Autoimmunity

Biography

Biography: José Moreno

Abstract

Understanding the pathogenesis of autoimmune diseases remains one of the major challenges of modern immunology. High-throughput analysis, including the study of the association of genetic variants to disease and the global analysis of gene-expression profiles provide the basis for in depth analysis of the molecular pathogenesis of diseases. We examined global gene expression profiles by immunocompetent cells in healthy (C57BL/6-J and Balb/c-J) and lupus (MRLlpr/lpr) mice by means of Affymetrix GeneChip™ Mouse Genome 430 2.0 microarrays to identify differentially- expressed genes (DEG) and pathways in autoimmunity. Regardless of differences between BOT strains of healthy mice, pathways over-represented in lpr-mice were: positive regulation of immune response, response to interferon-β, cell killing, immune response-regulating signaling pathway, response to interferon-g (GO-biological process); plus: abnormal response to infection, abnormal immune system physiology, abnormal innate immunity, abnormal cytokine secretion, abnormal adaptive immunity (GO-phenotype), among several others. Further analysis by means of CIBERSORTTM revealed that lpr-mice over-represented genes correspond to T follicular helper (Tfh) and plasma cells. By flow cytometry, relative numbers of both CD4+ and CD8+ T cells in the spleen were decreased, whereas B220+ CD5+ cells were greatly increased. Comparing to data from NZB/NZW F1 lupus mice available in public databases, there was a similar increase in plasma cell genes, but BW mice had an increased representation of memory CD4+ cell genes instead of Tfh. Among the most relevant DEGs found in lpr-mice (all of them overexpressed) were cytokines (Il21, Il10, Il4, Ifn-g etc.), chemokines (Ccl8, Ccl2, Ccl3, Ccl4, Cxcl10, Cxcl11, etc.) and their receptors (Ccr1, Ccr2, Cxcr3), costimulatory surface molecules (Cd28, Ctla-4, Pd-1, Icos, Slamf6, Lag3, Btn1a1), signal transduction (Tnk1, Pik3ap1, Grp84, Lat), transcription (Gfi1, E2f) proteins, and many others (Brca1, Brca2). In conclusion, our results suggest, as expected, that murine lupus is a highly complex syndrome in which varying patterns of gene expression, due to different genetic backgrounds yield closely resembling clinical phenotypes of what we know as systemic lupus erythematosus.