Results

Patents

Anticuerpo anti-Factor B, composición farmacéutica útil para el tratamiento de enfermedades del complemento y sus aplicaciones.

Inventors: Santiago Rodríguez de Córdoba y Mercedes Domínguez Rodríguez

 

Publications
2013
  • Bresin, E., Rurali, E., Caprioli, J., Sanchez-Corral, P., Fremeaux-Bacchi,V., Rodríguez de Córdoba, S., Pinto, S., Goodship, TH., Alberti, M., Ribes, D., Valoti, E., Remuzzi, G., Noris, M.; on behalf of the European Working Party on Complement Genetics in Renal Diseases. (2013). Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype. J Am Soc Nephrol 24, 475-486.
  • Campistol, J.M., Arias, M., Ariceta, G., Blasco, M., Espinosa, M., Grinyó, J.M., Praga, M., Torra, R., Vilalta, R. and Rodríguez de Córdoba, S. (2013). Actualización en síndrome hemolítico urémico atípico: diagnóstico y tratamiento. Documento de consenso. Nefrología 33, 27-45.
  • Fernandez, F.J., and Vega, M.C. (2013). Technologies to keep an eye on: alternative hosts for protein production in structural biology. Current opinion in structural biology.
  • Gómez-Traseira, C., López-Lera, A., Drouet, C., López-Trascasa, M., Pérez-Fernández, E., Favier, B., Prior, N., and Caballero, T. (2013) Hereditary Angioedema Caused By the p.Thr309Lys Mutation In the F12 Gene: A Multifactorial Disease. Accepted in Journal of Allergy and Clinical Immunology, 23 april 2013.
  • Hebecker, M., Alba-Domínguez, M., Roumenina, L.T., Reuter, S., Hyvärinen, S.,  Dragon-Durey, M.A., Sakari Jokiranta, T., Sánchez-Corral, P.,  and Józsi, M. (2013) An engineered construct combining complement regulatory and surface recognition domains represents a minimal-size functional factor H1. Accepted in Journal of Immunology, 11 May 2013
  • Lopez-Lera, A., Sanchez Cabo, F., Garrido, S., Dopazo, A., and Lopez-Trascasa, M. (2013). Disease-modifying factors in hereditary angioedema: an RNA expression-based screening. Orphanet J Rare Dis 8, 77.
  • Olivar, R., Luque, A., Naranjo-Gomez, M., Quer, J., Garcia de Frutos, P., Borras, F.E., Rodriguez de Cordoba, S., Blom, A.M., and Aran, J.M. (2013). The alpha7beta0 isoform of the complement regulator C4b-binding protein induces a semimature, anti-inflammatory state in dendritic cells. Journal of immunology 190, 2857-2872.
  • Rabasco, C., Huerta, A., Caro, J., Gutierrez, E., and Praga, M. (2013). C3 Glomerulopathies. A new perspective on glomerular diseases. Nefrología 33(2), 164-170.
  • Tortajada, A., Yébenes, H., Abarrategui-Garrido, C., Anter, J., García-Fernández, J.M., Martínez-Barricarte, R., Alba-Domínguez, M., Malik, T.H., Bedoya, R., Cabrera Pérez, R., López Trascasa, M., Pickering, M.C., Harris, C.L., Sánchez-Corral, P., Llorca, O. and Rodríguez de Córdoba, S. (2013).Novel CFHR1 genomic mutation and FHRs structural organization advance understanding of pathogenic mechanism in C3-Glomerulopathies. J Clin Invest. (in press)
2012
  • Aguilera, L., Ferreira, E., Gimenez, R., Fernandez, F.J., Taules, M., Aguilar, J., Vega, M.C., Badia, J., and Baldoma, L. (2012). Secretion of the housekeeping protein glyceraldehyde-3-phosphate dehydrogenase by the LEE-encoded type III secretion system in enteropathogenic Escherichia coli. The international journal of biochemistry & cell biology 44, 955-962.
  • Alba-Domínguez, M., López-Lera, A., Garrido, S., Nozal, P., González-Granado, I., Melero, J., Soler-Palacín, P., Cámara, C., López-Trascasa, M., and d’Hebron, U.V. (2012). Complement factor I deficiency: a not so rare immune defect. characterization of new mutations and the first large gene deletion. Orphanet journal of rare diseases 7, 42.
  • Alcorlo Pagés, M., Martínez-Barricarte, R., Fernandez, F.J., Rodriguez Gallego, C., Raund, A., Vega, M.C., Harris, C.L., Rodriguez de Cordoba, S., and Llorca, O. (2012). Structure of human complement iC3b revealed by 3D-electron microscopy and small-angle X-ray scattering. ERSF, 97-98.
