General Information

Most chronic diseases are complex having multiple factors behind their pathogenesis. Most immune mediated diseases are considered inflammatory with processes that may begin through infections, activation of the innate immune system, the adaptive immune system and the immunopathology that while attempting to restore tissue produces tissue damage. The group of Marta Alarcón- Riquelme has focused for years in understanding the genetic of the autoimmune or immune-mediated disease systemic lupus erythematosus and later on the role of various genomic and epigenomic markers that modulate gene expression and functionality of the genetic variants associated with disease. More recently she has been using machine learning to design predictive models of treatment responses using multi-omics integration. Her group has discovered several genes involved in the susceptibility to develop systemic lupus erythematosus. One of the genes, Bank1 has as primary function and impact on B cells that are implicated in the overproduction of specific populations of B cells that infiltrate the kidney, producing autoantibodies leading to kidney damage. In order to understand gene function, the group has been working with preclinical mouse models of disease making use of single cell RNA sequencing to understand which B cell development trajectories the gene impacts on.

Through genotyping, deep sequencing and imputation, the understanding of the genetic architecture of immune-mediated diseases is becoming a fact, but even more, through the combination of multiple layers of data: epigenome, transcriptome and proteome data, it will become even clearer the delineation of the functional variants modulating disease expression. This will be combined with genome editing technology that will help understand the functionality of the genetic architecture in disease.

Over 30-40% of patients with immune-mediated diseases respond poorly or not at all to their medication. There are several explanations one being the heterogeneity of these diseases where the molecular patterns differ between patients with the same diagnosis. Furthermore, a large group of individuals are never diagnosed and remain “undefined” their entire lives. We develop molecular models that predict response to therapies and molecular pathways that may stratify the diseases not into clinical diagnoses but into molecular diagnoses, and we study in-depth the single cell components that differentiate responders from non-responders.

The work on genetics also involves the understanding of the role of rare variants in disease, the role of the Human Leukocyte Antigen (HLA) system in disease and determination of the polygenic risk score. Furthermore, determination of epigenetic modifications particularly detecting methylated CpG sites which reflect environmental versus genetic influence on gene expression changes in disease. The role of the genotype in determining changes in the microbiota composition is also included in the studies described.

Work is also ongoing on urinary liquid biopsy and the early detection of markers and extracellular vesicles in lupus nephritis. This part of the project is led by the senior scientist in the group, Dr Concepción Marañón.

Scientific Impact

The understanding of the genetic architecture of disease and the mechanisms through which genes lead to the development of specific cellular populations and the pathways through which these do so, is of major importance to the application of new therapies, the early diagnosis of diseases with very late diagnostic rates, and the understanding of the mechanisms of susceptibility genes in the pathogenesis of disease and the molecular stratification of diseases also including those who never receive a clinical diagnosis, are important questions that require innovative approaches and multidisciplinary collaborations.

Social Impact

Despite being relatively rare diseases, systemic autoimmune diseases in conjunction reach about 5% of the population, particularly young and middle-aged women. Immune-mediated diseases affect the complete sphere of diseases, from all organs and systems where an inflammatory process is taking place. Many patients remain several years without a diagnosis and are therefore not treated with new biological drugs, while it is molecularly evident that they do have abnormalities in their immune system cellular patterns of the transcriptome. Earlier diagnosis and proper treatment are some of the social goals my group has. Possibility of predicting treatment responses will be of major importance to initiate the correct therapy and early to avoid organ damage.

Prof Alarcón-Riquelme has trained over 15 PhD students and a large number of postdocs. Her group is composed of 3 senior researchers (Guillermo Barturen, Elena Carnero and Concepción Marañón), each co-supervising PhD and masters students and 5 PhD students. Dr Alarcón-Riquelme is the PI of a Marie Sklodowska Curie predoctoral network called SIGNATURE co-coordinated by Dr Concepción Marañón.

Internacionalization

Dr Alarcón-Riquelme has coordinated a European Innovative Medicines Initiative (IMI-JU) funded project known as PRECISESADS (2014-2019) with the participation of the pharma industry and up to 20 academic centers around Europe with a budget of 22M€.

In this study, through the molecular reclassification of systemic autoimmune diseases the group identified new genetic loci involved in inflammation, and groups of individuals who shared molecular signatures, despite having different clinical diagnoses.

The results of this work are now part of the applied personalized medicine research line (SL3). Here, Prof. Alarcón-Riquelme coordinates a major study, 3TR (2019-2026), the largest in the topic of immunology funded by the IMI-JU and major pharmaceutical companies with a budget of 80M€ where 7 immune-mediated diseases are being prospectively studied and analyzed for the mechanisms of response and non-response to treatments.

Dr Alarcón has also a separate collaboration with Astra Zeneca to sequence the genome of several systemic autoimmune and inflammatory diseases and determine proteome modifications that may help identify novel therapeutic targets. Dr Alarcón received recently funding from the Lupus Research Alliance from the United States to perform single cell analyses of responses and non-response to treatments in SLE in paired blood and tissues of active patients. Various collaborations are ongoing with Latin America. Focusing on publications in D1.

Activities to Strengthen the Strategic Line

Promote senior researchers in the group to apply for national, regional, and European grants, including ERC grants. Increase contacts with the pharmaceutical industry and with international collaborators in the areas of immune-mediated diseases. Obtain new European funding. Continue with the training of PhD students and postdocs. Keep the level of MdM guarantor.

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