Complement Regulator FHR-3 Is Elevated either Locally or Systemically in a Selection of Autoimmune Diseases

Schäfer, Nicole; Grosche, Antje; Reinders, Jörg; Hauck, Stefanie M.; Pouw, Richard B.; Kuijpers, Taco W.; Wouters, Diana; Ehrenstein, Boris; Enzmann, Volker; Zipfel, Peter F.; Skerka, Christine; Pauly, Diana

doi:10.3389/fimmu.2016.00542

Cited by 26 publications

(55 citation statements)

References 74 publications

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“…These results suggest that increased FHR-3 levels predispose to aHUS. This observation is in line with a previous study ( 21 ) that determined FHR-3 levels in 21 patients with aHUS (1.60 ± 0.57 µg/mL) and 21 controls (1.06 ± 0.53 µg/mL), although the difference in FHR-3 levels between their patient and control cohorts was smaller than in our study, which could well be related to the cohort size and the variation in allele frequency. In our study, 4% of the controls and 9% of the patients with aHUS carried the CFHR3*Del/Del genotype (i.e., homozygous CFHR3-CFHR1 deletion), frequencies comparable to the 2.9% and 12.4% observed in a French study comparing 70 controls and 117 patients with aHUS ( 22 ).…”

Section: Discussionsupporting

confidence: 93%

High Complement Factor H-Related (FHR)-3 Levels Are Associated With the Atypical Hemolytic-Uremic Syndrome-Risk Allele CFHR3*B

et al. 2018

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Dysregulation of the complement alternative pathway (AP) is a major pathogenic mechanism in atypical hemolytic-uremic syndrome (aHUS). Genetic or acquired defects in factor H (FH), the main AP regulator, are major aHUS drivers that associate with a poor prognosis. FH activity has been suggested to be downregulated by homologous FH-related (FHR) proteins, including FHR-3 and FHR-1. Hence, their relative levels in plasma could be disease-relevant. The genes coding for FH, FHR-3, and FHR-1 (CFH, CFHR3, and CFHR1, respectively) are polymorphic and located adjacent to each other on human chromosome 1q31.3. We have previously shown that haplotype CFH(H3)–CFHR3*B–CFHR1*B associates with aHUS and reduced FH levels. In this study, we used a specific enzyme-linked immunosorbent assay to quantify FHR-3 in plasma samples from controls and patients with aHUS genotyped for the three known CFHR3 alleles (CFHR3*A, CFHR3*B, and CFHR3*Del). In the 218 patients carrying at least one copy of CFHR3, significant differences between CFHR3 genotype groups were found, with CFHR3*A/Del patients having the lowest FHR-3 concentration (0.684–1.032 µg/mL), CFHR3*B/Del and CFHR3*A/A patients presenting intermediate levels (1.437–2.201 µg/mL), and CFHR3*A/B and CFHR3*B/B patients showing the highest concentration (2.330–4.056 µg/mL) (p < 0.001). These data indicate that CFHR3*A is a low-expression allele, whereas CFHR3*B, associated with increased risk of aHUS, is a high-expression allele. Our study reveals that the aHUS-risk haplotype CFH(H3)–CFHR3*B–CFHR1*B generates twofold more FHR-3 than the non-risk CFH(H1)–CFHR3*A–CFHR1*A haplotype. In addition, FHR-3 levels were higher in patients with aHUS than in control individuals with the same CFHR3 genotype. These data suggest that increased plasma levels of FHR-3, altering the balance between FH and FHR-3, likely impact the FH regulatory functions and contribute to the development of aHUS.

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Section: Discussionsupporting

confidence: 93%

High Complement Factor H-Related (FHR)-3 Levels Are Associated With the Atypical Hemolytic-Uremic Syndrome-Risk Allele CFHR3*B

et al. 2018

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“…Hence, it is more likely that there is a difference in the Sf9-derived rhFHR-4A previously used ( 14 ) and the HEK293F-derived rhFHR-4A used here for the calibration of the assays. Considering the recently reported normal values for all other FHR proteins ( 6 , 18 , 21 , 22 ), ranging from 0.7 to 12 µg/mL (with FHR-1 being the most abundant FHR protein), it seems the values that we report for FHR-4A are likely to be correct.…”

Section: Discussionsupporting

confidence: 65%

“…Several reports have shown that recombinant FHR-4A and -4B indeed bind to known FH ligands and allow complement activation to occur in vitro ( 11 , 14 , 15 ). To date, normal levels of FHR-1, FHR-2, FHR-3, and FHR-5 have been reported and were found to be circulating at much lower concentration as compared to FH ( 6 , 18 , 21 , 22 ). In this report, we describe the circulating levels of FHR-4A in healthy individuals, using novel, well-characterized anti-FHR-4A mAbs.…”

