Marta E Alarcón-Riquelme

• MD, PhD
• Head of Department at Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research

Background Interpreting biological system changes requires interpreting vast amounts of multi-omics data. While user-friendly tools exist for single-omics analysis, integrating multiple omics still requires bioinformatics expertise, limiting accessibility for the broader scientific community. Results BiomiX tackles the bottleneck in high-throughpu...

Objective Nongenetic factors influence systemic sclerosis (SSc) pathogenesis, underscoring epigenetics as a relevant contributor to the disease. We aimed to unravel DNA methylation abnormalities associated with SSc through an epigenome‐wide association study. Methods We analyzed DNA methylation data from whole‐blood samples in 179 patients with SS...

Background Phenotypic data comparison is essential for disease association studies, patient stratification, and genotype–phenotype correlation analysis. To support these efforts, the Global Alliance for Genomics and Health (GA4GH) established Phenopackets v2 and Beacon v2 standards for storing, sharing, and discovering genomic and phenotypic data....

This study aimed at defining the role of the B-cell adaptor protein BANK1 in the appearance of age-associated B cells (ABCs) in two SLE mouse models (TLR7.tg6 and Imiquimod-induced mice), crossed with Bank1-/- mice. The absence of Bank1 led to a significant reduction in ABC levels, also affecting other B cell populations. To gain deeper insights in...

Objective Primary antiphospholipid syndrome (PAPS) is a rare autoimmune disease characterized by the presence of antiphospholipid antibodies and the occurrence of thrombotic events and pregnancy complications. Our study aimed to identify novel genetic susceptibility loci associated with PAPS. Methods We performed a genome‐wide association study co...

Background: Systemic autoimmune diseases (SADs) are characterized by internal heterogeneity, overlapping clinical symptoms, and shared molecular pathways. Therefore, they are difficult to diagnose and new tools allowing precise diagnosis are needed. Molecular-based reclassification studies enable to find patterns in a diagnosis-independent way. Obj...

Background Despite therapeutic advancements in rheumatoid arthritis (RA), a significant subset of patients (20-40%) remains unresponsive to current treatments, including biologics and targeted-synthetic DMARDs. A deeper understanding of the molecular impacts of these drugs could pave the way for tailored therapeutic strategies. Objectives 1 To de...

Background Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) are the two highly prevalent, debilitating, and sometimes life-threatening systemic inflammatory autoimmune diseases. The etiology and pathogenesis of RA and SLE are interconnected in several ways, yet there is limited knowledge about the underlying molecular mechanisms. O...

Clinical studies are conducted to better understand the pathological mechanism of diseases and to find biomarkers associated with disease activity, drug response, or outcome prediction. Mass cytometry (MC) is a high-throughput single-cell technology that measures hundreds of cells per second with more than 40 markers per cell. Thus, it is a suitabl...

Objective The management of neuropsychiatric (NP) systemic lupus erythematosus (SLE) is poorly optimised and specific treatment is lacking. The aim of this study was to perform an in-depth investigation of the transcriptome of SLE patients with active central nervous system (CNS) involvement to gain insights into underlying molecular mechanisms and...

Objective Lupus, an autoimmune disease primarily affecting women, is influenced by genetics and the environment. Recent research suggests that epigenetic changes play a role in connecting these factors. In females, a process called X chromosome inactivation (XCI) helps balance X chromosome dosage. However, some X-linked genes escape this process, w...

Objective Current therapeutic management of lupus nephritis (LN) fails to induce long-term remission in over 50% of patients, highlighting the urgent need for more effective drugs. The aim of this study was to investigate the LN transcriptome in depth to gain insights into underlying molecular mechanisms and to identify new potential drug targets f...

Background and Objective Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by persistent inflammation affecting multiple organs, including the intestine. Lupus-derived gut inflammation can alter the epithelial barrier, where millions of commensals have a dynamic interaction with the host immune system. A new feature that see...

Objective Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease with a diverse pathophysiology triggered by the loss of self-tolerance, resulting in inflammation and tissue damage in multiple organs. The use of animal models has been instrumental in advancing our understanding of SLE. The elimination of the requirement for animal model...

Introduction: Current therapeutic management of lupus nephritis (LN) fails to induce long-term remission in over 50% of patients, highlighting the urgent need for additional options. Methods: We analyzed differentially expressed genes (DEGs) in peripheral blood from patients with active LN (n � 41) and active nonrenal lupus (n � 62) versus healthy...

