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Atypical hemolytic uremic syndrome commonly presents as rapidly progressive renal failure and is histologically characterized by thrombotic microangiopathy (TMA). TMA presenting with acute renal failure requires aggressive medical management. Here, we present a case of a 30-year-old man who presented with a history of accelerated hypertension and a strong family history of end-stage renal disease, in September 2023. Upon evaluation, he was found to have a creatinine level of 2 mg/dl, bland urine and normal-sized kidneys; a renal biopsy revealed chronic interstitial nephritis. Genetic analysis for autosomal dominant tubulointerstitial kidney disease and nephronophthisis yielded negative results. The patient was managed with antihypertensive medications. In January 2024, he was admitted with a history of confusion, headache, and alcohol binge. He had a blood pressure of 200/100 mmHg and had grade 3 hypertensive retinopathy. Laboratory tests revealed anemia with thrombocytopenia, bland urine, normal coagulation parameters, indirect hyperbilirubinemia, normal-sized kidneys on ultrasound, and elevated lactate dehydrogenase levels. MRI of the brain revealed symmetrical hyperintensities in bilateral cerebellum and the dorsal brainstem. Complement levels revealed low C3 levels and genetic analysis revealed a homozygous deletion in the complement factor H-related 3 (CFHR3) gene. The autoantibody for complement factor H was negative. The patient was managed conservatively with adequate blood pressure control. This case highlights the effects of complement dysregulation on the renal tubulointerstitium.

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Mutations in the complement factor H (CFH) gene are associated with complement dysregulation and the development of atypical hemolytic uremic syndrome (aHUS). Several fusion genes that result from genomic structural variation in the CFH and complement factor H-related (CFHR) gene regions have been identified in aHUS. However, one allele has both CFHR gene duplication and CFH::CFHR1 fusion gene have not been reported. An 8-month-old girl (proband) presented with aHUS and was treated with ravulizumab. Her paternal grandfather developed aHUS previously and her paternal great grandmother presented with anti-neutrophil cytoplasmic antibody-associated vasculitis and thrombotic microangiopathy (TMA). However, the proband's parents have no history of TMA. A genetic analysis revealed the presence of CFH::CFHR1 fusion gene and a CFHR3-1-4-2 gene duplication in the patient, her father, and her paternal grandfather. Although several fusion genes resulting from structural variations of the CFH-CFHR genes region have been identified, this is the first report of the combination of a CFH::CFHR1 fusion gene with CFHR gene duplication. Because the CFH-CFHR region is highly homologous, we hypothesized that CFHR gene duplication occurred. These findings indicate a novel pathogenic genomic structural variation associated with the development of aHUS.

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We describe a case of full-house nephropathy without any underlying disease, including systemic lupus erythematosus. A 40-year-old woman was referred to our hospital with mild proteinuria and microscopic hematuria. The patient was diagnosed with immune complex-mediated glomerulonephritis with a predominant mesangioproliferative pattern based on renal histopathological results using full-house immunofluorescence staining. She showed no clinical criteria for the diagnosis of systemic lupus erythematosus, except for kidney disorders, and tested negative for antinuclear antibodies throughout her clinical course. However, in the second kidney biopsy, no C1q or C4 were detected in the immunofluorescence study, suggesting an immunoglobulin A nephropathy-like pattern. The patient responded favorably to corticosteroid treatment. We found a heterozygous CFHR3-CFHR1 deletion. The association between full-house nephropathy and CFHR3-CFHR1 deletion is unknown, but its influence on the histological pattern in our case is suspected. This indicates the diversity in the pathogenesis of non-lupus full-house nephropathy and warrants further investigation.

