Factor H Autoantibodies and Complement-Mediated Diseases

Zhang, Yuzhou; Borsa, Nicolò; Shao, Dingwu; Dopler, Arthur; Jones, Michael B.; Meyer, Nicole C.; Pitcher, Gabriella R.; Taylor, Amanda; Nester, Carla; Schmidt, Christoph Q.; Smith, Richard J.H.

doi:10.3389/fimmu.2020.607211

Cited by 23 publications

(23 citation statements)

References 40 publications

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“…At variance with aHUS patients, we did not observe a correlation between the presence of FHAAs and homozygosity for CFHR1 del in C3G/IC-MPGN patients, consistent with previous data ( Blanc et al, 2015 ; Valoti et al, 2019 ; Zhang et al, 2020 ). In addition, the prevalence of the common SVs ( CFHR3-CFHR1 del or CFHR1-CFHR4 del) did not differ between patients and healthy controls, indicating that common SVs are not risk factors for C3G/IC-MPGN.…”

Section: Discussionsupporting

confidence: 92%

“…IC-MPGN has typically been linked to the activation of the complement CP following infections, autoimmune diseases or malignancies, while C3G has primarily been linked to activation of the complement AP ( Sethi and Fervenza, 2011 ). In both C3G and IC-MPGN, genetic defects in complement AP genes like CFH , C3 , CFI , and CFB ( Servais et al, 2012 ; Iatropoulos et al, 2016 , 2018 ), and acquired factors, such autoantibodies that stabilize the C3 convertase complex C3bBb (called C3-nephritic factors, C3NeFs) or against FH, FB and C3b have been identified ( Zhang et al, 2012 , 2020 ; Blanc et al, 2015 ; Marinozzi et al, 2017 ; Donadelli et al, 2018 ). These findings indicate that the dysregulation of the complement AP may underlie the pathogenesis of both diseases ( Figure 2 ).…”

Section: Introductionmentioning

confidence: 99%

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CFH and CFHR Copy Number Variations in C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis

et al. 2021

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C3 Glomerulopathy (C3G) and Immune Complex-Mediated Membranoproliferative glomerulonephritis (IC-MPGN) are rare diseases characterized by glomerular deposition of C3 caused by dysregulation of the alternative pathway (AP) of complement. In approximately 20% of affected patients, dysregulation is driven by pathogenic variants in the two components of the AP C3 convertase, complement C3 (C3) and Factor B (CFB), or in complement Factor H (CFH) and Factor I (CFI), two genes that encode complement regulators. Copy number variations (CNVs) involving the CFH-related genes (CFHRs) that give rise to hybrid FHR proteins also have been described in a few C3G patients but not in IC-MPGN patients. In this study, we used multiplex ligation-dependent probe amplification (MLPA) to study the genomic architecture of the CFH-CFHR region and characterize CNVs in a large cohort of patients with C3G (n = 103) and IC-MPGN (n = 96) compared to healthy controls (n = 100). We identified new/rare CNVs resulting in structural variants (SVs) in 5 C3G and 2 IC-MPGN patients. Using long-read single molecule real-time sequencing (SMRT), we detected the breakpoints of three SVs. The identified SVs included: 1) a deletion of the entire CFH in one patient with IC-MPGN; 2) an increased number of CFHR4 copies in one IC-MPGN and three C3G patients; 3) a deletion from CFHR3-intron 3 to CFHR3-3′UTR (CFHR34–6Δ) that results in a FHR3-FHR1 hybrid protein in a C3G patient; and 4) a CFHR31–5-CFHR410 hybrid gene in a C3G patient. This work highlights the contribution of CFH-CFHR CNVs to the pathogenesis of both C3G and IC-MPGN.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

CFH and CFHR Copy Number Variations in C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis

et al. 2021

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“…In 2005, it was first reported that anti-complement factor H autoantibodies (FH autoAb) can cause complement system dysregulation leading to aHUS through neutralization of the complement factor H regulatory protein [ 3 ]. FH autoAbs have since been found in 10.9% of aHUS patient cohorts in North America, consistent with reports from Europe, and in 55.8% of the patients in the aHUS database in India, with children aged four to seven most affected [ 4 - 5 ].…”

Section: Introductionsupporting

confidence: 82%

Blockade of the Terminal Complement Cascade Using Ravulizumab in a Pediatric Patient With Anti-complement Factor H Autoantibody-Associated aHUS: A Case Report and Literature Review

