Following the explosion of genetics during the last 10 years, it has become clear that the contribution of common polymorphisms to the genetic susceptibility of complex diseases is not complete. Based on this, new ways of viewing disease have been put forward that may help in the molecular diagnosis of disease. This was the main goal of the PRECISESADS project funded by the Innovative Medicines Initiative. This project aimed at the molecular stratification of the systemic autoimmune diseases. In addition, based on this molecular stratification, the group is now working on the mechanisms of non-response to treatment and remission. This is funded by the IMI as well, for the project 3TR, both coordinated by Dr Alarcón-Riquelme. The group is therefore at the forefront of immune-mediated disease research in Europe through the coordination of two major European projects. Other research areas are also described.
Study of the genetic basis of systemic lupus erythematosus (SLE): SLE is a complex autoimmune disease whose etiology is still unknown. It is characterized by inflammation and tissue damage mediated by the immune system. There is substantial evidence to argue that genetic factors in SLE are of great importance, and that combined with environmental factors interact in the development of the disease. SLE has a strong genetic component: more than 8% of women with SLE have a first or second-degree relative who also suffers from the disease. The first published genetic association studies were about diseases treated with a genetic component much smaller than that of SLE (e.g. diabetes mellitus type 1 and type 2), or in which the prevalence of the disease in the population was higher (as in rheumatoid arthritis). We identified the gene BANK1 and have understood that as an adaptor protein it encodes for, it binds to MYD88 and TRAF6 and that mice that spontaneously develop lupus that are deficient for Bank1 have reduced levels of IgG and IgG autoantibodies, reduced production of IL-6 and normalized numbers of B cells. The aim of our research is to describe new genetic associations in other populations, and use molecular stratification to define new genetic associations. This an other studies are complemented with studies on mouse models of the disease. Related publications:
Kozyrev, S.V*., Abelson, A.K*., Wojcik, J., Zaghlool, A., Linga Reddy, P.M.V., Sanchez, E., Yin, H., Gunnarsson, I., Svenungsson, E., Sturfelt, G., Jönsen, A., Truedsson, L., Pons-Estel, B., Witte, T., D’Alfonso, S., Momigliano-Richiardi, P., Danieli, M.G., Gutierrez, C., Suárez, A., Junker, P., Laustrup, H., González-Escribano, M.F., Martin, J., Abderrahim, H., and Alarcón-Riquelme, M.E. The B Cell Gene BANK1 is Associated with Systemic Lupus Erythematosus Through the Effect of Several Functional Variants Nat Genet 40(2):211-6, 2008 Bentham, J., Morris, D.L., Cunninghame-Graham, D.S., Pinder, C.L., Tombleson, P., Behrens, T.W., Criswell, L.A., Gaffney, P., Martin, J., Fairfax, B., Knight, J., Syvannen, AC., Ronnblom, L., Graham, R.R., Wither, J.E., Rioux, J.D., Alarcón-Riquelme, M.E., and Vyse, T.J. Genetic Association Analyses Implicate aberrant gene regulation of the innate and adaptive immunity genes in the pathogenesis of SLE implicated by genetics. Nat Genet 47: 1457–1464, 2015. Wu, Y.Y., Kumar, R., Iida, R., Bagavant, H., and Alarcón-Riquelme, M.E. BANK1 Regulates IgG Production in a Lupus Model by Controlling STAT1 Activation. PLoS One. 11(5):e0156302, 2016.
Study of the molecular stratification of systemic autoimmune diseases (PRECISESADS):this study aims at the use of integrated gene expression and methylation data from blood and specific cell populations to define the molecular pathways for each patient´s disease. This will lead us to a new molecular diagnosis and to personalized medicine possibilities. More information can be found at www.precisesads.eu. Related publications:
Toro, D., Martorell-Marugán, J., Goldman, D., Petri, M., Carmona-Sáez, P., and Alarcón-Riquelme, M.E. Longitudinal Stratification of Gene Expression Reveals Three SLE Groups of Disease Activity Progression Arthritis Rheum 70(12):2025-2035, 2018.
Barturen, G., Beretta, L., Cervera, R., Van Vollenhoven, R., and Alarcón-Riquelme, M.E. Moving Towards a Molecular Taxonomy of Autoimmune Rheumatic Diseases. Nat Rev Rheumatol 14(2):75-93, 2018.
Toro-Domínguez, D., Domínguez-López, R., García Moreno, A., Villatoro-García, J.A., Martorell-Marugán, J., Goldman, D., Petri, M., Wojdyla, D., Pons-Estel, B.A., Isenberg, D., Morales-Montes de Oca, G., Trejo-Zambrano, M.I., García González, B., Gómez-Martín, D., Romero-Díaz, J., Carmona-Saez, P., and Alarcón-Riquelme, M.E. Differential Treatments and Risk for Severe Nephritis Based on a Longitudinal Systemic Lupus Erythematosus Stratification. Sci Rep 9(1): 15502, 2019.
Study on the mechanisms of non-response to therapies and remission of 7 immune-mediated diseases: This is a new project that has just started and is funded by the European Union Programme Innovative Medicines Initiative (3tr-imi.eu). The project will be stratifying the patients for blood and tissues to identify the best targets to prevent tissue damage. A prospective trial together with ongoing clinical studies will be analyzed tfor the best leverage towards understanding mechanisms of no-response to therapies. Up to 30% of the individuals treated with diverse medications do not respond to their treatment. Having discarded non-adherence or anti-drug antibodies, molecular mechanisms will be sought. This study began in september 2019.
The NExtSeq 500: Next-Generation Sequencing from Illumina
The iScan System from Illumina
Mass cytometry (Cytof/Helios) from Fluidigm
Flow cytometry: sorting, flow and imaging
European Science Foundation financiada por fondos de FMR (Austria), FNRS (Bélgica), FWO (Bélgica), RPF (Chipre), Danish Medical Research Council, DFG (Alemania), FCT (Portugal), CSIC (España, MICINN (España), Swedish Research Council, SNF (Suecia), MRC (Reino Unido). (2009-2014)
Instituto de Salud Carlos III (FIS, Miguel Servet, Rio Hortega and Sara Borrell programs) (2009-2015)
Ministerio de Economía y Competitividad, Plan Estatal de fomento de la Investigación Científica de Excelencia 2016 (2017-2020)
Swedish Research Council (2009-2013 and 2017-2020)
Fundación Ramón Areces (2011-2015)
Innovative Medicines Initiative Program of the European Unión (2014-2018): special funding of the project PRECISESADS
Innovative Medicines Initiative Program of the European Union (2019-2026): special funding of the project 3TR
Research group patents
Title:Interacting Genes of BANK1 Authors (1st Surname, Initials):Castillejo C, Delgado A, Alarcón M, Wojcik J Applicant:Merck Serono S.A. Priority Date:19/01/2012
Title:Un Método para la detección de la Interacción entre BANK1 y PLCG2 en la señalización celular Authors (1st Surname, Initials):Castillejo C, Bernal, M. Alarcón M Applicant:Consejería de Salud de Andalucía
International Collaborations: Dr Alarcón-Riquelme heads the Managing Entity of the IMI funded project PRECISESADS, on the “Molecular Re-classification of Systemic Autoimmune Diseases” which joins 21 European academic groups, 2 SMEs and 5 Big Pharma. She is also the coordinator of 3TR: Taxonomy, Treatment, Targets, and Remission: Identification of the Molecular Mechanisms of non-response to Treatments, Relapses and Remission in Autoimmune, Inflammatory, and Allergic Conditions. The project joins 58 European academic groups, 3 biotechnology companies and 8 pharmaceutical companies.