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Aboriginal and Torres Strait Islander People (respectfully referred to as Indigenous Australians herein) are disparately burdened by many infectious and chronic diseases relative to Australians with European genetic ancestry. Some of these diseases are described in other populations to be influenced by the inherited profile of complement genes. These include complement factor B, H, I and complement factor H-related (CFHR) genes that can contribute to a polygenic complotype. Here the focus is on the combined deletion of CFHR1 and 3 to form a common haplotype (CFHR3-1Δ). The prevalence of CFHR3-1Δ is high in people with Nigerian and African American genetic ancestry and correlates to a higher frequency and severity of systemic lupus erythematosus (SLE) but a lower prevalence of age-related macular degeneration (AMD) and IgA-nephropathy (IgAN). This pattern of disease is similarly observed among Indigenous Australian communities. Additionally, the CFHR3-1Δ complotype is also associated with increased susceptibility to infection with pathogens, such as Neisseria meningitidis and Streptococcus pyogenes, which also have high incidences in Indigenous Australian communities. The prevalence of these diseases, while likely influenced by social, political, environmental and biological factors, including variants in other components of the complement system, may also be suggestive of the CFHR3-1Δ haplotype in Indigenous Australians. These data highlight a need to define the Indigenous Australian complotypes, which may lead to the discovery of new risk factors for common diseases and progress towards precision medicines for treating complement-associated diseases in Indigenous and non-Indigenous populations. Herein, the disease profiles suggestive of a common complement CFHR3-1Δ control haplotype are examined.

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Neisseria meningitidis protects itself from complement-mediated killing by binding complement factor H (FH). Previous studies associated susceptibility to meningococcal disease (MD) with variation in CFH, but the causal variants and underlying mechanism remained unknown. Here we attempted to define the association more accurately by sequencing the CFH-CFHR locus and imputing missing genotypes in previously obtained GWAS datasets of MD-affected individuals of European ancestry and matched controls. We identified a CFHR3 SNP that provides protection from MD (rs75703017, p value = 1.1 × 10-16) by decreasing the concentration of FH in the blood (p value = 1.4 × 10-11). We subsequently used dual-luciferase studies and CRISPR gene editing to establish that deletion of rs75703017 increased FH expression in hepatocyte by preventing promotor inhibition. Our data suggest that reduced concentrations of FH in the blood confer protection from MD; with reduced access to FH, N. meningitidis is less able to shield itself from complement-mediated killing.

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Accumulating evidence has indicated that Complement factor H-related 3 (CFHR3) plays an essential role in various diseases. However, the biological functions of CFHR3 in hepatocellular carcinoma (HCC) remain largely unclear. Therefore, we perform a further study on CFHR3 in HCC. In this article, we report the suppressive role of CFHR3 in the proliferation and metastasis of HCC cells. CFHR3 downregulation is closely associated with large (T3-T4) HCC, tumor recurrence, and advanced (stage III-IV) clinical stage, functioning as an independent factor for the prognoses of HCC patients. Knockdown of CFHR3 promotes proliferation, migration, and invasion of HCC cells. Mechanistically, downregulation of CFHR3 is induced by miR-590-3p binding to the 3' untranslated region (UTR) of CFHR3. CFHR3 downregulation promotes the phosphorylation of STAT3 protein, thereby suppressing p53 expression. The promotional effect upon downregulation of CFHR3 induced by CFHR3 stable knockdown or miR-590-3p on HCC cell malignant phenotypes is attenuated by STAT3 inhibitor, S3I-201. In conclusion, our results reveal that CFHR3 is a protective biomarker for HCC patients, and targeting the miR-590-3p/CFHR3/p-STAT3/p53 signaling axis provides a promising strategy for HCC therapeutics.

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Hypoxia environment exists in already started hepatocellular carcinoma (HCC) and promotes its progression by driving changes in the gene expression profiles of cells. However, the status of hypoxia-driven genes in HCC is largely unknown. In the present study, 368 HCC tissues from The Cancer Genome Atlas were divided into high and low hypoxia groups according to their hypoxia signatures. A total of 1,142 differentially expressed genes (DEGs) were identified between the two groups, and 34 of these DEGs were highly expressed in HCC tissues compared with adjacent tissues, especially in HCC tissues from patients with stage III-IV HCC. After constructing a protein-protein interaction network and applying the least absolute shrinkage and selection operator Cox regression method for 34 DEGs, a three-gene signature (complement factor H related 3 [CFHR3], egl-9 family hypoxia inducible factor 3 [EGLN3], and chromogranin A [CHGA]) was constructed and had prognostic value to predicted outcome of patients with HCC. This three-gene signature was suitable for classifying patients with HCC in the International Cancer Genome Consortium. CFHR3 shows remarkable diagnostic value in HCC. Hypoxia decreased CFHR3 expression, but increased HCC cell proliferation and motility. Overexpression of CFHR3 in HCC cells under hypoxia reversed the stimulatory effects of hypoxia and suppressed cell proliferation and metastasis in vivo. In conclusion, we identified a novel hypoxia-driven gene signature (CFHR3, EGLN3, and CHGA) for reliable prognostic prediction of HCC, and demonstrated that overexpression of CFHR3 may be a potential strategy to overcome hypoxia and treat HCC.

