockade of AP activation by anti-C3b or CFB mAbs also extended survival and preserved kidney function.ConclusionsThe C3hu/hu mice are a useful model for C3G because they share many pathologic features consistent with the human disease. The C3G phenotype in C3hu/hu mice may originate from a dysregulated interaction of human C3 protein with multiple mouse complement proteins, leading to unregulated C3 activation via AP. The accelerated disease course in C3hu/hu mice may further enable preclinical studies to assess and validate new therapeutics for C3G.

Complement System in Healthy Term Newborns: Reference Values in Umbilical Cord Blood

1998 ◽  
Vol 1 (2) ◽  
pp. 131-135 ◽  
Author(s):  
J. Sonntag ◽  
U. Brandenburg ◽  
D. Polzehl ◽  
E. Strauss ◽  
M. Vogel ◽  
...  
Keyword(s):  
Cord Blood ◽  
Reference Values ◽  
Complement System ◽  
Alternative Pathway ◽  
Factor H ◽  
Reference Ranges ◽  
Complement Proteins ◽  
Factor I ◽  
Term Newborns ◽  
The Complement System

Activation of the complement system occurs in several diseases. For reliable identification of complement activation in neonates, we establish reference ranges of several components in cord blood of healthy term newborns. For this study cord blood samples were taken from 125 healthy term newborns. Concentrations of C1r, C2, C5, C7, Properdin, and factors D, H, and I were determined by single radial immunodiffusion. C3a and C5a were measured by specific EIA and complement function was measured by hemolytic assays. The results were expressed as 5th percentile, median, and 95th percentile. The following respective concentrations were found: C1r: 27, 47, 65 mg/l; C2: 12.0, 18.0, 24.0 mg/l; C5: 64, 92, 127 mg/l; C7: 32, 60, 89 mg/l; Properdin: 5.6, 9.7, 14.2 mg/l; factor D: 3.6, 5.2, 7.3 mg/l; factor H: 178, 234, 296 mg/l; and factor I: 15, 24, 32 mg/l. The functional activity of the whole complement system was 24%, 43%, 97% and for the alternative pathway 39%, 58%, 76%. The concentration of the activated split products C3a was 4, 65, 255 μg/l and of C5a, 0.11, 0.26, 1.19 μg/l. These reference values may be important for the detection of deficiencies of native complement proteins or perinatal processes leading to an activation of the complement system.

scholarly journals Changes in complement alternative pathway components, factor B and factor H during dengue virus infection in the AG129 mouse

2021 ◽  
Author(s):  
Sheila Cabezas-Falcon ◽  
Aidan J. Norbury ◽  
Jarrod Hulme-Jones ◽  
Sonja Klebe ◽  
Penelope Adamson ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Alternative Pathway ◽  
Severe Disease ◽  
Denv Infection ◽  
Factor H ◽  
Severe Dengue ◽  
Complement Alternative Pathway ◽  
Factor B ◽  
Dengue Disease

The complement alternative pathway (AP) is tightly regulated and changes in two important AP components, factor B (FB) and factor H (FH) are linked to severe dengue in humans. Here, a mouse model of dengue was investigated to define the changes in FB and FH and assess the utility of this model to study the role of the AP in severe dengue. Throughout the period of viremia in the AG129 IFN signalling-deficient mouse, an increase in FB and a decrease in FH was observed following dengue virus (DENV) infection, with the former only seen in a model of more severe disease associated with antibody-dependent enhancement (ADE). Terminal disease was associated with a decrease in FB and FH, with greater changes during ADE, and accompanied by increased C3 degradation consistent with complement activation. In silico analysis of NFκΒ, signal transducer and activator of transcription (STAT) and IFN-driven FB and FH promoter elements to reflect the likely impact of the lack of IFN-responses in AG129 mice, demonstrated that these elements differed markedly between human and mouse, notably with mouse FH lacking NFκΒ and key IFN-stimulated response elements (ISRE), and FB with many more NFκΒ and STAT-responsive elements than human FB. Thus, the AG129 mouse offers utility in demonstrating changes in FB and FH that, similar to humans, are associated with severe disease, but lack predicted important human-specific and IFN-dependent responses of FB and FH to DENV-infection that are likely to regulate the subtleties of the overall AP response during dengue disease in humans.

Sign in / Sign up

Export Citation Format

Share Document