Low-molecular weight inhibitors of the alternative complement pathway.

Dysregulation of the alternative complement pathway predisposes individuals to a number of diseases. It can either be evoked by genetic alterations in or by stabilizing antibodies to important pathway components and typically leads to severe diseases such as paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, C3 glomerulopathy, and age-related macular degeneration. In addition, the alternative pathway may also be involved in many other diseases where its amplifying function for all complement pathways might play a role. To identify specific alternative pathway inhibitors that qualify as therapeutics for these diseases, drug discovery efforts have focused on the two central proteases of the pathway, factor B and factor D. Although drug discovery has been challenging for a number of reasons, potent and selective low-molecular weight (LMW) oral inhibitors have now been discovered for both proteases and several molecules are in clinical development for multiple complement-mediated diseases. While the clinical development of these inhibitors initially focuses on diseases with systemic and/or peripheral tissue complement activation, the availability of LMW inhibitors may also open up the prospect of inhibiting complement in the central nervous system where its activation may also play an important role in several neurodegenerative diseases.

Inhibition of the Alternative Complement Pathway May Cause Secretion of Factor B, Enabling an Early Detection of Pancreatic Cancer.

This study aims to elucidate the cellular mechanisms behind the secretion of complement factor B (CFB), known for its dual roles as an early biomarker for pancreatic ductal adenocarcinoma (PDAC) and as the initial substrate for the alternative complement pathway (ACP). Using parallel reaction monitoring analysis, we confirmed a consistent ∼2-fold increase in CFB expression in PDAC patients compared with that in both healthy donors (HD) and chronic pancreatitis (CP) patients. Elevated ACP activity was observed in CP and other benign conditions compared with that in HD and PDAC patients, suggesting a functional link between ACP and PDAC. Protein-protein interaction analyses involving key complement proteins and their regulatory factors were conducted using blood samples from PDAC patients and cultured cell lines. Our findings revealed a complex control system governing the ACP and its regulatory factors, including Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, adrenomedullin (AM), and complement factor H (CFH). Particularly, AM emerged as a crucial player in CFB secretion, activating CFH and promoting its predominant binding to C3b over CFB. Mechanistically, our data suggest that the KRAS mutation stimulates AM expression, enhancing CFH activity in the fluid phase through binding. This heightened AM-CFH interaction conferred greater affinity for C3b over CFB, potentially suppressing the ACP cascade. This sequence of events likely culminated in the preferential release of ductal CFB into plasma during the early stages of PDAC. (Data set ID PXD047043.).

Complement Factor B (CFB) inhibits the malignant progression of lung adenocarcinoma by downregulating the Ras/MAPK signaling pathway.

Lung adenocarcinoma (LUAC) as the most common lung cancer, and its incidence is increasing. Complement factor B (CFB) is an important factor in the alternative complement pathway. CFB has been reported to be involved in the progression of many cancers, including in pancreatic cancer, cutaneous squamous cell carcinoma, and nasopharyngeal carcinoma, but the function and molecular mechanism of CFB in LUAC remains unclear. The present study aimed to explore the role of CFB in LUAC malignant progression. In our previous study, we found that CFB was downregulated expression in LUAC clinical samples. Here, we firstly detected the cell function in vitro. Cell proliferation and migration were increased, while cell apoptosis and cell cycle arrest were suppressed after CFB knockdown. Overexpression of CFB repressed the malignant progression of LUAC in vitro. Besides, in vivo experiments revealed that upregulation of CFB inhibited tumor growth and Ki67 expression. Additionally, our data indicated that CFB negatively regulated Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Furthermore, upregulation of CFB inhibited the progression of LUAC was reversed by Ras/MAPK pathway activators (ML-098 or C16-PAF). Our study uncovered that CFB acts as a tumor suppressor repressed tumorigenesis of LUAC through inhibiting the Ras/MAPK pathway, suggesting that CFB may be a potential biomarker and therapeutic target for LUAC.

Association between Loss of Immune Checkpoint Programmed Cell Death Protein 1 and Active ANCA-Associated Renal Vasculitis.

