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Molecular Basis of the Yaa Mutation in Murine SLE

Izui, Shozo, MD

University of Geneva - CMU (Switzerland)

The development of systemic lupus erythematosus (SLE) is a complex process in which many genetic factors play essential roles. A unique mutation has been described in lupus-prone mice. This mutant gene is called Yaa (for Y-linked autoimmune acceleration) since it is located on the male Y chromosome and dramatically accelerates the progression of SLE. Because of its remarkable effect on the development of SLE in lupus-prone mice, the identification of the nature of Yaa is of utmost importance for our understanding of the cellular and molecular mechanisms implicated in human SLE. Based on the results of their research to date, Dr. Izui and his colleagues believe that Yaa plays a double role in SLE: it favors the initiation of the autoimmune response at the beginning of the disease process and, later on, also contributes to the process of autoantibody-mediated tissue injury. In view of the multiple actions of Yaa on various types of immune cells during the development of SLE, they predict that Yaa’s molecular nature is unique. Thus, identification of Yaa’s molecular nature could have a tremendous impact on the development of novel therapeutic strategies in human SLE. 

What this study means for people with lupus: It may seem strange that these researchers are focusing on a male gene, when 90% of people with lupus are women, but it’s not so much what Yaa is that is important as what Yaa ultimately provokes. They are seeking to understand the pathways critically involved in lupus development — and Yaa may provide a unique doorway to that understanding because it likely encodes a protein that regulates the function of B cells and macrophages (immune system cells that play major roles in inflammatory diseases). As a result of this mutation, B cells and macrophages become hyperactive, dramatically accelerating the progression of lupus. Therefore, if they can identify the molecular nature of Yaa, they could then define the critical pathways responsible for lupus development in women. Consequently, it would be possible to design a novel therapeutic agent to down-regulate the activation of the B cells and macrophages implicated in the development of SLE.  

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