FHR-5 Serum Levels and CFHR5 Genetic Variations in Patients With Immune Complex-Mediated Membranoproliferative Glomerulonephritis and C3-Glomerulopathy

Garam, Nóra; Cserhalmi, Marcell; Prohászka, Zoltán; Szilágyi, Ágnes; Veszeli, Nóra; Szabó, Edina; Uzonyi, Barbara; Iliás, Attila; Aigner, Christof; Schmidt, Alice; Gaggl, Martina; Sunder‐Plassmann, Gere; Bajcsi, Dóra; Brunner, Jürgen; Dumfarth, Alexandra; Cejka, Daniel; Flaschberger, Stefan; Flögelová, Hana; Haris, Ágnes; Hartmann, Ágnes; Heilos, Andreas; Mueller, Thomas; Rusai, Krisztina; Arbeiter, Klaus; Hofer, Johannes; Jakab, Dániel; Sinkó, Mária; Szigeti, Erika; Bereczki, Csaba; Jankó, Viktor; Kelen, Kata; Reusz, György; Szabó, Attila; Klenk, Nóra; Kóbor, Krisztina; Kojc, Nika; Knechtelsdorfer, Maarten; Laganović, Mario; Lungu, Adrian; Meglič, Anamarija; Rus, Rina; Levart, Tanja Kersnik; Mačionienė, Ernesta; Miglinas, Marius; Pawłowska, Anna; Stompór, Tomasz; Podracká, Ľudmila; Rudnicki, Michael; Mayer, Gert; Ryšavá, R; Reiterová, Jana; Saraga, Marijan; Seeman, Tomáš; Zieg, Jakub; Sládková, Eva; Stajić, Nataša; Szabó, Tamás; Căpitănescu, Andrei; Sica, Simona; Tišljar, Miroslav; Gales̃ić, Kres̆imir; Tislér, András; Vainumäe, Inga; Windpessl, Martin; Zaoral, Tomáš; Zlatanova, Galia; Józsi, Mihály; Csuka, Dorottya

doi:10.3389/fimmu.2021.720183

Cited by 12 publications

(12 citation statements)

References 70 publications

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“…include C3, CFB, CFH, CFI, DGKE, and CFHR5. In addition, the CFHR genomic region should be screened for complex rearrangements typically by multiplex-ligation-dependent probe amplification (MLPA), a multiplex PCR-based method that can detect the copy number of each CFHR gene.When exon-specific probes are used, CFHR genomic rearrangements such as the CFHR5 fusion gene endemic to Cyprus can be easily identified(Gale et al, 2010;Garam et al, 2021;Schouten et al, 2002).…”

mentioning

confidence: 99%

C3 glomerulopathy: Understanding an ultra‐rare complement‐mediated renal disease

Heiderscheit

Hauer

Smith

2022

American J of Med Genetics Pt C

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C3 glomerulopathy (C3G) describes a pathologic pattern of injury diagnosed by renal biopsy. It is characterized by the dominant deposition of the third component of complement (C3) in the renal glomerulus as resolved by immunofluorescence microscopy. The underlying pathophysiology is driven by dysregulation of the alternative pathway of complement in the fluid-phase and in the glomerular microenvironment.Characterization of clinical features and a targeted evaluation for indices and drivers of complement dysregulation are necessary for optimal patient care. Autoantibodies to the C3 and C5 convertases of complement are the most commonly detected drivers of complement dysregulation, although genetic mutations in complement genes can also be found. Approximately half of patients progress to end-stage renal disease within 10 years of diagnosis, and, while transplantation is a viable option, there is high risk for disease recurrence and allograft failure. This poor outcome reflects the lack of disease-specific therapy for C3G, relegating patients to symptomatic treatment to minimize proteinuria and suppress renal inflammation. Fortunately, the future is bright as several anti-complement drugs are currently in clinical trials.

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confidence: 99%

C3 glomerulopathy: Understanding an ultra‐rare complement‐mediated renal disease

Heiderscheit

Hauer

Smith

2022

American J of Med Genetics Pt C

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“…110,111 One of these studies also showed that the reduced FHR-5 levels were independent of the presence of CFHR5 null alleles, and that the levels correlated positively with the levels of C3, C4, FH and the activity of the AP and the CP, suggesting that FHR-5 is consumed upon complement activation. 110 A study by Pouw et al…”

Section: Quantitative Variations Of the Fh Protein Familymentioning

confidence: 93%

“…Similarly, FHR‐5 plasma levels were also significantly elevated in IgAN, but whether this is due to genetic or environmental factors is unknown 57 . In contrast, reduced plasma FHR‐5 levels compared with controls have been observed in different cohorts of C3G and in immune complex‐mediated membranoproliferative glomerulonephritis 110,111 . One of these studies also showed that the reduced FHR‐5 levels were independent of the presence of CFHR5 null alleles, and that the levels correlated positively with the levels of C3, C4, FH and the activity of the AP and the CP, suggesting that FHR‐5 is consumed upon complement activation 110 .…”

