The UTSW-SLE-CORT is focused on translating lessons learned from genetically simplified mouse models to human SLE. Over the past decade, the study of murine lupus has been simplified with the steady replacement of polygenic mouse models of lupus with a series of monogenic mouse models, which greatly simplify the systematic analysis of pathogenic mechanisms leading to SLE. Importantly, these studies have uncovered at least 2 major steps leading to lupus, both genetically encoded. Whereas the first stage is characterized by the presence of anti-nuclear antibodies but not disease, the second stage is marked by the presence of potentially pathogenic autoantibodies and end-organ disease. In the mouse models, the first stage arises as a consequence of polymorphisms in the SLAM family genes, whereas the second stage is driven by genetic loci that encode """"""""hyperactive"""""""" pro-inflammatory DCs. Whereas Project 1 focuses on the molecular basis of the 2 stages using mouse models, Projects 2-4 are translational in nature, focusing on identifying similar stages and pathogenic mechanisms in human SLE. The translational Projects are based on 3 novel observations made by the UTSW-SLE-CORT Pis over the past 2 years: (1) We have succeeded in identifying individuals with """"""""early"""""""" or """"""""incomplete"""""""" lupus (or """"""""ILE""""""""), who fail to meet the minimum requirements for a diagnosis of SLE, reminiscent of some of the mouse models with """"""""early"""""""" lupus; (2) We have already established that certain ethnic subsets of their SLE patients show strong association with particular SLAM family genes, notably Ly108/SLAMF6 and CD84, reproducing the observations in mice; (3) It is also evident that human lupus DCs or IMF-treated DCs are better at helping B-cells produce antibodies, again echoing our findings in mice. Based on these exciting leads, the UTSWSLE-CORT proposes to ascertain the role of SLAM family gene polymorphisms and DC help in driving phenotypic maturation in different stages of human SLE. Besides uncovering the pathogenic mechanisms leading to lupus, these studies may also uncover early markers that best predict disease progression in human SLE. Finally, the basic Project (I) and the proposed DC:B-cell studies have the potential to uncover key molecular mediators of disease, which could potentially pave the way towards novel therapeutic opportunities in SLE. ? ? ? ?
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