Immune checkpoint inhibitors (ICIs) have made an important contribution to the survival of patients with certain cancers. ICIs interrupt co-inhibitory signaling pathways mediated by programmed cell death protein 1 (PD-1), programmed cell death protein ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen (CTLA-4) that result in the elimination of cancer cells by stimulating the immune system. However, immune-related adverse events have also been described and attributed to an enhanced immune system activation. Recent observations have suggested a dysregulation of immune checkpoints in active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We here analyzed intrarenal PD-1 and PD-L1 by immunostaining in a total of 15 kidney biopsies with ANCA-associated renal vasculitis in correlation with glomerular and tubulointerstitial lesions. For independent validation, publicly available datasets were analyzed for PD-1 expression (encoded by PDCD1). We here observed a predominant tubulointerstitial expression of PD-1 that is decreased in ANCA-associated renal vasculitis. Moreover, loss of tubulointerstitial PD-1 correlated with active ANCA-associated renal vasculitis. Consistent with the observed association with active glomerular and tubulointerstitial lesions, we identified that interstitial PD-1 correlated with tubular and/or glomerular PD-L1 positivity. Finally, PD-1 was associated with decreased local synthesis of complement factor B. Interestingly, we did not observe a correlation between PD-1 and complement C5 or its C5a receptor. Combined with our observations, this may implicate a link between impaired PD-1/PD-L1 signaling, complement factor B and active ANCA-associated renal vasculitis. These findings could be of relevance because experimental data have already described that PD-1 agonism can be used therapeutically to attenuate autoimmunity in multiple disease models. Furthermore, targeted therapy against a complement C5/C5a receptor and factor B are both available and currently evolving in the treatment of AAV. Therefore, this pilot study expands our current knowledge and describes a potential interplay between immune checkpoints and the alternative complement pathway in active ANCA-associated renal vasculitis.

Early Diagnostic Ability of Human Complement Factor B in Pancreatic Cancer Is Partly Linked to Its Potential Tumor-Promoting Role.

Although plasma complement factor B (CFB, NX_P00751), both alone and in combination with CA19-9 (i.e., the ComB-CAN), previously exhibited a reliable diagnostic ability for pancreatic cancer (PC), its detectability of the early stages and the cancer detection mechanism remained elusive. We first evaluated the diagnostic accuracy of ComB-CAN using plasma samples from healthy donors (HDs), patients with chronic pancreatitis (CP), and patients with different PC stages (I/II vs III/IV). An analysis of the area under the curve (AUC) by PanelComposer using logistic regression revealed that ComB-CAN has a superior diagnostic ability for early-stage PC (97.1.% [95% confidence interval (CI): (97.1-97.2)]) compared with CFB (94.3% [95% CI: 94.2-94.4]) or CA19-9 alone (34.3% [95% CI: 34.1-34.4]). In the comparisons of all stages of patients with PC vs CP and HDs, the AUC values of ComB-CAN, CFB, and CA19-9 were 0.983 (95% CI: 0.983-0.983), 0.950 (95% CI: 0.950-0.951), and 0.873 (95% CI: 0.873-0.874), respectively. We then investigated the molecular mechanism underlying the detection of early-stage PC by using stable cell lines of CFB knockdown and CFB overexpression. A global transcriptomic analysis coupled to cell invasion assays of both CFB-modulated cell lines suggested that CFB plays a tumor-promoting role in PC, which likely initiates the PI3K-AKT cancer signaling pathway. Thus our study establishes ComB-CAN as a reliable early diagnostic marker for PC that can be clinically applied for early PC screening in the general public.

IL-1/IL-1R signaling induced by all-trans-retinal contributes to complement alternative pathway activation in retinal pigment epithelium.

The underlying mechanisms of complement activation in Stargardt disease type 1 (STGD1) and age-related macular degeneration (AMD) are not fully understood. Overaccumulation of all-trans-retinal (atRAL) has been proposed as the pathogenic factor in both diseases. By incubating retinal pigment epithelium (RPE) cells with atRAL, we showed that C5b-9 membrane attack complexes (MACs) were generated mainly through complement alternative pathway. An increase in complement factor B (CFB) expression as well as downregulation of complement regulatory proteins CD46, CD55, CD59, and CFH were observed in RPE cells after atRAL treatment. Furthermore, interleukin-1ß production was provoked in both atRAL-treated RPE cells and microglia/macrophages. Coincubation of RPE cells with interleukin-1 receptor antagonist (IL1Ra) and atRAL ameliorated complement activation and downregulated CFB expression by attenuating both p38 and c-Jun N-terminal kinase (JNK) signaling pathways. Our findings demonstrate that atRAL induces an autocrine/paracrine IL-1/IL-1R signaling to promote complement alternative pathway activation in RPE cells and provide a novel perspective on the pathomechanism of macular degeneration.

