Síndrome hemolítico urémico: bases moleculares y modelos animales

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 26-11-200

VICARED: A Neural Network Based System for the Detection of Electrical Disturbances in Real Time

The study of the quality of electric power lines is usually known as Power Quality. Power quality problems are increasingly due to a proliferation of equipment that is sensitive and polluting at the same time. The detection and classification of the different disturbances which cause power quality problems is a difficult task which requires a high level of engineering knowledge. Thus, neural networks are usually a good choice for the detection and classification of these disturbances. This paper describes a powerful system for detection of electrical disturbances by means of neural networks

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

El Sistema del Complemento, interactivo y magnético. Memoria final

El modelo didáctico más empleado en la enseñanza universitaria es de tipo transmisivo, centrado en la exposición del profesor/a con el apoyo de las presentaciones y los libros de texto, siendo el alumno/a esencialmente receptor de la enseñanza. Sin embargo, cada vez más se emplean estrategias alternativas para abordar el proceso de enseñanza-aprendizaje desde modelos más centrados en el alumno/a, que favorezcan su implicación, actividad y protagonismo. Con el proyecto de innovación docente: El Sistema del Complemento, interactivo y magnético, queremos desarrollar una herramienta didáctica que nos permita implementar una estrategia de aprendizaje interactiva para el estudio de la cascada de activación del sistema del complemento. La propuesta se ha programado para la asignatura de Fisiopatología del Complemento impartida en el Máster de Investigación en Inmunología (UCM). Para ello, elaboramos material didáctico que consiste en fichas impresas en papel imantado que representan cada uno de los componentes que forman el sistema del complemento de manera que se puedan colocar y mover sobre una pizarra magnética. Este material se pone a disposición de los estudiantes para realizar actividades concretas propuestas por los profesores/as, en las que se trabaja en grupo y de forma interactiva, sirviendo también como herramienta para el repaso de conceptos y resolución de dudas durante las clases teóricas

The role of complement in kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Uncontrolled complement activation can cause or contribute to glomerular injury in multiple kidney diseases. Although complement activation plays a causal role in atypical hemolytic uremic syndrome and C3 glomerulopathy, over the past decade, a rapidly accumulating body of evidence has shown a role for complement activation in multiple other kidney diseases, including diabetic nephropathy and several glomerulonephritides. The number of available complement inhibitor therapies has also increased during the same period. In 2022, Kidney Diseases: Improving Global Outcomes (KDIGO) convened a Controversies Conference, “The Role of Complement in Kidney Disease,” to address the expanding role of complement dysregulation in the pathophysiology, diagnosis, and management of various glomerular diseases, diabetic nephropathy, and other forms of hemolytic uremic syndrome. Conference participants reviewed the evidence for complement playing a primary causal or secondary role in progression for several disease states and considered how evidence of complement involvement might inform management. Participating patients with various complement-mediated diseases and caregivers described concerns related to life planning, implications surrounding genetic testing, and the need for inclusive implementation of effective novel therapies into clinical practice. The value of biomarkers in monitoring disease course and the role of the glomerular microenvironment in complement response were examined, and key gaps in knowledge and research priorities were identified

