Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases

Objective Clinical heterogeneity, a hallmark of systemic autoimmune diseases, impedes early diagnosis and effective treatment, issues that may be addressed if patients could be classified into groups defined by molecular pattern. This study was undertaken to identify molecular clusters for reclassifying systemic autoimmune diseases independently of clinical diagnosis. Methods Unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data on 955 patients with 7 systemic autoimmune diseases and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed up for 6 or 14 months to validate the results and analyze whether or not cluster assignment changed over time. Results Four clusters were identified and validated. Three were pathologic, representing “inflammatory,” “lymphoid,” and “interferon” patterns. Each included all diagnoses and was defined by genetic, clinical, serologic, and cellular features. A fourth cluster with no specific molecular pattern was associated with low disease activity and included healthy controls. A longitudinal and independent inception cohort showed a relapse–remission pattern, where patients remained in their pathologic cluster, moving only to the healthy one, thus showing that the molecular clusters remained stable over time and that single pathogenic molecular signatures characterized each individual patient. Conclusion Patients with systemic autoimmune diseases can be jointly stratified into 3 stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of nonresponse to therapy, marking a paradigm shift in our view of systemic autoimmune diseases

Epidemiology, landscape architecture, “one health,” and innovation: Experience in an amazonian community [Epidemiología, arquitectura paisajista, «una salud» e innovación: Experiencia en una comunidad amazónica]

Estas ideas acerca de la salud y el medio ambiente fueron el fundamento de la propuesta que la Universidad Nacional Mayor de San Marcos (UNMSM) presentó al concurso que el Consejo Nacional de Ciencia y Tecnología de Perú (CONCYTEC) convocó sobre centros de excelencia el 2014 y que dio lugar a la creación del Centro de Investigaciones Tecnológicas, Biomédicas y Medioambientales (CITBM) con dos líneas de investigación: Biotecnología y salud; y Agua, suelo y sociedad, con la misión de contribuir al bienestar y la salud de las poblaciones y la integridad del medio ambiente a través del desarrollo de tres estrategias: una alianza efectiva y eficiente entre el Estado, la academia y la empresa; un trabajo interdisciplinario y la promoción de una formación integral del científico y de los profesionales. El proceso de desarrollo de esta iniciativa, que lleva casi cuatro años, ha comenzado a proporcionar evidencias acerca de las bondades de este enfoque.Consejo Nacional de Ciencia, Tecnología e Innovación Tecnológica - Concyte

Gene expression profiling comes closer to the clinic

International audienc

SLE redefined on the basis of molecular pathways

International audienc

Genetics of systemic lupus erythematosus and Sjögrenʼs syndrome

International audienc

Omics studies: their use in diagnosis and reclassification of SLE and other systemic autoimmune diseases

International audienc

Omics studies: their use in diagnosis and reclassification of SLE and other systemic autoimmune diseases

International audienc

Urinary and plasma metabolite differences detected by HPLC-ESI-QTOF-MS in systemic sclerosis patients

International audienc

Concordance of Increased B1 Cell Subset and Lupus Phenotypes in Mice and Humans Is Dependent on BLK Expression Levels

Polymorphisms in the B lymphoid tyrosine kinase (BLK) gene have been associated with autoimmune diseases, including systemic lupus erythematosus, with risk correlating with reduced expression of BLK. How reduced expression of BLK causes autoimmunity is unknown. Using Blk(+/+) , Blk(+/-) , and Blk(-/-) mice, we show that aged female Blk(+/-) and Blk(-/-) mice produced higher anti-dsDNA IgG Abs and developed immune complex-mediated glomerulonephritis, compared with Blk(+/+) mice. Starting at young age, Blk(+/-) and Blk(-/-) mice accumulated increased numbers of splenic B1a cells, which differentiated into class-switched CD138(+) IgG-secreting B1a cells. Increased infiltration of B1a-like cells into the kidneys was also observed in aged Blk(+/-) and Blk(-/-) mice. In humans, we found that healthy individuals had BLK genotype-dependent levels of anti-dsDNA IgG Abs as well as increased numbers of a B1-like cell population, CD19(+)CD3(-)CD20(+)CD43(+)CD27(+), in peripheral blood. Furthermore, we describe the presence of B1-like cells in the tubulointerstitial space of human lupus kidney biopsies. Taken together, our study reveals a previously unappreciated role of reduced BLK expression on extraperitoneal accumulation of B1a cells in mice, as well as the presence of IgG autoantibodies and B1-like cells in humans