MicroRNAs in immune tolerance, autoimmune diseases and cancer

Functional analysis of microRNAs and their target genes in immune tolerance and autoimmunity

Our research aims at understanding the cellular and molecular basis of autoimmune diseases and cancer with a central focus on immune tolerance. Our immune system continuously faces the challenge of protecting the organism from a large variety of invading pathogens and arising tumors without attacking our own tissues. This exquisitely regulated specificity of recognition is achieved through a series of immune tolerance mechanisms that operate in different immune cell subsets, including T and B cells. Defects in immune tolerance constitute the basis for the development of autoimmune diseases, including lupus erythematosus, rheumatoid arthritis, type 1 diabetes and multiple sclerosis. On the other hand, immune tolerance is central to the failure of tumor immunosurveillance and certain cancer immunotherapies. Despite intensive study, the mechanisms underlying immune tolerance are poorly understood. Specifically, the role of microRNAs (miRNAs) in these mechanisms remains largely unexplored. miRNAs are endogenously encoded small RNAs 19–23 nucleotides in length that regulate the expression of their target genes by pairing through imperfect sequence complementarity with their target messenger RNAs (mRNAs) and promoting degradation and/or translational repression of the mRNA. Hundreds of miRNAs are expressed in the immune system, and they have essential roles in regulating the development and function of lymphocytes. Expression-profiling studies have revealed that many miRNAs are dysregulated in lymphocytes from patients with autoimmune diseases, and mouse genetic studies have established causative roles for a few of those miRNAs in regulating autoimmunity. The present project focuses on studying the role of specific miRNAs and their target genes in immune tolerance. Uncovering the mechanisms governing immune tolerance is key for understanding autoimmune diseases and tumor progression and for the development of new therapeutic strategies for the treatment of these diseases.