The central theme of the University of Chicago Autoimmune Center of Excellence (UCACE) is tolerance and adaptive immunity in autoimmune diseases. The UCACE has two over-riding goals. The first is to determine how adaptive autoimmunity evolves and is propagated in situ in autoimmune diseases with specific end organ involvement. We will focus on lupus nephritis (LuN) which is the most common severe manifestation of systemic lupus erythematosus (SLE). Progression to renal failure correlates with tubulointerstitial inflammation (TII) and that the immunological processes associated with TII are intrinsic to the kidney. These processes are not fully reflected in the peripheral blood and murine models of SLE do not mimic the in situ adaptive immune responses of human lupus TII. Therefore, animal models cannot substitute for primary studies in humans. During the last cycle of the ACE, we developed novel methods to study in situ immunity in human tissue. We can now clone in situ expressed antibodies, express these antibodies and characterize the antigens they bind. However, identifying the antigens recognized in situ is not sufficient to understand how those B cells are being selected in situ. As described in the Collaborative and Pilot Projects, we have developed novel computational tools to identify both cognate cell:cell interactions and global patterns of cellular organization in human inflammation. In the Collaborative Project, we will extend these studies to other disease states to establish specific and global mechanisms by which in situ tolerance fails in autoimmunity. The second goal to be pursued by the UCACE is complementary to the first. While the first addresses how autoimmunity is propagated in situ, the second examines the consequences of a loss of tolerance, and autoimmunity, in the development of protective immunity to infection. Surprisingly, SLE patients mount more effective humoral immune responses to influenza vaccination than normal controls. In the Primary Project, we will determine if enhanced protective immunity is a consequence of the broader immunoglobulin repertoire associated with SLE and/or if the cytokine milieu of SLE enables better protective immunity.
The focus of the University of Chicago Autoimmunity is on lupus. Lupus is a severe body-wide autoimmune disease with severe consequences and for which we have few effective therapies. Furthermore, many of these treatments are very toxic. One goal of the UCACE is to better understand lupus which will enable the development of more effective and less toxic therapies.
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