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OBJECTIVES: Atypical hemolytic uremic syndrome (aHUS) is characterized by a triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure resulting from platelet thrombi in the microcirculation of the kidney and other organs, in the absence of a preceding diarrheal illness. This report describes a case in which copy number variation (CNV) analysis using next-generation sequencing (NGS) identified the CFHR3/CFHR1 deletion in a patient with aHUS. METHODS: A 49-year-old Korean female was diagnosed with aHUS based on clinical findings, including schistocytes in peripheral blood and marked thrombocytopenia, suggesting the presence of thrombotic microangiopathy, elevated serum lactate dehydrogenase, and acute kidney injury. Sequence variants and CNV generated from NGS data were estimated to determine if there was a potential genetic cause. Multiplex ligation-dependent probe amplification (MLPA) was conducted to confirm the CFHR3/CFHR1 deletion identified by NGS with CNV analysis. RESULTS: No known or novel pathogenic single nucleotide variant or small insertion/deletion that would be predicted to have damaging effects that could lead to aHUS were identified. However, CNV analysis of NGS data identified the heterozygous CFHR3/CFHR1 deletion. MLPA confirmed this loss of one copy number between the CFHR3 and the CFHR1 genes on chromosome 1q31.3. CONCLUSION: We genetically diagnosed a Korean woman harboring a heterozygous CFHR3/CFHR1 deletion of a known causative gene for aHUS. Our report emphasizes the need for CNV analysis of NGS data and gene dosage assays, such as MLPA, to evaluate large-scale deletions or duplications and generate hybrid CFH genes in patients with suspected aHUS.

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The wide-spread use of the anti-complement component 5 monoclonal antibody (moAb) eculizumab has greatly reduced the incidence of relapsing atypical hemolytic uremic syndrome (aHUS) after kidney transplantation (KT). However, the optimal management of aHUS transplant candidates with anti-Complement Factor H (CFH) antibodies remains debated. In these patients, the benefits of chronic eculizumab administration should be weighed against the risk of fatal infections, repeated hospital admissions, and excessive costs. We report the case of a 45-year-old female patient with CFHR1/CFHR3 homozygous deletion-associated aHUS who underwent deceased-donor KT despite persistently elevated anti-CFH antibody titers. As induction and aHUS prophylaxis, she received a combination of eculizumab and obinutuzumab, a humanized type 2 anti-CD20 moAb. The post-operative course was uneventful. After 1-year of follow-up, she is doing well with excellent allograft function, undetectable anti-CFH antibodies, sustained B-cell depletion, and no signs of aHUS activity. A brief review summarizing current literature on the topic is also included. Although anecdotal, our experience suggests that peri-operative obinutuzumab administration can block anti-CFH antibodies production safely and effectively, thus ensuring long-lasting protection from post-transplant aHUS relapse, at a reasonable cost. For the first time, we have demonstrated in vivo that obinutuzumab B-cell depleting properties are not significantly affected by eculizumab-induced complement inhibition.

