The Factor H protein family: The switchers of the complement alternative pathway

The factor H (FH) protein family is emerging as a complex network of proteins controlling the fate of the complement alternative pathway (AP) and dictating susceptibility to a wide range of diseases including infectious, inflammatory, autoimmune, and degenerative diseases and cancer. Composed, in man, of seven highly related proteins, FH, factor H-like 1, and 5 factor H-related proteins, some of the FH family proteins are devoted to down-regulating the AP, while others exert an opposite function by promoting AP activation. Recent findings have provided insights into the molecular mechanisms defining their biological roles and their pathogenicity, illustrating the relevance that the balance between the regulators and the activators within this protein family has in defining the outcome of complement activation on cell surfaces. In this review we will discuss the emerging roles of the factor H protein family, their impact in the complement cascade, and their involvement in the pathogenesis of complementmediated diseases associated with the AP dysregulation

Factor H-related protein 1 drives disease susceptibility and prognosis in C3 glomerulopathy

17 p.-8 fig.Background: C3 glomerulopathy (C3G) is a heterogeneous group of chronic renal diseases characterized predominantly by glomerular C3 deposition and complement dysregulation. Mutations in factor H-related (FHR) proteins resulting in duplicated dimerization domains are prototypical of C3G, although the underlying pathogenic mechanism is unclear.Methods: Using in vitro and in vivo assays, we performed extensive characterization of an FHR-1 mutant with a duplicated dimerization domain. To assess the FHR-1 mutant's association with disease susceptibility and renal prognosis, we also analyzed CFHR1 copy number variations and FHR-1 plasma levels in two Spanish C3G cohorts and in a control population.Results: Duplication of the dimerization domain conferred FHR-1 with an increased capacity to interact with C3-opsonized surfaces, which resulted in an excessive activation of the alternative pathway. This activation does not involve C3b binding competition with factor H. These findings support a scenario in which mutant FHR-1 binds to C3-activated fragments and recruits native C3 and C3b; this leads to formation of alternative pathway C3 convertases, which increases deposition of C3b molecules, overcoming FH regulation. This suggests that a balanced FHR-1/FH ratio is crucial to control complement amplification on opsonized surfaces. Consistent with this conceptual framework, we show that the genetic deficiency of FHR-1 or decreased FHR-1 in plasma confers protection against developing C3G and associates with better renal outcome.Conclusions: Our findings explain how FHR-1 mutants with duplicated dimerization domains result in predisposition to C3G. They also provide a pathogenic mechanism that may be shared by other diseases, such as IgA nephropathy or age-related macular degeneration, and identify FHR-1 as a potential novel therapeutic target in C3G.E. Goicoechea de Jorge is supported by Ministerio de Ciencia e Innovación grant RTI2018-095955-B-100 and the European Union’s Horizon 2020 Framework Programme grant 899163. J. Gutiérrez-Tenorio is supported by Ministerio de Ciencia e Innovación grant BES-2015-073833. L. Lucientes Continente is supported by the Autonomous Region of Madrid grant S2017/BMD-3673. G. Fernández-Juarez, P. Sánchez-Corral, B. Márquez-Tirado, and M. Praga are supported by the Instituto de Salud Carlos III and the European Union’s European Regional Development Fund grants PI19/01695, PI19/00970, and PI19/01624, respectively. M.C. Pickering is a Wellcome Trust Senior Fellow in Clinical Science (212252/Z/18/Z). S. Rodríguez de Córdoba is supported by the Ministerio de Economía y Competitividad grant PID2019-104912RB-100 and Autonomous Region of Madrid grant S2017/BMD-3673.Peer reviewe

Factor H–Related Protein 1 Drives Disease Susceptibility and Prognosis in C3 Glomerulopathy