Changes in complement alternative pathway components, factor B and factor H during dengue virus infection in the AG129 mouse.

The complement alternative pathway (AP) is tightly regulated and changes in two important AP components, factor B (FB) and factor H (FH) are linked to severe dengue in humans. Here, a mouse model of dengue was investigated to define the changes in FB and FH and assess the utility of this model to study the role of the AP in severe dengue. Throughout the period of viremia in the AG129 IFN signalling-deficient mouse, an increase in FB and a decrease in FH was observed following dengue virus (DENV) infection, with the former only seen in a model of more severe disease associated with antibody-dependent enhancement (ADE). Terminal disease was associated with a decrease in FB and FH, with greater changes during ADE, and accompanied by increased C3 degradation consistent with complement activation. In silico analysis of NFκΒ, signal transducer and activator of transcription (STAT) and IFN-driven FB and FH promoter elements to reflect the likely impact of the lack of IFN-responses in AG129 mice, demonstrated that these elements differed markedly between human and mouse, notably with mouse FH lacking NFκΒ and key IFN-stimulated response elements (ISRE), and FB with many more NFκΒ and STAT-responsive elements than human FB. Thus, the AG129 mouse offers utility in demonstrating changes in FB and FH that, similar to humans, are associated with severe disease, but lack predicted important human-specific and IFN-dependent responses of FB and FH to DENV-infection that are likely to regulate the subtleties of the overall AP response during dengue disease in humans.

Complement component factor B has thrombin-like activity.

Serine proteases are fundamental components of biology, including innate immunity, which is systematically orchestrated in an orderly, balanced fashion in the healthy host. Such serine proteases are found in two well-recognized pathways of an innate immune network, coagulation and complement. Both pathways, if uncontrolled due to a variety of causes, are pathogenic in numerous diseases, including coagulation disorders and infectious diseases. Previous studies have reported sequence homologies, functional similarities and interplay between these two pathways with some implications in health and disease. The current study newly reveals that complement component factor B (Bf), the second component of the alternative complement pathway, has thrombin-like activity, which is supported by a characteristic homology of the trypsin-like domain of Bf to that of thrombin. Moreover, we newly report that the trypsin-like domain of Bf is closely related to Limulus clotting factor C, the LPS sensitive clotting factor of the innate immune system. We will also discuss potential implications of our findings in diseases.

Is the atypical hemolytic uremic syndrome risk polymorphism in Membrane Cofactor Protein MCPggaac relevant in kidney transplantation? A case report.

aHUS is a rare disease characterized by episodes of TMA that frequently progresses to CKD and often recurs after KT. The most frequent cause of aHUS is defective regulation of complement activation because of genetic anomalies. Eculizumab interrupts the process of TMA and improves renal function. We describe one female patient with aHUS who debuted in 2005 at 3-mo-old with extrarenal manifestations and progressed to end-stage kidney disease (ESKD) within a year. Her family history included several affected members with similar bad outcomes. Our patient carries a strong aHUS genetic predisposition consisting in a pathogenic gain-of-function mutation in complement factor B concurrent with the MCP aHUS risk haplotype MCPggaac. She received a kidney transplant in 2011 without eculizumab prophylaxis. The graft, which was negative for the MCPggaac risk haplotype, had an unexpected excellent evolution without aHUS recurrence. Different retrospective studies have shown that the risk of aHUS recurrence after KT correlates well with the genetic load of aHUS risk factors. Knowing important contribution of the MCPggaac risk haplotype to the risk of developing aHUS in Factor B mutations carriers, we speculate whether the absence of this polymorphism in the graft that our patient received may have decreased the risk of aHUS recurrence after KT.

Complement Factor B Mediates Ocular Angiogenesis through Regulating the VEGF Signaling Pathway.

Complement factor B (CFB), a 95-kDa protein, is a crucial catalytic element of the alternative pathway (AP) of complement. After binding of CFB to C3b, activation of the AP depends on the proteolytic cleavage of CFB by factor D to generate the C3 convertase (C3bBb). The C3 convertase contains the catalytic subunit of CFB (Bb), the enzymatic site for the cleavage of a new molecule of C3 into C3b. In addition to its role in activating the AP, CFB has been implicated in pathological ocular neovascularization, a common feature of several blinding eye diseases, however, with somewhat conflicting results. The focus of this study was to investigate the direct impact of CFB on ocular neovascularization in a tightly controlled environment. Using mouse models of laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR), our study demonstrated an increase in CFB expression during pathological angiogenesis. Results from several in vitro and ex vivo functionality assays indicated a promoting effect of CFB in angiogenesis. Mechanistically, CFB exerts this pro-angiogenic effect by mediating the vascular endothelial growth factor (VEGF) signaling pathway. In summary, we demonstrate compelling evidence for the role of CFB in driving ocular angiogenesis in a VEGF-dependent manner. This work provides a framework for a more in-depth exploration of CFB-mediated effects in ocular angiogenesis in the future.

