scholarly journals Amnion epithelial cells are an effective source of factor H and prevent kidney complement deposition in factor H-deficient mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Federica Casiraghi ◽  
Pamela Yossenaidy Rodriguez Ordonez ◽  
Nadia Azzollini ◽  
Marta Todeschini ◽  
Daniela Rottoli ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Epithelial Cells ◽  
Complement Activation ◽  
Therapeutic Option ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Complement Factor ◽  
Complement Deposition ◽  
Amnion Epithelial Cells

AbstractComplement factor H (FH) is the main plasma regulator of the alternative pathway of complement. Genetic and acquired abnormalities in FH cause uncontrolled complement activation amplifying, with the consequent accumulation of complement components on the renal glomeruli. This leads to conditions such as C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS). There is no effective therapy for these diseases. Half of the patients progress to end-stage renal disease and the condition recurs frequently in transplanted kidneys. Combined liver/kidney transplantation is a valid option for these patients, but the risks of the procedure and donor organ shortages hamper its clinical application. Therefore, there is an urgent need for alternative strategies for providing a normal FH supply. Human amnion epithelial cells (hAEC) have stem cell characteristics, including the capability to differentiate into hepatocyte-like cells in vivo.Here, we administered hAEC into the livers of newborn Cfh−/− mice, which spontaneously developed glomerular complement deposition and renal lesions resembling human C3G. hAEC engrafted at low levels in the livers of Cfh−/− mice and produced sufficient human FH to prevent complement activation and glomerular C3 and C9 deposition. However, long-term engraftment was not achieved, and eventually hAEC elicited a humoral immune response in immunocompetent Cfh−/− mice.hAEC cell therapy could be a valuable therapeutic option for patients undergoing kidney transplantation in whom post-transplant immunosuppression may protect allogeneic hAEC from rejection, while allogeneic cells provide normal FH to prevent disease recurrence.

scholarly journals Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition

Blood ◽  
2020 ◽  
Vol 136 (18) ◽  
pp. 2080-2089 ◽  
Author(s):  
Jia Yu ◽  
Xuan Yuan ◽  
Hang Chen ◽  
Shruti Chaturvedi ◽  
Evan M. Braunstein ◽  
...  
Keyword(s):  
Complement Activation ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Spike Protein ◽  
Target Cells ◽  
Antiphospholipid Antibody ◽  
Antiphospholipid Antibody Syndrome ◽  
Complement Factor ◽  
Spike Proteins

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious respiratory virus that can lead to venous/arterial thrombosis, stroke, renal failure, myocardial infarction, thrombocytopenia, and other end-organ damage. Animal models demonstrating end-organ protection in C3-deficient mice and evidence of complement activation in humans have led to the hypothesis that SARS-CoV-2 triggers complement-mediated endothelial damage, but the mechanism is unclear. Here, we demonstrate that the SARS-CoV-2 spike protein (subunit 1 and 2), but not the N protein, directly activates the alternative pathway of complement (APC). Complement-dependent killing using the modified Ham test is blocked by either C5 or factor D inhibition. C3 fragments and C5b-9 are deposited on TF1PIGAnull target cells, and complement factor Bb is increased in the supernatant from spike protein–treated cells. C5 inhibition prevents the accumulation of C5b-9 on cells, but not C3c; however, factor D inhibition prevents both C3c and C5b-9 accumulation. Addition of factor H mitigates the complement attack. In conclusion, SARS-CoV-2 spike proteins convert nonactivator surfaces to activator surfaces by preventing the inactivation of the cell-surface APC convertase. APC activation may explain many of the clinical manifestations (microangiopathy, thrombocytopenia, renal injury, and thrombophilia) of COVID-19 that are also observed in other complement-driven diseases such as atypical hemolytic uremic syndrome and catastrophic antiphospholipid antibody syndrome. C5 inhibition prevents accumulation of C5b-9 in vitro but does not prevent upstream complement activation in response to SARS-CoV-2 spike proteins.

scholarly journals De Novo Atypical Haemolytic Uremic Syndrome after Kidney Transplantation

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.

scholarly journals Novel Complement Factor H mutation, a case report of atypical hemolytic uremic syndrome

2017 ◽  
Vol 4 (2) ◽  
pp. 13 ◽  
Author(s):  
Rodrigo Andrés Sepúlveda ◽  
Rodrigo Tagle ◽  
Aquiles Jara
Keyword(s):  
Renal Failure ◽  
Hemolytic Uremic Syndrome ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Complement Factor H ◽  
Complement Factor ◽  
Severe Renal Failure ◽  
Uremic Syndrome ◽  
I Factor

 Atypical hemolytic uremic syndrome (aHUS) is a rare but catastrophic disease. It is characterized by a triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. When the aHUS is primary, the cause is due to mutations in proteins that regulate the alternative pathway of complement, such as Factor H, Factor I, Factor B, C3, Membrane Co-Factor Protein and Thrombomodulin. Usually primary aHUS is associated with other amplifiers complement factors. We present a case of aHUS in a 25-year-old female patient; she presented with malignant hypertension and severe renal failure. After a widespread study, the etiology of the aHUS was a mutation in the complement factor H, not previously described in the literature (p.Tyr1177His). After treatment with Eculizumab (C5 inhibitor monoclonal antibody), she recovered renal function with not hemodialysis requirements. 