Objectives To unveil biological milieus underlying low disease activity (LDA) and remission versus active systemic lupus erythematosus (SLE). Methods We determined differentially expressed pathways (DEPs) in SLE patients from the PRECISESADS project (NTC02890121) stratified into patients fulfilling and not fulfilling the criteria of (1) Lupus LDA...

Objective The biologic diagnosis of primary Sjögren disease (SjD) mainly relies on anti‐Ro60/SSA antibodies, whereas the significance of anti‐Ro52/TRIM21 antibodies currently remains unclear. The aim of this study was to characterize the clinical, serological, biologic, transcriptomic, and interferon profiles of patients with SjD according to their...

The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigate...

Objective Systemic lupus erythematosus (SLE) is an autoimmune disease resulting in debilitating clinical manifestations that vary in severity by race and ethnicity with a disproportionate burden in African American, Mestizo, and Asian populations compared with populations of European descent. Differences in global and local genetic ancestry may she...

Lupus nephritis (LN) represents one of the most severe complications of systemic lupus erythematosus, leading to end-stage kidney disease in worst cases. Current first-line therapies for LN, including mycophenolate mofetil (MMF) and azathioprine (AZA), fail to induce long-term remission in 60–70% of the patients, evidencing the urgent need to delve...

Introduction Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease that presents a challenge for clinicians. To identify potential biomarkers for diagnosis and disease activity in SLE, we investigated a selected yet broad panel of cytokines and autoantibodies in patients with SLE, healthy controls (HC), and patients with other au...

Recently, a letter to the Editor entitled ‘Testing the Effectiveness of MyPROSLE in Classifying Patients with Lupus Nephritis’ has been submitted by Leventhal et al. to Briefings in Bioinformatics. In this letter, the authors test MyPROSLE, a web application we recently introduced [1], to characterizelupus patients from the molecular point of view....

Fine mapping and bioinformatic analysis of the DDX6-CXCR5 genetic risk association in Sjogrens Disease (SjD) and Systemic Lupus Erythematosus (SLE) identified five common SNPs with functional evidence in immune cell types: rs4938573, rs57494551, rs4938572, rs4936443, rs7117261. Functional interrogation of nuclear protein binding affinity, enhancer/...

Background Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease that leads to significant worsening of quality of life and mortality. The enormous molecular heterogeneity of SLE is reflected in different clinical manifestations, disease progression and also in a different drug efficacy across patients.¹Lupus nephritis (LN) is the most...

Primary Sjogren disease (pSD) is an autoimmune disease characterized by lymphoid infiltration of exocrine glands leading to dryness of the mucosal surfaces and by the production of autoantibodies. The pathophysiology of pSD remains elusive and no treatment with demonstrated efficacy is available yet. To better understand the biology underlying pSD...

Background The diagnosis of primary Sjögren Disease (SjD) is currently based on a combination of clinical, histological and biological findings [1]. Current thinking supports anti-Ro60 antibodies as the most specific serum marker, while the impact of anti-Ro52 remains unclear [2]. Objectives The aim of this study was to characterize the clinical,...

Introduction Systemic lupus erythematosus is an autoimmune disease with multisystemic involvement including intestinal inflammation. Lupus-associated intestinal inflammation may alter the mucosal barrier where millions of commensals have a dynamic and selective interaction with the host immune system. Here, we investigated the consequences of the i...

With Varicella-Zoster Virus (VZV) being an exclusive human pathogen, human induced pluripotent stem cell (hiPSC)-derived neural cell culture models are an emerging tool to investigate VZV neuro-immune interactions. Using a compartmentalized hiPSC-derived neuronal model allowing axonal VZV infection, we previously demonstrated that paracrine interfe...

Background: Meniere Disease (MD) is an inner ear syndrome, characterized by episodes of vertigo, tinnitus and fluctuating sensorineural hearing loss. The pathological mechanism leading to sporadic MD is still poorly understood, however an allergic inflammatory response seems to be involved in some patients with MD. Objective: Decipher an immune...

Objectives: We aimed at investigating the whole-blood transcriptome, expression quantitative trait loci (eQTLs), and levels of selected serological markers in patients with SLE versus healthy controls (HC) to gain insight into pathogenesis and identify drug targets. Methods: We analyzed differentially expressed genes (DEGs) and dysregulated gene...