Wu¹,

Szarzanowicz²,

Garba³

et al. 2021

Cureus

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Atypical hemolytic uremic syndrome (aHUS) is a rare disease in pediatrics with 6-10% of cases associated with complement factor H autoantibodies . Ravulizumab is a new treatment option available for long-term management through blockage of the terminal complement cascade. We report a case of a previously healthy eight-year-old female who presented with hemolytic anemia, thrombocytopenia, and acute kidney injury. Low complement C3, normal ADAMTS13, and negative rheumatology and infectious disease panels suggested aHUS. A follow-up complement aHUS/TMA gene panel was negative for ADAMTS13, C3, CD46, CFB, CFD, CFH, CFHR1, CFHR3, CFHR5, CRI, DGKE, PLG, and THBD mutations and positive for MCP/CD46 haplotype and CFH-H3 haplotype. Further testing found decreased factor H (B1H) plasma level and increased factor H autoantibody, suggesting anti-factor H antibody-associated aHUS. She received hemodialysis (2 treatments) and eculizumab was initiated promptly. The patient had complete renal recovery after one month of therapy, and anemia, thrombocytopenia, and hemolysis resolved after two months of therapy. After five months of therapy, eculizumab was successfully switched to ravulizumab. After 12 months of initial diagnosis, complement C3 and factor H normalized, however, factor H autoantibody remained elevated. The case supports the notion that timely recognition of anti-FH-associated aHUS is important for disease management and that early specific therapy with immunosuppression results in favorable outcomes. It also illustrates that the blockade of the terminal complement cascade using eculizumab holds promise for pediatric cases. Finally, eculizumab can be safely switched to ravulizumab with an optimal longer duration between treatments in the context of aHUS.

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“…FH is the main inhibitor of the alternative pathway, which is continuously activated in plasma but also in an amplification loop of the classical and lectin pathways. Genetic variants as well as autoantibodies affecting the C-terminal domains of FH impair the simultaneous binding of FH to sialic acid and C3b and are associated with complement-related diseases such as atypical hemolytic uremic syndrome, age-related macular degeneration and C3 glomerulopathy ( 12 , 13 ). Decreased levels of the FH ligand sialic acid might result in the same outcome.…”

Section: Introductionmentioning

confidence: 99%

Severe Congenital Thrombocytopenia Characterized by Decreased Platelet Sialylation and Moderate Complement Activation Caused by Novel Compound Heterozygous Variants in GNE

et al. 2021

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BackgroundHereditary thrombocytopenias constitute a genetically heterogeneous cause of increased bleeding. We report a case of a 17-year-old boy suffering from severe macrothrombocytopenia throughout his life. Whole genome sequencing revealed the presence of two compound heterozygous variants in GNE encoding the enzyme UDP-N-acetyl-glucosamine-2-epimerase/N-acetylmannosamine kinase, crucial for sialic acid biosynthesis. Sialic acid is required for normal platelet life span, and biallelic variants in GNE have previously been associated with isolated macrothrombocytopenia. Furthermore, sialic acid constitutes a key ligand for complement factor H (FH), an important inhibitor of the complement system, protecting host cells from indiscriminate attack.MethodsSialic acid expression and FH binding to platelets and leukocytes was evaluated by flow cytometry. The binding of FH to erythrocytes was assessed indirectly by measuring the rate of complement mediated hemolysis. Complement activation was determined by measuring levels of C3bBbP (alternative pathway), C4d (classical/lectin pathway) and soluble terminal complement complex assays.ResultsThe proband exhibited markedly decreased expression of sialic acid on platelets and leukocytes. Consequently, the binding of FH was strongly reduced and moderate activation of the alternative and classical/lectin complement pathways was observed, together with an increased rate of erythrocyte lysis.ConclusionWe report two previously undescribed variants in GNE causing severe congenital macrothrombocytopenia in a compound heterozygous state, as a consequence of decreased platelet sialylation. The decreased sialylation of platelets, leukocytes and erythrocytes affects the binding of FH, leading to moderate complement activation and increased hemolysis.

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Factor H Autoantibodies and Complement-Mediated Diseases

Cited by 23 publications

References 40 publications

CFH and CFHR Copy Number Variations in C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis

CFH and CFHR Copy Number Variations in C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis

Blockade of the Terminal Complement Cascade Using Ravulizumab in a Pediatric Patient With Anti-complement Factor H Autoantibody-Associated aHUS: A Case Report and Literature Review

Severe Congenital Thrombocytopenia Characterized by Decreased Platelet Sialylation and Moderate Complement Activation Caused by Novel Compound Heterozygous Variants in GNE

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