Role of complement factor B rs4151667 (L9H) polymorphisms and its interactional role with CFH Y402H and C3 rs2230199 (R102G) risk variants in age-related macular degeneration: a case control study.

BACKGROUND: Age-related Macular Degeneration (AMD) is a complex eye disease, which is genetically associated with different susceptibility loci. We planned to investigate the possible association of Complement Factor B (CFB) rs4151667 (L9H) variants and their possible interaction with Complement Factor H (CFH) Y402H and Complement factor 3 (C3) rs2230199 (R102G) in AMD. METHODS: This case-control association study included 216 advanced type AMD patients and 191 healthy individuals for evaluation. Extracted-DNA samples were genotyped for the polymorphic regions of CFB rs4151667 (L9H), CFH Y402H and C3 rs2230199 (R102G). RESULTS: The distribution of CFB rs4151667 (L9H) genotypes was not significantly different in the AMD patients compared to that of controls (P = 0.18). The AT genotype frequencies for CFB was non significantly lower in AMD group (6.5% vs. 13.1%, AOR = 0.49, CI = 0.23-1.04, P = 0.064(. The A allele of CFB rs4151667 (L9H) was found to be non-significantly lower in AMD patients. CFB rs4151667 (L9H) had no protective interactional effect against CFH (Y402H) and C3 (R102G) risk variants. CONCLUSIONS: This study showed that the protective role of CFB rs4151667 (L9H) in AMD is not significant and it has no significant protective interactional effect against CFH (Y402H) and C3 (R102G) risk variants.

Magnetized Carbon Nanotube Based Lateral Flow Immunoassay for Visual Detection of Complement Factor B.

The authors describe a magnetized carbon nanotube (MCNT) based lateral flow immunoassay (LFI) for visual detection of complement factor B (CFB) in blood. MCNT was prepared by decorating magnetic Fe3O4 nanoparticles on multi-walled CNT surface and used as a colored tag for LFI. Monoclonal antibody (mAb, Ab1) of CFB was covalently immobilized on the MCNT surface via diimide-activated conjugation between the carboxyl groups on the MCNT surface and amino groups of antibodies. Polyclonal antibody of CFB (Ab2) and the secondary antibody were used to prepare the lateral flow test strips. The assay involved: (1) the capture of CFB in blood with the mAb-functionalized MCNT; (2) magnetic separation of the formed CFB-mAb-MCNT and excess of mAb-MCNT from the blood with an external magnet; (3) lateral flow test to capture the CFB-mAb-MCNT complex on the test zone and the excess of mAb-MCNT on the control zone; (4) Recording the intensities of the produced the characteristic brown bands with a portable strip reader and quantitating the concentration of CFB. The proof-of-concept was demonstrated by testing CFB in the buffer, and the detection limit was 5 ng mL-1 under the optimized analytical parameters. CFB in 1 µL of human blood was detected successfully in 30 min with this LFI and the results had a high correlation with commercial ELISA kit. Thence, the MCNT-based LFI offers a rapid and low-cost tool for detecting CFB in human blood directly.

Adipose tissue complement factor B promotes adipocyte maturation.

OBJECTIVES: It is well-known that the complement system plays an essential role in host immunity. Observational studies have indicated that complement system-related molecules such as complement factor B (CfB) and other components are correlated with obesity and/or insulin resistance parameters. In this study, we investigated the role of adipocyte-derived CfB in adipose tissue metabolism. METHODS: We investigated the expression level of complement system-related genes in adipocytes. To understand the role of CfB in adipocyte, we performed Cfb overexpression in 3T3-L1 preadipocytes and generated adipocyte-specific Cfb transgenic mice. RESULTS: Cfb expression was markedly enhanced in 3T3-L1 adipocytes co-cultured with macrophages following endotoxin stimulation. In Cfb-overexpressing cells, the expression of adipocyte differentiation/maturation-related genes encoding peroxisome proliferator-activated receptor γ (Pparγ), adipocyte Protein 2 and perilipin was significantly enhanced. Cfb transgenic mice showed a marked increase in the expression of genes encoding Pparγ, perilipin, sterol regulatory element-binding protein 1 c, and Cd36 in the subcutaneous adipose tissue. CONCLUSIONS: CfB plays a crucial role in late-phase of adipocyte differentiation and subsequent lipid droplet formation.