scholarly journals Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains

2007 ◽  
Vol 204 (6) ◽  
pp. 1249-1256 ◽  
Author(s):  
Matthew C. Pickering ◽  
Elena Goicoechea de Jorge ◽  
Rubén Martinez-Barricarte ◽  
Sergio Recalde ◽  
Alfredo Garcia-Layana ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Risk Haplotype ◽  
Complement Factor ◽  
Age Related ◽  
Uremic Syndrome

Factor H (FH) is an abundant serum glycoprotein that regulates the alternative pathway of complement-preventing uncontrolled plasma C3 activation and nonspecific damage to host tissues. Age-related macular degeneration (AMD), atypical hemolytic uremic syndrome (aHUS), and membranoproliferative glomerulonephritis type II (MPGN2) are associated with polymorphisms or mutations in the FH gene (Cfh), suggesting the existence of a genotype–phenotype relationship. Although AMD and MPGN2 share pathological similarities with the accumulation of complement-containing debris within the eye and kidney, respectively, aHUS is characterized by renal endothelial injury. This pathological distinction was reflected in our Cfh association analysis, which demonstrated that although AMD and MPGN2 share a Cfh at-risk haplotype, the haplotype for aHUS was unique. FH-deficient mice have uncontrolled plasma C3 activation and spontaneously develop MPGN2 but not aHUS. We show that these mice, transgenically expressing a mouse FH protein functionally equivalent to aHUS-associated human FH mutants, regulate C3 activation in plasma and spontaneously develop aHUS but not MPGN2. These animals represent the first model of aHUS and provide in vivo evidence that effective plasma C3 regulation and the defective control of complement activation on renal endothelium are the critical events in the molecular pathogenesis of FH-associated aHUS.

scholarly journals Control of Complement Activation by the Long Pentraxin PTX3: Implications in Age-Related Macular Degeneration

2020 ◽  
Vol 11 ◽  
Author(s):  
Matteo Stravalaci ◽  
Francesca Davi ◽  
Raffaella Parente ◽  
Marco Gobbi ◽  
Barbara Bottazzi ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Complement Activation ◽  
Hot Spot ◽  
Alternative Pathway ◽  
Retinal Pigment ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Complement Factor ◽  
Rpe Cells ◽  
Age Related

Dysregulation of the complement system is central to age-related macular degeneration (AMD), the leading cause of blindness in the developed world. Most of the genetic variation associated with AMD resides in complement genes, with the greatest risk associated with polymorphisms in the complement factor H (CFH) gene; factor H (FH) is the major inhibitor of the alternative pathway (AP) of complement that specifically targets C3b and the AP C3 convertase. Long pentraxin 3 (PTX3) is a soluble pattern recognition molecule that has been proposed to inhibit AP activation via recruitment of FH. Although present in the human retina, if and how PTX3 plays a role in AMD is still unclear. In this work we demonstrated the presence of PTX3 in the human vitreous and studied the PTX3-FH-C3b crosstalk and its effects on complement activation in a model of retinal pigment epithelium (RPE). RPE cells cultured in inflammatory AMD-like conditions overexpressed the PTX3 protein, and up-regulated AP activating genes. PTX3 bound RPE cells in a physiological setting, however this interaction was reduced in inflammatory conditions, whereby PTX3 had no complement-inhibiting activity on inflamed RPE. However, on non-cellular surfaces, PTX3 formed a stable ternary complex with FH and C3b that acted as a “hot spot” for complement inhibition. Our findings suggest a protective role for PTX3 in response to complement dysregulation in AMD and point to a novel mechanism of complement regulation by this pentraxin with potential implications in pathology and pharmacology of AMD.

scholarly journals Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome

Blood ◽  
2009 ◽  
Vol 114 (13) ◽  
pp. 2837-2845 ◽  
Author(s):  
Lubka T. Roumenina ◽  
Mathieu Jablonski ◽  
Christophe Hue ◽  
Jacques Blouin ◽  
Jordan D. Dimitrov ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Hemolytic Uremic Syndrome ◽  
Umbilical Vein ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Immune Defense ◽  
Factor B ◽  
Uremic Syndrome ◽  
Complement Deposition

Abstract Complement is a major innate immune defense against pathogens, tightly regulated to prevent host tissue damage. Atypical hemolytic uremic syndrome (aHUS) is characterized by endothelial damage leading to renal failure and is highly associated with abnormal alternative pathway regulation. We characterized the functional consequences of 2 aHUS-associated mutations (D254G and K325N) in factor B, a key participant in the alternative C3 convertase. Mutant proteins formed high-affinity C3-binding site, leading to a hyperfunctional C3 convertase, resistant to decay by factor H. This led to enhanced complement deposition on the surface of alternative pathway activator cells. In contrast to native factor B, the 2 mutants bound to inactivated C3 and induced formation of functional C3-convertase on iC3b-coated surface. We demonstrated for the first time that factor B mutations lead to enhanced C3-fragment deposition on quiescent and adherent human glomerular cells (GEnCs) and human umbilical vein endothelial cells (HUVECs), together with the formation of sC5b-9 complexes. These results could explain the occurrence of the disease, since excessive complement deposition on endothelial cells is a central event in the pathogenesis of aHUS. Therefore, risk factors for aHUS are not only mutations leading to loss of regulation, but also mutations, resulting in hyperactive C3 convertase.

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