Circulating complement factor H–related proteins 1 and 5 correlate with disease activity in IgA nephropathy

Medjeral-Thomas, Nicholas; Lomax-Browne, Hannah J.; Beckwith, Hannah; Willicombe, Michelle; McLean, A.G.; Brookes, Paul; Pusey, Charles D.; Falchi, Mario; Cook, H. Terence; Pickering, Matthew C.

doi:10.1016/j.kint.2017.03.043

Cited by 111 publications

(139 citation statements)

References 41 publications

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“…We provided data that show FHR-1 levels are increased in IgAN patients and that this increase correlates with decreased renal function. Importantly, these data have been replicated in an independent IgAN cohort (Medjeral-Thomas et al 24 ). Although it remains unclear how to translate our observations in a clinical setting, the data strongly support a role of FHR-1 in IgAN pathogenesis in which FHR-1 competes with complement regulation by FH.…”

Section: Discussionmentioning

confidence: 69%

Elevated factor H–related protein 1 and factor H pathogenic variants decrease complement regulation in IgA nephropathy

Tortajada

Gutiérrez

Jorge

et al. 2017

Kidney International

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IgA nephropathy (IgAN), a frequent cause of chronic kidney disease worldwide, is characterized by mesangial deposition of galactose-deficient IgA1-containing immune complexes. Complement involvement in IgAN pathogenesis is suggested by the glomerular deposition of complement components and the strong protection from IgAN development conferred by the deletion of the CFHR3 and CFHR1 genes (Δ). Here we searched for correlations between clinical progression and levels of factor H (FH) and FH-related protein 1 (FHR-1) using well-characterized patient cohorts consisting of 112 patients with IgAN, 46 with non-complement-related autosomal dominant polycystic kidney disease (ADPKD), and 76 control individuals. Patients with either IgAN or ADPKD presented normal FH but abnormally elevated FHR-1 levels and FHR-1/FH ratios compared to control individuals. Highest FHR-1 levels and FHR-1/FH ratios are found in patients with IgAN with disease progression and in patients with ADPKD who have reached chronic kidney disease, suggesting that renal function impairment elevates the FHR-1/FH ratio, which may increase FHR-1/FH competition for activated C3 fragments. Interestingly, Δ homozygotes are protected from IgAN, but not from ADPKD, and we found five IgAN patients with low FH carrying CFH or CFI pathogenic variants. These data support a decreased FH activity in IgAN due to increased FHR-1/FH competition or pathogenic CFH variants. They also suggest that alternative pathway complement activation in patients with IgAN, initially triggered by galactose-deficient IgA1-containing immune complexes, may exacerbate in a vicious circle as renal function deterioration increase FHR-1 levels. Thus, a role of FHR-1 in IgAN pathogenesis is to compete with complement regulation by FH.

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Section: Discussionmentioning

confidence: 69%

Elevated factor H–related protein 1 and factor H pathogenic variants decrease complement regulation in IgA nephropathy

Tortajada

Gutiérrez

Jorge

et al. 2017

Kidney International

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“…For example, the lack of FHR-1 and FHR-3 due to the prevalent CFHR3-CFHR1 gene deletion is strongly associated with lower risk of developing IgA nephropathy [45] and AMD [46], likely due to the less amount of FHRs to interfere with the complement regulatory activity of factor H [30]. It was very recently shown indeed, that FHR-1 serum levels and the FHR-1:factor H ratio are higher in IgA nephropathy patients compared with healthy controls [47,48]. Factor H pathogenic variants causing decreased factor H activity and certain haplotypes that determine different factor H and FHR-1/FHR-3 serum levels modulate the FH/FHR balance and influence susceptibility to diseases [48][49][50][51][52].…”

Section: The Factor H-related (Fhr) Proteins As Positive Modulators Omentioning

confidence: 99%

Complement factor H family proteins in their non-canonical role as modulators of cellular functions

Józsi

Schneider

Kárpáti

et al. 2019

Seminars in Cell & Developmental Biology

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Complement factor H is a major regulator of the alternative pathway of the complement system. The factor H-related proteins are less characterized, but recent data indicate that they rather promote complement activation. These proteins have some common ligands with factor H and have both overlapping and distinct functions depending on domain composition and the degree of conservation of amino acid sequence. Factor H and some of the factor H-related proteins also appear in a non-canonical function that is beyond their role in the modulation of complement activation. This review covers our current understanding on this emerging role of factor H family proteins in modulating the activation and function of various cells by binding to receptors or receptor ligands.

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“…Fewer CFHRs in serum could lead to less CFH deregulation, enabling tighter control of complement activation and inflammation. Conversely, circulating CFHR proteins 1 and 5 may correlate with increased disease activity, as shown in a large cohort of patients with IgA nephropathy [63].…”

Section: The Role Of Cfhr5 In Complement Regulationmentioning

confidence: 91%

C3 Glomerulopathy

Kojc¹

2018

Advances in Nephropathy

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Understanding the role of alternative complement pathway dysregulation in membranoproliferative glomerulonephritis (MPGN) has led to a new classification into two subgroups: immune complex-mediated MPGN and complement-mediated MPGN. Immune complex-mediated MPGN results from the deposition of immunoglobulin deposits and complements component C3 driven by classical complement pathway activation, while complement-mediated disease may be associated with complement alternative pathway dysregulation and is a new entity, C3 glomerulopathy. C3 glomerulopathy is an umbrella term, encompassing dense deposit disease (DDD), former MPGN type II, and C3 glomerulonephritis. C3 glomerulonephritis comprises examples of MPGN types I and III, in which immunofluorescence reveals predominant C3 deposits. By light microscopy, distinctive histologic patterns can be observed in both entities, including membranoproliferative, mesangial proliferative, crescentic and acute proliferative and exudative patterns, of which the membranoproliferative pattern seems to be the most common. DDD is defined by the presence of dense osmiophilic transformation of the glomerular basement membrane (GBM) on electron microscopy (EM). Only EM enables definite distinction of DDD from C3 glomerulonephritis. C3 glomerulopathy is a heterogeneous disease; genetic or acquired complement alternative pathway abnormalities have been identified in up to 40% of patients, including mutations in complement factors or autoantibodies directed against them.

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Circulating complement factor H–related proteins 1 and 5 correlate with disease activity in IgA nephropathy

Cited by 111 publications

References 41 publications

Elevated factor H–related protein 1 and factor H pathogenic variants decrease complement regulation in IgA nephropathy

Elevated factor H–related protein 1 and factor H pathogenic variants decrease complement regulation in IgA nephropathy

Complement factor H family proteins in their non-canonical role as modulators of cellular functions

C3 Glomerulopathy

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