Decay accelerating factor (DAF, CD55) is a member of the complement-regulatory protein family that protects cells from attack by autologous complement proteins. Recently DAF was identified as a negative regulator of adaptive immune responses. Furthermore, Daf1 deficiency was shown to exacerbate lupus, myasthenia gravis and experimental autoimmune encephalomyelitis (EAE) in animal models. We found that DBA/2 mice, which are resistant to induction of systemic autoimmunity, have higher expression of Daf1 compared with lupus-prone strains (NZB, NZW, MRL). Induction of mercury-induced autoimmunity (HgIA) in B10.S mice decreases Daf1 mRNA levels and cell surface expression on CD4 T cells. Cell sorting identified CD4 CD44hi T cells from HgIA mice as having the lowest level of Daf1, and this was associated with elevated IL- 4;a marker of active disease in this model. Although primary control of Daf1 protein expression appears to be at the level of transcription, we found that the differential expression between NZB and DBA/2 mice was not from Daf1 gene and promoter polymorphisms. Further characterization of the Daf1 promoter revealed positive and negative regulatory regions, and basal transcriptional activity that requires functional cooperation of Sp1-binding sites. We hypothesize that Daf1 plays a critical role in the adaptive immune response, particularly of CD4 T cells, and that low endogenous expression of Daf1 predisposes to autoimmunity.
The specific aims of this application will address the following:- 1) We will use spontaneous models of systemic autoimmunity to define the relationship between reduced Daf1 expression and the development of systemic autoimmunity, 2) We will use viral and non-viral gene delivery systems to ask if manipulation of the level of Daf1 influences expression of systemic autoimmunity, 3) We will examine what regulates expression of Daf1, and test the hypothesis that regulation of Daf1 expression in autoimmunity is due to mechanisms regulating the transcriptional activity of Sp1. Experimental confirmation of a role for Daf1 in regulating lymphoid cell activity, and development of systemic autoimmunity, will contribute significantly to our understanding of the autoimmune disease process and aid in the development of novel therapeutic interventions. Project Narrative: The complement regulatory protein decay accelerating factor (DAF) is hypothesized to play a protective role in regulating lymphoid cell activity and development of systemic autoimmunity. This project will use gene therapy to determine if increasing the level of expression of Daf1 in autoimmune prone mice offers a defense against autoimmunity.
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|Pollard, K Michael; Hultman, Per; Toomey, Christopher B et al. (2012) Definition of IFN-?-related pathways critical for chemically-induced systemic autoimmunity. J Autoimmun 39:323-31|
|Cauvi, David M; Toomey, Christopher B; Pollard, K Michael (2012) Depletion of complement does not impact initiation of xenobiotic-induced autoimmune disease. Immunology 135:333-43|
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