Objective. The heterogeneity of systemic lupus erythematosus (SLE) can be explained by epigenetic alterations that disrupt transcriptional programs mediating environmental and genetic risk. This study evaluated the epigenetic contribution to SLE heterogeneity considering molecular and serological subtypes, genetics and transcriptional status, follo...

The present review is aimed at describing the main works that have used gene expression to analyze tissue kidney samples of lupus nephritis patients. Most studies used the gene expression arrays, which enormously advanced our knowledge on the possible mechanisms behind lupus nephritis. However, using bulk gene expression platforms, either as arrays...

Mass cytometry (MC) is a powerful large-scale immune monitoring technology. To maximize MC data quality, we present a protocol for whole blood analysis together with an R package, Cyto Quality Pipeline (CytoQP), which minimizes the experimental artifacts and batch effects to ensure data reproducibility. We describe the steps to stimulate, fix, and...

Systemic lupus erythematosus and primary Sjogren's syndrome are complex systemic autoimmune diseases that are often misdiagnosed. In this article, we demonstrate the potential of machine learning to perform differential diagnosis of these similar pathologies using gene expression and methylation data from 651 individuals. Furthermore, we analyzed t...

Objective Anti‐Ro autoantibodies are among the most frequently detected extractable nuclear antigen autoantibodies, mainly associated with primary Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), and undifferentiated connective tissue disease (UCTD). This study was undertaken to determine if there is a common signature for all patients...

Objectives Systemic Lupus Erythematosus is a complex autoimmune disease that leads to significant worsening of quality of life and mortality. Flares appear unpredictably during the disease course and therapies used are often only partially effective. These challenges are mainly due to the molecular heterogeneity of the disease, and in this context,...

SARS-CoV-2 infection can cause an inflammatory syndrome (COVID-19) leading, in many cases, to bilateral pneumonia, severe dyspnea, and in ~5% of these, death. DNA methylation is known to play an important role in the regulation of the immune processes behind COVID-19 progression, however it has not been studied in depth. In this study, we aim to ev...

Sjögren’s disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögren’s cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic ri...

Systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, and Sjögren’s syndrome are four major autoimmune rheumatic diseases characterized by the presence of autoantibodies, caused by a dysregulation of the immune system that leads to a wide variety of clinical manifestations. These conditions present complex etiologies strongly infl...

Background Involvement of the nervous system is a common but poorly understood manifestation of systemic lupus erythematosus (SLE), termed neuropsychiatric SLE (NPSLE). Although studies have reported varying prevalence estimates [1], NPSLE affects at least 20% of patients with SLE within the first years of the disease course [2]. The management of...

Background Lupus nephritis (LN) is one of the most severe organ manifestations of systemic lupus erythematosus (SLE) and constitutes an important cause of morbidity and death among patients with SLE [1]. The associated renal injury, and ultimately damage, is the result of an immune-mediated process which involves leukocytes, immune complexes, compl...

Background Anti-SSA/Ro autoantibodies are among the most frequently detected extractable nuclear antigen autoantibodies and have mainly been associated with primary Sjögren’s syndrome (pSS), systemic lupus erythematosus (SLE) and undifferentiated connective tissue disease (UCTD). Objectives Is there a common signature to all patients expressing an...

This viewpoint article on a forecast of clinically meaningful changes in the management of systemic lupus erythematosus (SLE) in the next 10 years is based on a review of the current state of the art. The groundwork has been laid by a robust series of classification criteria and treatment recommendations that have all been published since 2019. Bui...

Background Type I IFN (IFN-I) is a family of cytokines involved in the pathogenesis of autoimmune and autoinflammatory diseases such as psoriasis. SIDT1 is an ER-resident protein expressed in the lymphoid lineage, and involved in anti-viral IFN-I responses in vivo, through an unclear mechanism. Herein we have dissected the role of SIDT1 in the natu...

Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and ove...

SARS-CoV-2 causes a severe inflammatory syndrome (COVID-19) leading, in many cases, to bilateral pneumonia, severe dyspnea and in ∼5% of these, death. DNA methylation is known to play an important role in the regulation of the immune processes behind COVID-19 progression, however it has not been studied in depth, yet. In this study, we aim to evalu...

Background Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by loss of tolerance and activation of the immune response. Clinical manifestations are heterogeneous and several organs can be affected including skin, joints, central nervous system and kidney. Traditional treatments include the use of hydroxychloroquine, glucoco...