  • Ariceta, G., Arrizabalaga, B., Aguirre, M., Morteruel, E., and Lopez-Trascasa, M. (2012). Eculizumab in the treatment of atypical hemolytic uremic syndrome in infants. American journal of kidney diseases : the official journal of the National Kidney Foundation 59, 707-710.
  • de Cordoba, S.R., Tortajada, A., Harris, C.L., and Morgan, B.P. (2012). Complement dysregulation and disease: from genes and proteins to diagnostics and drugs. Immunobiology 217, 1034-1046.
  • de la Cruz, R.M., Lopez-Lera, A., and Lopez-Trascasa, M. (2012). Analysis of SERPING1 expression on hereditary angioedema patients: quantitative analysis of full-length and exon 3 splicing variants. Immunology letters 141, 158-164.
  • Hadders, M.A., Bubeck, D., Roversi, P., Hakobyan, S., Forneris, F., Morgan, B.P., Pangburn, M.K., Llorca, O., Lea, S.M., and Gros, P. (2012). Assembly and regulation of the membrane attack complex based on structures of C5b6 and sC5b9. Cell reports.
  • Harris, C.L., Heurich, M., Cordoba, S.R.d., and Morgan, B.P. (2012). The complotype: dictating risk for inflammation and infection. Trends in Immunology.
  • Johnston, D.T. and López-Trascasa, M. (2012). Angioedema hereditario: un trastorno poco frecuente pero potencialmente mortal. Med Gen y Fam (digital) 1(7):321-332.
  • Kopp, A., Strobel, S., Tortajada, A., Rodriguez de Cordoba, S., Sanchez-Corral, P., Prohaszka, Z., Lopez-Trascasa, M., and Jozsi, M. (2012). Atypical hemolytic uremic syndrome-associated variants and autoantibodies impair binding of factor h and factor h-related protein 1 to pentraxin 3. Journal of immunology 189, 1858-1867.
  • Leban, N., Abarrategui‐Garrido, C., Fariza‐Requejo, E., Amiñoso‐Carbonero, C., Pinto, S., Chibani, J., Khelil, A., and Sánchez‐Corral, P. (2012). Factor H and CFHR1 polymorphisms associated with atypical Haemolytic Uraemic Syndrome (aHUS) are differently expressed in Tunisian and in Caucasian populations. International Journal of Immunogenetics.
  • Marcos, C., Lopez Lera, A., Varela, S., Linares, T., Alvarez-Eire, M.G., and Lopez-Trascasa, M. (2012). Clinical, biochemical, and genetic characterization of type III hereditary angioedema in 13 Northwest Spanish families. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 109, 195-200 e192.
  • Martinez-Barricarte, R., Recalde, S., Fernandez-Robredo, P., Millan, I., Olavarrieta, L., Vinuela, A., Perez-Perez, J., Garcia-Layana, A., Rodriguez de Cordoba, S., and Spanish Multicenter Group on, A.M.D. (2012). Relevance of complement factor H-related 1 (CFHR1) genotypes in age-related macular degeneration. Investigative ophthalmology & visual science 53, 1087-1094.
  • Nozal, P., Strobel, S., Ibernon, M., López, D., Sánchez-Corral, P., de Córdoba, S.R., Józsi, M., and López-Trascasa, M. (2012). Anti-factor H antibody affecting factor H cofactor activity in a patient with dense deposit disease. Clinical Kidney Journal 5.
  • Paixão-Cavalcante, D., López-Trascasa, M., Skattum, L., Giclas, P.C., Goodship, T.H., de Córdoba, S.R., Truedsson, L., Morgan, B.P., and Harris, C.L. (2012). Sensitive and specific assays for C3 nephritic factors clarify mechanisms underlying complement dysregulation. Kidney International.
  • Zhou, H.-f., Yan, H., Stover, C.M., Fernandez, T.M., de Cordoba, S.R., Song, W.-C., Wu, X., Thompson, R.W., Schwaeble, W.J., and Atkinson, J.P. (2012). Antibody directs properdin-dependent activation of the complement alternative pathway in a mouse model of abdominal aortic aneurysm. Proceedings of the National Academy of Sciences 109, E415-E422.
Thesis

Title: Análisis estructural y funcional de proteínas del complemento asociadas con patología.