Thrombotic microangiopathy in patients with malignant hypertension

10 p.-4 fig.-4 tab.Background: Thrombotic microangiopathy (TMA) is a complication of malignant hypertension (mHTN) attributed to high blood pressure (BP). However, no studies have investigated in patients with mHTN of different aetiologies whether the presence of TMA is associated with specific causes of mHTN.Methods: We investigated the presence of TMA (microangiopathic haemolytic anaemia and thrombocytopenia) in a large and well-characterized cohort of 199 patients with mHTN of different aetiologies [primary HTN 44%, glomerular diseases 16.6%, primary atypical haemolytic uraemic syndrome (aHUS) 13.1%, renovascular HTN 9.5%, drug-related HTN 7%, systemic diseases 5.5%, endocrine diseases 4.5%]. Outcomes of the study were kidney recovery and kidney failure.Results: Patients with TMA [40 cases (20.1%)] were younger, were more likely female and had lower BP levels and worse kidney function at presentation. Their underlying diseases were primary aHUS (60%), drug-related mHTN (15%), glomerular diseases [all of them immunoglobulin A nephropathy (IgAN); 10%], systemic diseases (10%) and primary HTN (5%). The presence of TMA was 92.3% in primary aHUS, 42.9% in drug-related HTN, 36.4% in systemic diseases, 12.1% in glomerular diseases and 2.3% in primary HTN. No patient with renovascular HTN or mHTN caused by endocrine diseases developed TMA, despite BP levels as high as patients with TMA. A higher proportion of TMA patients developed kidney failure as compared with patients without TMA (56.4% versus 38.9%, respectively).Conclusions: The presence of TMA in patients with mHTN should guide the diagnosis towards primary aHUS, drug-related mHTN, some systemic diseases and IgAN, while it is exceptional in other causes of mHTN.Work in this study was supported by the Instituto de Salud Carlos III/Fondo Europeo de Desarrollo Regional [ISCIII/FEDER;grants PI13/02502 and PICI14/00350 (to M.P.) and PI16/01685 and PI19/01624 (to M.P. and T.C.)]; the Spanish Ministerio de Economía y Competitividad/FEDER [SAF2015-66287-R and PID2019-104912RB-I00 (to S.R.d.C.)]; the Spanish ‘Ministerio de Ciencia Innovación y Universidades’ [RTI2018-095955-B-100 (to E.G.J.)]; the Autonomous Region of Madrid [S2017/BMD-3673 (to E.G.J., S.R.d.C. and M.P.)] and Red de Investigación Renal [RD12/0021/0029 (to M.P.)].Peer reviewe

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

Tumor cells in light-chain amyloidosis and myeloma show distinct transcriptional rewiring of normal plasma cell development

Although light-chain amyloidosis (AL) and multiple myeloma (MM) are characterized by tumor plasma cell (PC) expansion in bone marrow (BM), their clinical presentation differs. Previous attempts to identify unique pathogenic mechanisms behind such differences were unsuccessful, and no studies have investigated the differentiation stage of tumor PCs in patients with AL and MM. We sought to define a transcriptional atlas of normal PC development in secondary lymphoid organs (SLOs), peripheral blood (PB), and BM for comparison with the transcriptional programs (TPs) of tumor PCs in AL, MM, and monoclonal gammopathy of undetermined significance (MGUS). Based on bulk and single-cell RNA sequencing, we observed 13 TPs during transition of normal PCs throughout SLOs, PB, and BM. We further noted the following: CD39 outperforms CD19 to discriminate newborn from long-lived BM-PCs; tumor PCs expressed the most advantageous TPs of normal PC differentiation; AL shares greater similarity to SLO-PCs whereas MM is transcriptionally closer to PB-PCs and newborn BM-PCs; patients with AL and MM enriched in immature TPs had inferior survival; and protein N-linked glycosylation–related TPs are upregulated in AL. Collectively, we provide a novel resource to understand normal PC development and the transcriptional reorganization of AL and other monoclonal gammopathies

Factor H-related proteins determine complement-activating surfaces.

Complement factor H-related proteins (FHRs) are strongly associated with different diseases involving complement dysregulation, which suggests a major role for these proteins regulating complement activation. Because FHRs are evolutionarily and structurally related to complement inhibitor factor H (FH), the initial assumption was that the FHRs are also negative complement regulators. Whereas weak complement inhibiting activities were originally reported for these molecules, recent developments indicate that FHRs may enhance complement activation, with important implications for the role of these proteins in health and disease. We review these findings here, and propose that FHRs represent a complex set of surface recognition molecules that, by competing with FH, provide improved discrimination of self and non-self surfaces and play a central role in determining appropriate activation of the complement pathway