Objectives Systemic Lupus Erythematosus is a complex autoimmune disease that leads to important worsening of the quality of life and significant suffering to those affected. Currently, therapies used are partially inefficient, mainly due to the molecular heterogeneity of the disease, being personalized medicine the big promise for the future of aut...

In cytometry analysis, a large number of markers is measured for thousands or millions of cells, resulting in high-dimensional datasets. During the measurement of these samples, erroneous events can occur such as clogs, speed changes, slow uptake of the sample etc. which can influence the downstream analysis and can even lead to false discoveries....

Objective The effector T cell and B cell cytokine networks have been implicated in the pathogenesis of systemic autoimmune diseases, but the association of these cytokine networks with the heterogeneity of clinical manifestations and immune profiles has not been carefully examined. This study was undertaken to examine whether cytokine profiles can...

American populations are one of the most interesting examples of recently admixed groups, where ancestral components from three major continental human groups (Africans, Eurasians and Native Americans) have admixed within the last 15 generations. Recently, several genetic surveys focusing on thousands of individuals shed light on the geography, chr...

Autoimmune diseases are heterogeneous pathologies with difficult diagnosis and few therapeutic options. In the last decade, several omics studies have provided significant insights into the molecular mechanisms of these diseases. Nevertheless, data from different cohorts and pathologies are stored independently in public repositories and a unified...

Much is said about precision medicine, but its real significance and the possibility of making it a real possibility is far from certain. Several studies in each of the autoimmune diseases have provided important insight into molecular pathways but the use of molecular studies, particularly those looking into transcriptome pathways, have seldom app...

Objective To identify the genetic variants that affect gene expression (expression quantitative trait loci [eQTLs]) in systemic sclerosis (SSc) and to investigate their role in the pathogenesis of the disease. Methods We performed an eQTL analysis using whole‐blood sequencing data from 333 SSc patients and 524 controls and integrated them with SSc...

La presente invención se encuentra dentro del campo de la medicina, y más preferiblemente dentro del campo de la medicina de precisión. Específicamente se refiere a un método para predecir o pronosticar la respuesta al tratamiento con un medicamento del lupus eritematoso sistémico (LES), para el seguimiento de la evolución del tratamiento de un pac...

Much is said about precision medicine, but its real significance and the possibility of making it a real possibility is far from certain. Several studies in each of the autoimmune diseases have provided important insight into molecular pathways but the use of molecular studies, particularly those looking into transcriptome pathways, have seldom app...

The B cell scaffold protein with ankyrin repeats (BANK1) is expressed primarily in B cells and with multiple but discrete roles in B cell signaling, including B cell receptor signaling, CD40-related signaling, and Toll-like receptor (TLR) signaling. The gene for BANK1, located in chromosome 4, has been found to contain genetic variants that are ass...

Despite promising candidates for new therapeutic options in the treatment of systemic lupus erythematosus (SLE), many clinical trials have failed in the past few years. The disappointing results have been at least partly be attributed to trial designs. With the aim of stimulating new developments in SLE trial design, an international open space mee...

Mass cytometry is a powerful tool for deep immune monitoring studies. To ensure maximal data quality, a careful experimental and analytical design is required. However even in well-controlled experiments variability caused by either operator or instrument can introduce artifacts that need to be corrected or removed from the data. Here we present a...

The heterogeneity of SLE is a major limitation when designing clinical trials and understanding the mechanisms of the disease. The analyses conducted before the new technologies for the identification of the single cell transcriptome focused on the detection of molecular patterns such as interferon signature in total blood or through the analysis o...

Background: Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease with diverse clinical manifestations. Although most of the SLE-associated loci are located in regulatory regions, there is a lack of global information about transcription factor (TFs) activities, the mode of regulation of the TFs, or the cell or sample-specific regula...

High amount of polyclonal free light chains (FLC) are reported in systemic autoimmune diseases (SAD) and we took advantage of the PRECISESADS study to better characterize them. Serum FLC levels were explored in 1979 patients with SAD (RA, SLE, SjS, Scl, APS, UCTD, MCTD) and 614 healthy controls. Information regarding clinical parameters, disease ac...

The interaction between genes and environment has a strong influence on gene regulation and the ultimate expression of our genes and proteins. The pathways through which these interactions occur require the activation of mechanisms that open or close chromatin, activate or deactivate promoters and enhancers, and suppress or promote the expression o...

