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

Tortajada, Agustín; Gutiérrez, Eduardo; Jorge, Elena Goicoechea de; Anter, Jaouad; Segarra, Alfons; Espinosa, Mario; Blasco, Miquel; Román, Elena; Marco, Helena; Quintana, Luís F.; Gutiérrez, J Ruiz; Pinto, Sheila; López‐Trascasa, Margarita; Praga, Manuel; Córdoba, Santiago Rodrı́guez de

doi:10.1016/j.kint.2017.03.041

Cited by 86 publications

(94 citation statements)

References 32 publications

(40 reference statements)

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“…10A), with the lowest and highest recombinant FHR-1:FH ratio being 0.23 and 7.5, respectively. Physiological FHR-1:FH ratios were reported to be in the range of 0.4-0.8 (43) or lower (44). Even the addition of such moderate concentrations of recombinant FHR-1 dimers to NHS (already containing natural FHR molecules) led to noticeable but small increases in C3b deposition.…”

Section: Fhl-1 Resists Deregulation By Fhr-1 and Occurs Late In Evolumentioning

confidence: 99%

Self versus Nonself Discrimination by the Soluble Complement Regulators Factor H and FHL-1

Dopler

Guntau

Harder

et al. 2019

The Journal of Immunology

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The plasma proteins Factor H (FH) and its alternate splice variant FH-like protein 1 (FHL-1) are the major regulators of the complement alternative pathway. The indiscriminate nature of alternative pathway activation necessitates the regulators to be host selective, but the underlying principles of selectivity remained largely elusive. By analyzing human FH and FHL-1 for protection of different host and foreign cells (rabbit and yeast), we uncovered a 2-fold discriminatory mechanism of FH in favor of self: relative to FHL-1, FH exhibits a regulatory benefit on self but importantly, also, a regulatory penalty on nonself surfaces, yielding a selectivity factor of ∼2.4 for sialylated host surfaces. We further show that FHL-1 possesses higher regulatory activity than known but is relatively unselective. The reason for this unexpected high activity of FHL-1 is the observation that the complement regulatory site in FH exceeds the established first four domains. Affinity for C3b, cofactor and decay-accelerating activities, and serum assays demonstrate that the regulatory site extends domains 1–4 and includes domains 5–7. But unlike FH, FHL-1 exhibits a fast plasma clearance in mice, occurs sparsely in human plasma (at one fortieth of the FH concentration), and resists deregulation by FH-related proteins. These physiological differences and its late phylogenetic occurrence argue that FHL-1 is crucial for local rather than systemic compartments. In conclusion, we demonstrate a 2-fold discriminatory power of FH to promote selectivity for self over foreign and show that FHL-1 is more active than known but specialized for regulation on local tissues.

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Section: Fhl-1 Resists Deregulation By Fhr-1 and Occurs Late In Evolumentioning

confidence: 99%

Self versus Nonself Discrimination by the Soluble Complement Regulators Factor H and FHL-1

Dopler

Guntau

Harder

et al. 2019

The Journal of Immunology

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“…The functional consequence of the third mutation, c.50T > G is yet to be determined. Finally, the last of the newly described CFH mutations c2933G > T was associated with both CFH and C3 decreased levels in the studied IgAN individual and this subject' relatives [117]. Although the CFH levels in IgAN patients are in most cases normal, its activity seems to be decreased due to the competition with various CFHRs.…”

Section: Iganmentioning

confidence: 68%

“…Tortajada et al independently confirmed the role of the competition between CFH and CFHR1 in the pathogenesis of IgAN [117]. In a group of 112 IgAN patients and 46 patients with a disease unrelated to complement activation (autosomal dominant polycystic kidney disease, ADPKD), the CFHR1 levels and the CFHR1/CFH ratios were elevated in comparison with the 76 controls.…”

Section: Iganmentioning

confidence: 91%

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The role of the alternative pathway of complement activation in glomerular diseases

2018

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The complement system (CS) has recently been recognized as a bridge between innate and adaptive immunity that constitutes a very complex mechanism controlling the clearance of pathogens, cellular debris, and immune complexes. Out of three known pathways of complement activation, the alternative pathway (AP) plays a critical role in host defense by amplifying the complement response, independently of initiation pathway and continuously maintaining low-level activity in a process called 'thick-over.' A key molecule of the CS is C3, in which the AP is constantly activated. To prevent host cell destruction, a group of the AP regulators tightly controls this pathway of the CS activation. Acquired and genetic abnormalities of the CS may alter the delicate balance between enhancing and inhibiting the AP cascade. These can lead to the uncontrolled CS activation, inflammatory response, and subsequent tissue damage. Since complement components are locally produced and activated in the kidney, the abnormalities targeting the AP may cause glomerular injury. C3 glomerulopathy is a new entity, in which the AP dysregulation has been well established. However, recent studies indicate that the AP may also contribute to a wide range of kidney pathologies, including immune-complex-mediated glomerulonephritis (GN), pauci-immune GN, and primary membranous nephropathy (PMN). This article provides insight into current knowledge on the role of the AP in the pathogenesis of glomerular diseases, focusing mainly on various types of primary and secondary GN and PMN.

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“…Moreover, Tortajada et al[14] found 5 IgAN patients with low factor H carrying CFH or CFI pathogenic variants, which suggested a decreased factor H activity in IgAN caused by increased factor H-related protein 1/factor H competition or pathogenic CFH variants. These findings suggest that there are genetic susceptibility factors for IgAN that involve complement.…”

Section: Discussionmentioning

confidence: 99%

Atypical Hemolytic Uremic Syndrome Associated with Complement Factor H Mutation and IgA Nephropathy: A Case Report Successfully Treated with Eculizumab

Nakamura

Anayama

Makino

et al. 2017

Nephron

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We present a rare case of IgA nephropathy in a patient who developed atypical hemolytic uremic syndrome (aHUS) associated with a complement factor H (CFH) gene mutation, and who was successfully treated with eculizmab. A 76-year-old man was admitted as the patients had thrombotic microangiopathies findings. The patient was treated with plasma exchange, hemodialysis and methylprednisolone. A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 level was not decreased. Light microscopy findings were consistent with hemolytic uremic syndrome and immunofluorescence analysis revealed IgA and C3 were detected. Genetic analysis revealed that mutation of p.Arg1215Gln in CFH was identified. The diagnosis of aHUS was confirmed and eculizmab therapy was currently effective for 5 months.

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

Cited by 86 publications

References 32 publications

Self versus Nonself Discrimination by the Soluble Complement Regulators Factor H and FHL-1

Self versus Nonself Discrimination by the Soluble Complement Regulators Factor H and FHL-1

The role of the alternative pathway of complement activation in glomerular diseases

Atypical Hemolytic Uremic Syndrome Associated with Complement Factor H Mutation and IgA Nephropathy: A Case Report Successfully Treated with Eculizumab

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