Gene Transcription in SLE

The multitude of mechanisms that lead to general break of tolerance and organ pathology in patients with systemic lupus erythematosus (SLE) have challenged both basic immunologists and translational researchers. Our studies in people and mice with SLE have documented molecular mechanisms that account for the opposite production of interleukin 2 and interleukin 17, both of which are being exploited in clinical trials to treat people with SLE. We found that the transcription factor cAMP response element modulator, which accounts for the opposite transcription of the genes encoding for these two cytokines, controls also the expression of ADAM9, a disintegrin metalloproteinase. Early information indicates that ADAM9, a new comer in the field of autoimmunity, controls peripheral autoimmunity and organ inflammation. ADAM9 is expressed at increased levels in peripheral blood lymphocytes, lymphocytes entering tissues and tissue resident cells. We have built the hypothesis that ADAM9 controls systemic autoimmunity and organ damage through distinct molecular mechanisms. Using human cells and tissues and a series of newly constructed mice and novel technology to alter gene expression by delivering gRNA in a cell-targeted manner, we will establish that ADMA9 controls autoimmunity in SLE, that tissue hypoxia further promotes the expression of ADAM9 by cells entering tissues and its expression by tissue resident cells and how ADAM9 is involved in the aberrant tissue growth factor beta cell signaling in SLE T cells. Through this work metaloproteinases are introduced in the field of autoimmunity for the first time. The value of the work is based on the parallel use of human cells and tissues, novel engineered mice and cutting-edge approaches to alter the expression of molecules involved in the pathogenesis of SLE in a highly precise manner.