American populations are one of the most interesting examples of recently admixed groups, where ancestral components from three major continental human groups (Africans, Eurasians and Native Americans) have admixed within the last 15 generations. Recently, several genetic surveys focusing on thousands of individuals shed light on the geography, chr...

Whole blood is often collected for large‐scale immune monitoring studies to track changes in cell frequencies and responses using flow (FC) or mass cytometry (MC). In order to preserve sample composition and phenotype, blood samples should be analyzed within 24 h after bleeding, restricting the recruitment, analysis protocols, as well as biobanking...

Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study we identified vast coordinated hypomethylation and overe...

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and multiple organ involvement in individuals under 21 years following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To identify genes, pathways and cell types driving MIS-C, we sequenced the blood transcriptomes of MIS-C cases, pediatr...

One of the most challenging objective for clinical cytometry in prospective multicenter immunomonitoring trials is to compare frequencies, absolute numbers of leukocyte populations and further the mean fluorescence intensities of cell markers, especially when the data are generated from different instruments. Here, we describe an innovative standar...

IgM antibodies against phosphorylcholine (anti-PC) and malondialdehyde (anti-MDA) may have protective properties in cardiovascular and rheumatic diseases. We here compare these antibodies in systemic rheumatic conditions and study their properties. Anti-PC and anti-MDA was measured using ELISA in patients with SLE (374), RA (354), Mixed connective...

Antiphospholipid (aPL) autoantibodies are uncommon in systemic autoimmune diseases (SADs). However, the European PRECISESADS study provides the opportunity to better characterize this rare association. The study was composed of 1818 patients with SADs including 453 with systemic lupus erythematosus (SLE), 359 with rheumatoid arthritis (RA), 385 wit...

Objectives The analysis of annotated transcripts from genome-wide expression studies may help to understand the pathogenesis of complex diseases, such as systemic sclerosis (SSc). We performed a whole blood (WB) transcriptome analysis on RNA collected in the context of the European PRECISESADS project, aiming at characterising the pathways that dif...

Background: Approximately 50% of systemic lupus erythematosus (SLE) patients develop nephritis, which is among the most severe and frequent complications of the disease and a leading cause of morbidity and mortality. Despite intensive research, there are still no reliable lupus nephritis (LN) markers in clinical use that can assess renal damage an...

Autoimmune diseases are heterogeneous pathologies with difficult diagnosis and few therapeutic options. In the last decade, several omics studies have provided significant insights into the molecular mechanisms of these diseases. Nevertheless, data from different cohorts and pathologies are stored independently in public repositories and a unified...

Background The analysis of annotated transcripts from genome-wide expression studies data is of paramount importance to understand the molecular phenomena underlying the occurrence of complex diseases, such as systemic sclerosis (SSc). Objectives To perform whole-blood transcriptome and pathway analysis on whole-blood (WB) RNA collected in two coh...

Background Objectives 1. This study, developed within the Innovative Medicines Initiative Joint Undertaking project PRECISESADS framework, aimed to identify specific molecular profiles involved in the enhanced CV-risk present in SLE patients and to analyze the relevance of the sustained positivity for anti-dsDNA on the establishment of their ather...

Background Genome-wide gene expression profiles and pathways analysis may help to discover deregulated processes underlying the pathogenesis of complex diseases or their phenotypic expression. Little or nothing is currently known about pathways associated with disease severity and damage in SSc. Objectives To perform a whole blood transcriptome an...

Background IgM antibodies against phosphorylcholine (anti-PC) and malondialdehyde (anti-MDA) may have protective properties in both atherosclerosis and rheumatic disease, especially anti-PC. Low levels of IgM anti-PC is associated with SLE itself and also with atherosclerotic plaques ¹ and with being a non-responder to biologics in RA. ¹ We determi...

Systemic Autoimmune Diseases (SADs) are characterized by dysfunction of the immune system, which cause damage in several tissues and organs. Among these pathologies are systemic lupus erythematosus, systemic sclerosis or scleroderma, Sjögren’s syndrome, rheumatoid arthritis, the primary antiphospholipid syndrome, mixed connective tissue disease, an...

Background: Pathogenesis and aetiology of systemic sclerosis (SSc) are currently unclear, thus rendering disease prognosis, diagnosis and treatment challenging. The aim of this study was to use paired skin biopsy samples from affected and unaffected areas of the same patient, in order to compare the proteomes and identify biomarkers and pathways w...