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Wheat intolerance has various systemic manifestations that can affect people's quality of life, and few studies have focused on the mechanism of wheat intolerance and the signaling pathways involved in wheat intolerance have not been fully identified. We compared the protein profiles of patients with wheat intolerance with those of healthy controls using LASSO (least absolute shrinkage and selection operator) and PLS (partial least squares regression) to obtain DEPs (differentially expressed proteins) for GO (Gene Ontology) analysis, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis, and PPI (protein-protein interaction) network analysis. Internal validation and external validation were conducted for target proteomics testing. The correlation between differently expressed protein and the wheat-specific IgG antibody concentration was analyzed. Then ROC curve (receiver operating characteristic curve) was generated to validate the differentially expressed proteins. We identified 33 DEPs as significant candidate proteins of wheat intolerance. These proteins were mainly enriched in complement and coagulation cascade pathways, immune activation, and immune response-related pathways. After internal and external target proteomics validation, CFHR3 (complement factor H-related protein 3) was identified as a key protein that may have an important role in wheat intolerance. We found CFHR3 protein expression abundance and the wheat-specific IgG antibody concentration were significantly negatively correlated (P = 0.035; Spearman correlation coefficient r = -0.565). The AUC (median area under the ROC curve) of CFHR3 is 0.857 in external verification data. This study provides insights into wheat intolerance that can be used to further explore the pathogenesis of this condition. SIGNIFICANCE: Proteomics has performed important potential in food allergy research and is conducive to improving our comprehension on molecular mechanisms of food allergy. The present study identified significant signaling pathways and differentially expressed proteins in patients with wheat intolerance by means of bioinformatics from the viewpoint of mass spectrometry-based proteomics, which provided insights into further research on the pathogenesis and timely diagnosis of wheat intolerance.

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We report a case of atypical hemolytic uremic syndrome (HUS) that occurred after childbirth. A 33-year-old female was admitted to the emergency room, complaining of abdominal pain six days after giving birth to twins. The patient was diagnosed with hemoperitoneum due to hepatic hemangioma rupture and a left lateral hepatectomy was performed. Angioembolization was performed for the accompanying uterine artery bleeding. After that, her kidney function worsened after the 12th day postpartum. Microangiopathic anemia, thrombocytopenia and renal dysfunction were observed. Shiga toxin-producing Escherichia coli was negative in the stool. Plasma ADMATS 13 activity was normal. After transfer to the nephrology department with suspected atypical HUS, the patient underwent fresh frozen plasma (FFP) transfusion with three hemodialysis sessions. The patient improved without additional dialysis, but a renal biopsy was performed because of persistent proteinuria. Renal pathologic findings were compatible with thrombotic microangiopathy. A genetic test for atypical HUS revealed variants of uncertain significance in the complement factor H related (CFHR) 4 gene and the presence of CFHR3-CFHR1 copy number gain. The CFHR3-CFHR1 copy number gain found in this case is a rare causative mutation of atypical HUS. This case suggests that genetic testing of atypical HUS should include analysis of CFH-CFHR rearrangements as well as general screening for complement-associated genes.

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BACKGROUND: This study aimed to explore the associations between the complement factor H (CFH) rs6677604 and clinico-pathological characteristics of lupus nephritis. MATERIALS AND METHODS: A total of 188 patients with lupus nephritis with complete clinico-pathological data were enrolled and genotyping of CFH rs6677604 was conducted by TaqMan SNP genotyping assays. Patients were divided into two groups by rs6677604-AA/AG or -GG, and the clinico-pathological features between the two groups were further compared. RESULTS: We found that patients with rs6677604-AA/AG presented with lower prevalence of anti-dsDNA antibody (12/24 [50.0%] vs 121/164 [73.8%], P = 0.028), higher level of plasma C3a (2642.96 ± 1575.05 vs 1640.01 ± 1209.40, ng/ml, P = 0.024), and a tendency for higher level of plasma CFH (505.76 ± 169.28 vs 397.67 ± 179.11, µg/ml, P = 0.087). Patients with rs6677604-AA/AG had milder renal histopathological features, including total activity indices score (4.5[0, 13] vs 8[0, 19], P = 0.013), endocapillary hypercellularity (1.5[0, 3] vs 3[0, 3], P = 0.013), sub-endothelial hyaline deposits (0.5[0, 3] vs 1[0,3], P = 0.021), glomerular leukocyte infiltration (0.5[0, 1] vs 1[0, 12], P = 0.023) and tubular atrophy (1[0, 1] vs 1[0, 3], P = 0.027) than those with rs6677604-GG, which was further confirmed by the stratified analysis. The rs6677604-A was not a risk factor for patients' renal outcomes (hazard ratio=0.898; 95% CI: 0.264-3.059, P = 0.863). CONCLUSIONS: The rs6677604-A genotype in CFH was associated with milder renal pathological features in lupus nephritis, and its protective effect on the pathogenesis of the disease remained to be elucidated.

