Factor H Competitor Generated by Gene Conversion Events Associates with Atypical Hemolytic Uremic Syndrome

Jorge, Elena Goicoechea de; Tortajada, Agustín; García, Sheila Pinto; Gastoldi, Sara; Merinero, Héctor Martín; García-Fernández, Jesús; Arjona, Emilia; Cao, Mercedes; Remuzzi, Giuseppe; Noris, Marina; Córdoba, Santiago Rodrı́guez de

doi:10.1681/asn.2017050518

Cited by 34 publications

(43 citation statements)

References 31 publications

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“…Moreover, certain genetic variants of CFH induce generation of autoantibodies that neutralize CFH and prevent complement regulation (90). Mutated CFH and CFHR hybrid proteins are unable to protect endogenous cells from MACinduced phenotype alteration of endothelial cells, favoring platelet aggregation (91). C3a-and, most excessively, C5a-mediated inflammation and myeloid cell immigration lead to a prothrombotic state, especially in the endothelium, since the fenestrated structure favors exposure to circulating complement components.…”

Section: Atypical Hemolytic Uremic Syndromementioning

confidence: 99%

Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway

et al. 2020

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The complement system comprises the frontline of the innate immune system. Triggered by pathogenic surface patterns in different pathways, the cascade concludes with the formation of a membrane attack complex (MAC; complement components C5b to C9) and C5a, a potent anaphylatoxin that elicits various inflammatory signals through binding to C5a receptor 1 (C5aR1). Despite its important role in pathogen elimination, priming and recruitment of myeloid cells from the immune system, as well as crosstalk with other physiological systems, inadvertent activation of the complement system can result in self-attack and overreaction in autoinflammatory diseases. Consequently, it constitutes an interesting target for specialized therapies. The paradigm of safe and efficacious terminal complement pathway inhibition has been demonstrated by the approval of eculizumab in paroxysmal nocturnal hematuria. In addition, complement contribution in rare kidney diseases, such as lupus nephritis, IgA nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, or antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated. This review summarizes the involvement of the terminal effector agents of the complement system in these diseases and provides an overview of inhibitors for complement components C5, C5a, C5aR1, and MAC that are currently in clinical development. Furthermore, a link between increased complement activity and lung damage in severe COVID-19 patients is discussed and the potential for use of complement inhibitors in COVID-19 is presented.

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Section: Atypical Hemolytic Uremic Syndromementioning

confidence: 99%

Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway

et al. 2020

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“…Sera were from 2 Dutch aHUS patients (aHUS#1 and aHUS#2) and 9 patients from the Spanish aHUS registry (aHUS#3-aHUS#11) carrying different CFH variants. Functional data for Arg53Ser 29 (aHUS#7), Ser411Thr 30 (aHUS#10, also carrying a CFHR1::CFH hybrid gene), Val1007Leu 31 (aHUS#5), Trp1157Arg 32 (aHUS#6), Arg1182Lys 29 (aHUS#8), Trp1183Leu 33 (aHUS#3), Ser1191Leu 34 (aHUS#1), and Val1197Ala 18 (aHUS#9) mutations were described previously. The functional consequences of Val383Ala (aHUS#11), Glu847Val 22 (aHUS#4), and Tyr1058His (aHUS#2) are unknown.…”

Section: Patients and Controlsmentioning

confidence: 99%

Potentiation of complement regulator factor H protects human endothelial cells from complement attack in aHUS sera

et al. 2019

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Mutations in the gene encoding for complement regulator factor H (FH) severely disrupt its normal function to protect human cells from unwanted complement activation, resulting in diseases such as atypical hemolytic uremic syndrome (aHUS). aHUS presents with severe hemolytic anemia, thrombocytopenia, and renal disease, leading to end-stage renal failure. Treatment of severe complement-mediated disease, such as aHUS, by inhibiting the terminal complement pathway, has proven to be successful but at the same time fails to preserve the protective role of complement against pathogens. To improve complement regulation on human cells without interfering with antimicrobial activity, we identified an anti-FH monoclonal antibody (mAb) that induced increased FH-mediated protection of primary human endothelial cells from complement, while preserving the complement-mediated killing of bacteria. Moreover, this FH-activating mAb restored complement regulation in sera from aHUS patients carrying various heterozygous mutations in FH known to impair FH function and dysregulate complement activation. Our data suggest that FH normally circulates in a less active conformation and can become more active, allowing enhanced complement regulation on human cells. Antibody-mediated potentiation of FH may serve as a highly effective approach to inhibit unwanted complement activation on human cells in a wide range of hematological diseases while preserving the protective role of complement against pathogens.

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“…Anti-CFH antibodies aHUS is not strictly an acquired form, as they are associated with CFHR3–1 homozygous deletion in 90% of cases. This form is more frequent in pediatric (25–50%) than in adult patients (5–10%) [27, 28].…”

Section: Genetics Of Ahusmentioning

confidence: 99%

Atypical Hemolytic Uremic Syndrome: New Challenges in the Complement Blockage Era

Bernabeu

Escribano

Vilariño

2020

Nephron

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Atypical hemolytic uremic syndrome (aHUS) is a rare cause of thrombotic microangiopathy (TMA), characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and multisystem end organ involvement, most commonly affecting the kidney. Diagnosis is clinical, after exclusion of other TMA causes. Primary aHUS arises from genetic abnormalities, resulting in uncontrolled complement activity, while a variety of clinical scenarios cause secondary aHUS, including infection, pregnancy, malignancy, autoimmune disease, and medications. They can also induce a temporary complement deregulation with an overlap between both scenarios, which can make differential diagnosis difficult. Primary aHUS can be sporadic or familial and is associated with a high rate of progression to ESRD. Many aHUS patients relapse in the native or transplanted kidneys, leading to kidney failure. The introduction of eculizumab has changed the prognosis of aHUS, by inducing hematologic remission, improving or stabilizing kidney functions, and preventing graft failure. The early institution of appropriate therapy can prevent multiorgan damage, so is essential to recognize and differentiate the TMA syndromes. Eculizumab is considered now the first-line treatment, and it is recommended lifelong therapy. However, the high cost of therapy has led to make efforts to develop precise complement functional and genetic studies that help physicians to determine the appropriate duration of eculizumab therapy. Nowadays, more studies are needed to select candidates to adjustment of therapy.

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Factor H Competitor Generated by Gene Conversion Events Associates with Atypical Hemolytic Uremic Syndrome

Cited by 34 publications

References 31 publications

Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway

Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway

Potentiation of complement regulator factor H protects human endothelial cells from complement attack in aHUS sera

Atypical Hemolytic Uremic Syndrome: New Challenges in the Complement Blockage Era

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