Rare genetic variant in the CFB gene presenting as atypical hemolytic uremic syndrome and immune complex diffuse membranoproliferative glomerulonephritis, with crescents, successfully treated with eculizumab.

BACKGROUND: Complement factor B gene (CFB) is an important component of the alternate pathway of complement activation that provides an active subunit that associates with C3b to form the C3 convertase, which is an essential element in complement activation. Among the complement-associated disorders, mutations and pathogenic variants in the CFB gene are relatively rare phenomena. Moreover, mutated CFB affiliation with immune-complex diffuse membranoproliferative glomerulonephritis (IC-MPGN) and atypical hemolytic uremic syndrome (aHUS) are considered a highly rare occurrence. CASE PRESENTATION: We describe the clinical presentation, course, and pathological findings in a 7-year-old boy who has confirmed CFB heterozygous variants with pathological features compatible with IC-MPGN. Mutational analysis revealed a heterozygous variant p.Glu566Arg in exon 13 of the CFB gene. The patient did not respond to steroids and mycophenolate mofetil (MMF) therapy but responded clinically and biochemically to eculizumab treatment. This is the first case report of CFB alteration associated with IC-MPGN and aHUS that was successfully treated with eculizumab. CONCLUSIONS: Heterozygous variants in the CFB gene can be pathogenic and associated with IC-MPGN and aHUS. Early diagnosis and prompt management can be essential in preventing end-stage renal disease. Eculizumab may provide an effective modality of treatment.

Familial C3 glomerulonephritis associated with mutations in the gene for complement factor B.

We report the first case of familial C3 glomerulonephritis (C3GN) associated with mutations in the gene for complement factor B (CFB). A 12-year-old girl was diagnosed with biopsy-proven C3GN. Her mother had a history of treatment for membranoproliferative glomerulonephritis, and her brother had hypocomplementemia without urinary abnormalities. DNA analysis revealed heterozygosity for CFB p.S367R in the patient, mother and brother. Evaluation of the structure-function relationship supports that this mutation has gain-of-function effects in CFB. The present case suggests that CFB has an important role in the etiology of C3GN and provides a new insight into anticomplement therapy approaches.

Identification of human complement factor B as a novel biomarker candidate for pancreatic ductal adenocarcinoma.

Pancreatic cancer (PC; pancreatic ductal adenocarcinoma) is characterized by significant morbidity and mortality worldwide. Although carbohydrate antigen (CA) 19-9 has been known as a PC biomarker, it is not commonly used for general screening because of its low sensitivity and specificity. Therefore, there is an urgent need to develop a new biomarker for PC diagnosis in the earlier stage of cancer. To search for a novel serologic PC biomarker, we carried out an integrated proteomic analysis for a total of 185 pooled or individual plasma from healthy donors and patients with five disease groups including chronic pancreatitis (CP), PC, and other cancers (e.g., hepatocellular carcinoma, cholangiocarcinoma, and gastric cancer) and identified complement factor b (CFB) as a candidate serologic biomarker for PC diagnosis. Immunoblot analysis of CFB revealed more than two times higher expression in plasma samples from PC patients compared with plasma from individuals without PC. Immunoprecipitation coupled to mass spectrometry analysis confirmed both molecular identity and higher expression of CFB in PC samples. CFB showed distinctly higher specificity than CA 19-9 for PC against other types of digestive cancers and in discriminating PC patients from non-PC patients (p < 0.0001). In receiver operator characteristic curve analysis, CFB showed an area under curve of 0.958 (95% CI: 0.956 to 0.959) compared with 0.833 (95% CI: 0.829 to 0.837) for CA 19-9. Furthermore, the Y-index of CFB was much higher than that of CA 19-9 (71.0 vs 50.4), suggesting that CFB outperforms CA 19-9 in discriminating PC from CP and other gastrointestinal cancers. This was further supported by immunoprecipitation and qRT-PCR assays showing higher expression of CFB in PC cell lines than in normal cell lines. A combination of CFB and CA 19-9 showed markedly improved sensitivity (90.1 vs 73.1%) over that of CFB alone in the diagnosis of PC against non-PC, with similar specificity (97.2 vs 97.9%). Thus, our results identify CFB as a novel serologic PC biomarker candidate and warrant further investigation into a large-scale validation and its role in molecular mechanism of pancreatic carcinogenesis.