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Complement factor H-related 3 (CFHR3) is a protein-coding gene acting in various diseases. However, its prognostic values of CFHR3 in hepatocellular carcinoma (HCC) are not understandable. Therefore, we present a further study on CFHR3 in HCC. CFHR3 expression data were acquired from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). We compared the differential expression of CFHR3 between the low-stage (stage I and II) and high-stage (stage III and IV) patients with HCC in the TCGA and ICGC cohorts. Furthermore, we assessed the CFHR3 expression as a prognostic marker using the Kaplan-Meier survival analysis, univariate, and multivariate analysis. The Kaplan-Meier analysis declared that CFHR3 overexpression was correlated with a good prognosis for HCC patients. Multivariate analysis proved the prognostic significance of CFHR3 expression levels (P < .001 and .003 for TCGA and ICGC, respectively). Immune-related scores in low-risk cohorts were higher than high-risk cohorts. Gene set enrichment analysis implied that the low CFHR3 expression phenotype was significantly enriched in critical biological functions and pathways and was associated with tumorigenesis, such as regulation of cell activation cycle, and the WNT and NOTCH signal pathway. Above all, CFHR3 could be a novel prognostic biomarker and therapeutic target for HCC.

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[This corrects the article DOI: 10.3389/fimmu.2018.00848.].

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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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The human complement factor H-related protein-3 (FHR-3) is a soluble regulator of the complement system. Homozygous cfhr3/1 deletion is a genetic risk factor for the autoimmune form of atypical hemolytic-uremic syndrome (aHUS), while also found to be protective in age-related macular degeneration (AMD). The precise function of FHR-3 remains to be fully characterized. We generated four mouse monoclonal antibodies (mAbs) for FHR-3 (RETC) without cross-reactivity to the complement factor H (FH)-family. These antibodies detected FHR-3 from human serum with a mean concentration of 1 µg/mL. FHR-3 levels in patients were significantly increased in sera from systemic lupus erythematosus, rheumatoid arthritis, and polymyalgia rheumatica but remained almost unchanged in samples from AMD or aHUS patients. Moreover, by immunostaining of an aged human donor retina, we discovered a local FHR-3 production by microglia/macrophages. The mAb RETC-2 modulated FHR-3 binding to C3b but not the binding of FHR-3 to heparin. Interestingly, FHR-3 competed with FH for binding C3b and the mAb RETC-2 reduced the interaction of FHR-3 and C3b, resulting in increased FH binding. Our results unveil a previously unknown systemic involvement of FHR-3 in rheumatoid diseases and a putative local role of FHR-3 mediated by microglia/macrophages in the damaged retina. We conclude that the local FHR-3/FH equilibrium in AMD is a potential therapeutic target, which can be modulated by our specific mAb RETC-2.

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UNLABELLED: aHUS is a clinical challenge for successful renal transplantation. CASE REPORT: A 14-yr-old girl lost her kidneys at the age of 7, due to CFH antibodies and CFH-related protein (CFHR1/CFHR3) homozygous deletion-associated aHUS. CFH, CFI, and MCP gene mutations were excluded. The patient was a candidate for renal transplantation despite persistent presence of CFH antibodies (up to 539 AU/mL). Treatment with MMF, IVIG, and repeated PF (n = 8) was introduced while being placed on urgent waiting list. Three years after aHUS onset, the patient underwent the deceased donor renal transplantation "under cover" of PF, as PF was performed directly prior to surgery and, then, PFs were repeated up to overall 14 sessions. Quadruple immunosuppression (basiliximab + tacrolimus + MMF + prednisolone) was used. Moderate symptoms of aHUS (hemolysis, low platelets, and low C3) were present within first seven days post-transplant and then normalized with PF therapy. The patient remained stable during four yr of further follow-up after transplantation. CONCLUSION: Specific pre- and post-transplant management allowed successful renal transplantation in a CFH antibody-positive patient.

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