Section: Discussionmentioning

confidence: 99%

“…However, a third, independent, group recently reported combined, total FHR-1, FHR-2, and FHR-5 levels, measured in an immunoassay, to be 10.7 (±5.4) μg/mL, thus supporting the lower levels for FHR-1 and FHR-2 ( 20 ). FHR-3 circulates at average concentrations of 0.7–1.1 µg/mL ( 6 , 21 ). For FHR-4A and FHR-4B, only total FHR-4 levels ranging from 6.5 to 53.9 µg/mL with an average concentration of 25.4 µg/mL have been described, measured in only 11 healthy individuals ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

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Complement Factor H-Related Protein 4A Is the Dominant Circulating Splice Variant of CFHR4

et al. 2018

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Recent research has elucidated circulating levels of almost all factor H-related (FHR) proteins. Some of these proteins are hypothesized to act as antagonists of the important complement regulator factor H (FH), fine-tuning complement regulation on human surfaces. For the CFHR4 splice variants FHR-4A and FHR-4B, the individual circulating levels are unknown, with only total levels being described. Specific reagents for FHR-4A or FHR-4B are lacking due to the fact that the unique domains in FHR-4A show high sequence similarity with FHR-4B, making it challenging to distinguish them. We developed an assay that specifically measures FHR-4A using novel, well-characterized monoclonal antibodies (mAbs) that target unique domains in FHR-4A only. Using various FHR-4A/FHR-4B-specific mAbs, no FHR-4B was identified in any of the serum samples tested. The results demonstrate that FHR-4A is the dominant splice variant of CFHR4 in the circulation, while casting doubt on the presence of FHR-4B. FHR-4A levels (avg. 2.55 ± 1.46 µg/mL) were within the range of most of the previously reported levels for all other FHRs. FHR-4A was found to be highly variable among the population, suggesting a strong genetic regulation. These results shed light on the physiological relevance of the previously proposed role of FHR-4A and FHR-4B as antagonists of FH in the circulation.

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“…On the other hand, little information on the extrahepatic expression of the FHR proteins is available. Both CFHR3 mRNA and FHR-3 protein have been identified in retinal macrophages, while no FHR-3 expression was found in other retinal cell types ( 47 ). Extrahepatic synthesis of FH/FHRs most likely contributes to an efficient control of complement activation locally, but a relevant contribution to the plasma levels of these proteins is unlikely, considering the relative low expression compared to the hepatic source.…”

Section: Quantitation Of Fhr Proteinsmentioning

confidence: 99%

Self-Damage Caused by Dysregulation of the Complement Alternative Pathway: Relevance of the Factor H Protein Family

et al. 2018

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The alternative pathway is a continuously active surveillance arm of the complement system, and it can also enhance complement activation initiated by the classical and the lectin pathways. Various membrane-bound and plasma regulatory proteins control the activation of the potentially deleterious complement system. Among the regulators, the plasma glycoprotein factor H (FH) is the main inhibitor of the alternative pathway and its powerful amplification loop. FH belongs to a protein family that also includes FH-like protein 1 and five factor H-related (FHR-1 to FHR-5) proteins. Genetic variants and abnormal rearrangements involving the FH protein family have been linked to numerous systemic and organ-specific diseases, including age-related macular degeneration, and the renal pathologies atypical hemolytic uremic syndrome, C3 glomerulopathies, and IgA nephropathy. This review covers the known and recently emerged ligands and interactions of the human FH family proteins associated with disease and discuss the very recent experimental data that suggest FH-antagonistic and complement-activating functions for the FHR proteins.

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Complement Regulator FHR-3 Is Elevated either Locally or Systemically in a Selection of Autoimmune Diseases

Cited by 26 publications

References 74 publications

High Complement Factor H-Related (FHR)-3 Levels Are Associated With the Atypical Hemolytic-Uremic Syndrome-Risk Allele CFHR3*B

High Complement Factor H-Related (FHR)-3 Levels Are Associated With the Atypical Hemolytic-Uremic Syndrome-Risk Allele CFHR3*B

Complement Factor H-Related Protein 4A Is the Dominant Circulating Splice Variant of CFHR4

Self-Damage Caused by Dysregulation of the Complement Alternative Pathway: Relevance of the Factor H Protein Family

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