Author: Agustín Tortajada Alonso

Director: Santiago Rodríguez de Córdoba. CIB-CSIC

Link: http://tdx.cesca.cat/handle/10803/87178

Summary:

The complement system is a major component of the innate immunity, with crucial roles against infections, modulating the adaptive immune response and in apoptotic cell clearance and immune complex handling. The complement system is composed of a group of plasma proteins, arranged in cascades which are activated by specific signals on pathogens and foreign surfaces. The critical event in complement activation is the hydrolysis of component C3 to the active molecule C3b, which is catalyzed by unstable protease complexes, named C3 convertases. In order to avoid nonspecific activation and prevent self-injury, both the presence of C3b and the formation of the C3 convertases are strictly controlled by the regulatory proteins that limit complement activation. Thus, the proper functioning of the complement system depends on the balance between the components that activate the cascades and regulators that control the components.

Environmental factors, mutations, polymorphisms and autoantibodies with fuctional consequences on the complement proteins or altering their plasma concentration, may disturb the balance between complement activation and regulation. Thereby, many of these alterations are risk factors associated with pathological situations. Atypical hemolytic uremic syndrome (aHUS), dense deposit disease (DDD) and age-related macular degeneration (AMD) are three of these complement associated diseases. The available data has shown that deregulation of the alternative pathway (AP) of complement is a common pathological feature for these disorders. Genetic and functional studies illustrate how the mutations in regulators of the AP, such as those found in factor H (fH), MCP and factor I, are loss of function mutations, while those present in activating components, such as factor B (fB) and C3 are gain of function mutations. Both situations lead to an uncontrolled activation of complement, which drives to the development of the pathology. However, the functional consequences of mutations or polymorphisms are not always known and additional risk factors for these conditions are not identified. The overall objectives of this thesis were on one hand to study the C3 convertase complex from a structural and functional approach, and secondly to identify additional risk factors and the functional characterization of variants associated with disease.

From purified proteins, we have generated and isolated pro-convertase and C3 convertase complexes. Using single-particle electron microscopy we have determined the 3-dimensional models of these complexes. The results show important aspects of the assembling mechanism of C3 convertase, such as the conformational change that undergoes on fB upon binding to C3b to form the pro-convertase, and which domains are involved in the formation and stability of the C3 convertase of both C3b and fB.

Also, the proposed models provide information on the regulatory mechanisms of these complexes. They also constitute a structural framework for the study of relevant residues involved in pathologies associated with deregulation of the AP of complement.

On the other hand, we have designed antibodies that specificaly recognize the two variants of a common polymorphism located in fH (Tyr402His), which is strongly associated with AMD. These specific antibodies have allowed us to genotype this polymorphism and to identify risk carriers for this pathology. Also, using these antibodies, we have performed allele-specific quantification of fH in different populations, which has helped us to identify low expression alleles carriers within aHUS patients, which represent an additional and measurable risk factor that can be crucial in the development of the disease. Further, our antibodies have been a useful tool in the purification of mutants fH from plasma, to perform fuctional assays.

Finally, we have functionally characterized some of the variants associated with AMD, aHUS and DDD. On the one hand, the common polymorphisms of fB, Arg32Trp/Gln, and of fH, Val62Ile, whose situation in the protein directly influences the formation and regulation of C3 convertase. On the other hand, the rare variants of fH, Ser890Ile / Val1007Leu, which have been repeatedly associated with aHUS, DDD and AMD. We have designed a set of functional assays which reveal the molecular basis of the association of these variants with disease, and provide information on the pathological mechanisms by which complement dysregulation is more or less involved in the development disease.