Background: C3 glomerulopathy (C3G) is a heterogeneous group of chronic renal diseases characterized predominantly by glomerular C3 deposition and complement dysregulation. Mutations in factor H–related (FHR) proteins resulting in duplicated dimerization domains are prototypical of C3G, although the underlying pathogenic mechanism is unclear. Methods: Using in vitro and in vivo assays, we performed extensive characterization of an FHR-1 mutant with a duplicated dimerization domain. To assess the FHR-1 mutant’s association with disease susceptibility and renal prognosis, we also analyzed CFHR1 copy number variations and FHR-1 plasma levels in two Spanish C3G cohorts and in a control population. Results: Duplication of the dimerization domain conferred FHR-1 with an increased capacity to interact with C3-opsonized surfaces, which resulted in an excessive activation of the alternative pathway. This activation does not involve C3b binding competition with factor H. These findings support a scenario in which mutant FHR-1 binds to C3-activated fragments and recruits native C3 and C3b; this leads to formation of alternative pathway C3 convertases, which increases deposition of C3b molecules, overcoming FH regulation. This suggests that a balanced FHR-1/FH ratio is crucial to control complement amplification on opsonized surfaces. Consistent with this conceptual framework, we show that the genetic deficiency of FHR-1 or decreased FHR-1 in plasma confers protection against developing C3G and associates with better renal outcome. Conclusions: Our findings explain how FHR-1 mutants with duplicated dimerization domains result in predisposition to C3G. They also provide a pathogenic mechanism that may be shared by other diseases, such as IgA nephropathy or age-related macular degeneration, and identify FHR-1 as a potential novel therapeutic target in C3G

Relationship between Mental Disorders, Smoking or Alcoholism and Benign Prostate Disease

Introduction: Mental disorders, smoking, or alcoholism and benign prostate disease are highly prevalent in men. Aims: To identify the relationship between mental disorders, smoking, or alcoholism and benign prostate disease. Methodology: A prospective multicenter study that evaluated prostate health status in 558 men from the community. Groups: GP—men who request a prostate health examination and whose medical history includes a mental disorder, smoking, or alcoholism prior to a diagnosis of benign prostate disease; GU—men who request a prostate health examination and whose medical history includes a benign prostate disease prior to a diagnosis of mental disorder, smoking, or alcoholism. Variables: age, body mass index (BMI), prostate specific antigen (PSA), follow-up of the mental disorder, smoking or alcoholism, time elapsed between urological diagnosis and the mental disorder, smoking or alcoholism diagnosis, status of the urological disease (cured or not cured), concomitant diseases, surgical history, and concomitant treatments. Descriptive statistics, Student’s t-test, Chi2, multivariate analysis. Results: There were no mental disorders, smoking, or alcoholism in 51.97% of men. Anxiety, smoking, major depressive disorder, pathological insomnia, psychosis, and alcoholism were identified in 19.71%, 13.26%, 5.73%, 4.30%, 2.87%, and 2.15% of individuals, respectively. Nonbacterial prostatitis (31.54%), urinary tract infection (other than prostatitis, 24.37%), prostatic intraepithelial neoplasia (13.98%), and prostatodynia (1.43%) were prostate diseases. Unresolved symptomatic benign prostate disease was associated with anxiety, depression, and psychosis (p = 0.002). Smoking was the disorder that men managed to eliminate most frequently. The dominant disorder in patients with symptomatic benign prostatic disease was alcoholism (p = 0.006). Conclusions: Unresolved symptomatic benign prostatic disease is associated with anxiety, depression, and psychosis. Alcoholism is associated with a worse prognosis in the follow-up of symptomatic benign prostatic disease

Complement alternative pathway determines disease susceptibility and severity in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis

Activation of the alternative pathway (AP) of complement is involved in the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), although the underlying molecular mechanisms are unclear. To gain insight into the role of the AP, common gene variants in CFH/CFHR1-5, CFB, C3 and MCP, and longitudinal determinations of plasma C3, C4, FH, FHR-1, FHR-2, FHR-5, FB, properdin and sC5b-9 levels were analyzed in a Spanish AAV cohort consisting of 102 patients; 54 with active AAV (active cohort) and 48 in remission not receiving immunosuppressants or dialysis therapy (remission cohort). The validation cohort consisted of 100 patients with ANCA-associated glomerulonephritis. Here, we demonstrated that common genetic variants in complement components of the AP are associated with disease susceptibility (CFB32Q/W) or severity of kidney damage in AAV (CFH-H1, CFH1H2 and DCFHR3/1). Plasma levels of complement components were significantly different between active and remission cohorts. In longitudinal observations, a high degree of AP activation at diagnosis was associated with worse disease outcome, while high basal FHR-1 levels and lower FH/FHR-1 ratios determined severe forms of kidney associated AAV. These genetic and plasmatic findings were confirmed in the validation cohort. Additionally, autoantibodies against FH and C3 convertase were identified in one and five active patients, respectively. Thus, our study identified key genetic and plasma components of the AP that determine disease susceptibility, prognosis, and severity in AAV. Our data also suggests that balance between FH and FHR-1 is critical and supports FHR-1 as a novel AP -specific therapeutic target in AAV. Kidney International (2024) 105, 177-188; https://doi.org/10.1016/ j.kint.2023.10.01