Section: The Factor H Protein Family In Diseasementioning

confidence: 98%

“…In contrast, reduced plasma FHR‐5 levels compared with controls have been observed in different cohorts of C3G and in immune complex‐mediated membranoproliferative glomerulonephritis 110,111 . One of these studies also showed that the reduced FHR‐5 levels were independent of the presence of CFHR5 null alleles, and that the levels correlated positively with the levels of C3, C4, FH and the activity of the AP and the CP, suggesting that FHR‐5 is consumed upon complement activation 110 . A study by Pouw et al reported increased FHR‐3 plasma levels in aHUS compared with controls independently of the genetic factors known to determine FHR‐3 plasma levels (i.e., Δ CFHR3‐CFHR1 and FHR‐3*A/B isoforms), supporting that additional factors may modulate the protein levels.…”

Section: The Factor H Protein Family In Diseasementioning

confidence: 98%

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The Factor H protein family: The switchers of the complement alternative pathway

Lucientes

Márquez-Tirado

Jorge

2022

Immunological Reviews

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The factor H (FH) protein family is emerging as a complex network of proteins controlling the fate of the complement alternative pathway (AP) and dictating susceptibility to a wide range of diseases including infectious, inflammatory, autoimmune, and degenerative diseases and cancer. Composed, in man, of seven highly related proteins, FH, factor H-like 1, and 5 factor H-related proteins, some of the FH family proteins are devoted to down-regulating the AP, while others exert an opposite function by promoting AP activation. Recent findings have provided insights into the molecular mechanisms defining their biological roles and their pathogenicity, illustrating the relevance that the balance between the regulators and the activators within this protein family has in defining the outcome of complement activation on cell surfaces. In this review we will discuss the emerging roles of the factor H protein family, their impact in the complement cascade, and their involvement in the pathogenesis of complementmediated diseases associated with the AP dysregulation.

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“…While FHL-1 retains the same function as its larger FH counterpart, the FHR proteins are FH/FHL-1 antagonists and drive complement activation instead of inhibition ( 21 ). Altered levels of these proteins play a key role in several complement-related diseases, including renal diseases such as atypical haemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G) ( 22 , 23 ) and Age-Related Macular Degeneration (AMD) ( 24 ). FHRs 2 and 5 have also been identified as potentially differentially expressed in association with severe COVID-19 in global proteomics studies ( 12 , 25 ).…”

Section: Introductionmentioning

confidence: 99%

Levels of soluble complement regulators predict severity of COVID-19 symptoms

Tierney

Alali²,

Scott³

et al. 2022

Front. Immunol.

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The SARS-CoV-2 virus continues to cause significant morbidity and mortality worldwide from COVID-19. One of the major challenges of patient management is the broad range of symptoms observed. While the majority of individuals experience relatively mild disease, a significant minority of patients require hospitalisation, with COVID-19 still proving fatal for some. As such, there remains a desperate need to better understand what drives this severe disease, both in terms of the underlying biology, but also to potentially predict at diagnosis which patients are likely to require further interventions, thus enabling better outcomes for both patients and healthcare systems. Several lines of evidence have pointed to dysregulation of the complement cascade as a major factor in severe COVID-19 outcomes. How this is underpinned mechanistically is not known. Here, we have focussed on the role of the soluble complement regulators Complement Factor H (FH), its splice variant Factor H-like 1 (FHL-1) and five Factor H-Related proteins (FHR1-5). Using a targeted mass spectrometry approach, we quantified these proteins in a cohort of 188 plasma samples from controls and SARS-CoV-2 patients taken at diagnosis. This analysis revealed significant elevations in all FHR proteins, but not FH, in patients with more severe disease, particularly FHR2 and FHR5 (FHR2: 1.97-fold, p<0.0001; FHR5: 2.4-fold, p<0.0001). Furthermore, for a subset of 77 SARS-CoV-2 +ve patients we also analysed time course samples taken approximately 28 days post-diagnosis. Here, we see complement regulator levels drop in all individuals with asymptomatic or mild disease, but regulators remain high in those with more severe outcomes, with elevations in FHR2 over baseline levels in this group. These data support the hypothesis that elevation of circulating levels of the FHR family of proteins could predict disease severity in COVID-19 patients, and that the duration of elevation (or lack of immune activation resolution) may be partly responsible for driving poor outcomes in COVID-19.

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FHR-5 Serum Levels and CFHR5 Genetic Variations in Patients With Immune Complex-Mediated Membranoproliferative Glomerulonephritis and C3-Glomerulopathy

Cited by 12 publications

References 70 publications

C3 glomerulopathy: Understanding an ultra‐rare complement‐mediated renal disease

C3 glomerulopathy: Understanding an ultra‐rare complement‐mediated renal disease

The Factor H protein family: The switchers of the complement alternative pathway

Levels of soluble complement regulators predict severity of COVID-19 symptoms

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