First Successful Treatment of a Patient with a Primary Immune Complex-Membranoproliferative Glomerulonephritis with Iptacopan: A Case Report.

Introduction: Nowadays, there is insufficient evidence for the recommendation of management patients with a primary membranoproliferative glomerulonephritis (MPGN). A better understanding of the pathogenesis has led to the reclassification of primary MPGN and distinction into the two main entities of either primary immune complex-MPGN or C3 glomerulopathy. Both entities share overlapping pathophysiological features with complement alternative pathway (AP) dysregulation. Iptacopan is an oral inhibitor of the complement factor B that effectively blocks the complement AP. Case Presentation: We report the first successful treatment of a 47-year-old man suffering from a primary immune complex-MPGN with iptacopan. So far established immunosuppressive therapies with prednisone and mycophenolate mofetil failed to control the current flare of the disease, mainly presenting with impaired kidney function and proteinuria within the nephrotic range. However, 3 months after starting the treatment with iptacopan urine protein-creatinine ratio decreased impressively to a level of 100-150 mg/mmol. Thereafter, low-level proteinuria and kidney function remained stable during follow-up. Do date, the treatment with iptacopan is continued as a monotherapy and is well tolerated. Conclusion: To the best of our knowledge, this is the first case report which suggests that iptacopan may be an interesting treatment option for primary immune complex-MPGN.

Eculizumab in an anephric patient with atypical haemolytic uraemic syndrome and advanced vascular lesions.

BACKGROUND: Atypical haemolytic uraemic syndrome (aHUS) is associated with dysfunction of the alternative pathway of complement. Disease activity subsides as renal failure progresses but recurs upon renal transplantation, indicating that viable renal tissue contributes to disease activity. We present evidence of cerebrovascular occlusive disease indicating that vascular injury may occur in the absence of kidneys. METHODS: A currently 12-year-old girl developed renal failure at the age of 20 months. She underwent bilateral nephrectomy and renal transplantation but lost the transplant due to recurrences. She was on haemodialysis for 7 years. At 10 years of age she developed a transient ischaemic attack. Imaging, genetic investigation and mutation characterization were performed. RESULTS: Imaging demonstrated occlusion and stenosis of the carotid arteries. Two complement mutations, a novel mutation in factor B and a previously described mutation in factor I, and the H3-factor H haplotype, were identified. The factor B mutation, L433S, did not induce excessive complement activation in vitro. Measurement of C3 degradation products indicated ongoing complement activation. In spite of the patient being anephric, treatment was initiated with eculizumab, a humanized anti-C5 antibody that blocks terminal complement activation. She underwent a successful kidney transplant 9 months later and has not developed a recurrence or progression of vascular stenosis 1 year later. CONCLUSIONS: The course of disease in this patient with aHUS suggests that complement-mediated vascular injury may occur in the total absence of renal tissue and overt recurrences. To our knowledge, this is the first description of eculizumab treatment in an anephric aHUS patient.

Complement factor B is essential for the proper function of the peripheral auditory system.

Sensorineural hearing loss is associated with dysfunction of cochlear cells. Although immune cells play a critical role in maintaining the inner ear microenvironment, the precise immune-related molecular mechanisms underlying the pathophysiology of hearing loss remain unclear. The complement cascade contributes to the regulation of immune cell activity. Additionally, activation of the complement cascade can lead to the cellular opsonization of cells and pathogens, resulting in their engulfment and elimination by phagocytes. Complement factor B (fB) is an essential activator protein in the alternative complement pathway, and variations in the fB gene are associated with age-related macular degeneration. Here we show that mice of both sexes deficient in fB functional alleles (fB-/-) demonstrate progressive hearing impairment. Transcriptomic analysis of auditory nerves from adult mice detected 706 genes that were significantly differentially expressed between fB-/- and wild-type control animals, including genes related to the extracellular matrix and neural development processes. Additionally, a subset of differentially expressed genes was related to myelin function and neural crest development. Histological and immunohistochemical investigations revealed pathological alterations in auditory nerve myelin sheathes of fB-/- mice. Pathological alterations were also seen in the stria vascularis of the cochlear lateral wall in these mice. Our results implicate fB as an integral regulator of myelin maintenance and stria vascularis integrity, underscoring the importance of understanding the involvement of immune signaling pathways in sensorineural hearing loss.