Sle1 on murine chromosome 1 and SleS on murine chromosome 7 represent 2 of the strongest loci for lupus in the NZM2410 mouse model. Whereas normal (B6)mice engineered to have Sle1 alone exhibit mild lupus, normal mice engineered to bear both loci develop severe lupus. Hence, B6, B6.Sle1z and B6.Sle1z.Sle3z congenic strains capture 3 distinct stages of disease development in lupus, reminiscent of the stages seen in human lupus development. More recently, we have documented that B-cells in these mice exhibit a progressive activation of multiple signaling pathways, including the AKT/mTOR axis, various MARK pathways, NFkB, STATS and STATS, and various Bcl-2 family members, with the levels of activation correlating well with disease severity. We have also learned that the candidate gene for the strongestsub- locus within Slelz, SLAM/Ly108, functions in a B-cell intrinsic fashion to breach early B-cell tolerance. Though the culprit genes for SleSz remain unknown, it is apparent that SleSz impacts the function of DCs and B-cells intrinsically. Based on these observations, we propose 3 Aims.
Aim 1. To ascertain if the signaling pathways upregulated in Slelz B-cells are the direct consequence of chronic stimulation by autoantigens and/or polymorphic differences between the normal and lupus- associated alleles/isoforms of Ly108. We will ascertain how chronic BCR stimulation, as well as the lupus- associated Ly108.1 and the """"""""normal"""""""" Ly108.2 isoforms of Sle1b/SLAM, might contribute to the signaling fingerprints observed in Slelz B-cells.
Aim 2. To distinguish between the B-cell intrinsic versus DC-dependent molecular mechanisms through which SleSz might contribute to B-cell activation in lupus. In addition to determining how SleSz affects B-cell signaling intrinsically, we will also elucidate the cellular and molecular mechanisms that may explain why lupus DCs may be better at """"""""helping"""""""" B-cells makeautoantibodies.
Aim 3. To ascertain the degree to which B-cell intrinsic activation of the AKT axis, or STATS (or other axes, where indicated) is necessary for the lupus phenotypes seen in B6.Slelz.SleSz mice. By ablating or hyper- expressing these molecules in a B-cell intrinsic fashion, we will ascertain how the activation of these 2 pathways in B-cells might contribute to lupus in B6.Slelz.SleSz congenic mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center (P50)
Project #
5P50AR055503-03
Application #
7941908
Study Section
Special Emphasis Panel (ZAR1)
Project Start
2009-09-01
Project End
2012-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
3
Fiscal Year
2009
Total Cost
$293,944
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Type
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Strauß, Romy; Rose, Thomas; Flint, Shaun M et al. (2017) Type I interferon as a biomarker in autoimmunity and viral infection: a leukocyte subset-specific analysis unveils hidden diagnostic options. J Mol Med (Berl) 95:753-765
Orme, Jacob J; Du, Yong; Vanarsa, Kamala et al. (2016) Heightened cleavage of Axl receptor tyrosine kinase by ADAM metalloproteases may contribute to disease pathogenesis in SLE. Clin Immunol 169:58-68
Du, Yong; Wu, Tianfu; Zhou, Xin J et al. (2016) Blockade of CD354 (TREM-1) Ameliorates Anti-GBM-Induced Nephritis. Inflammation 39:1169-76
Huang, Qi-Quan; Perlman, Harris; Birkett, Robert et al. (2015) CD11c-mediated deletion of Flip promotes autoreactivity and inflammatory arthritis. Nat Commun 6:7086
Solow, Elizabeth Blair; Vongpatanasin, Wanpen; Skaug, Brian et al. (2015) Antinuclear Antibodies Are Associated With All-Cause Mortality and Cardiovascular Outcomes in the General Population. J Am Coll Cardiol 65:2669-2670
Arriens, Cristina; Hynan, Linda S; Lerman, Robert H et al. (2015) Placebo-controlled randomized clinical trial of fish oil's impact on fatigue, quality of life, and disease activity in Systemic Lupus Erythematosus. Nutr J 14:82
Min, So-Youn; Yan, Mei; Kim, Sang Bum et al. (2015) Green Tea Epigallocatechin-3-Gallate Suppresses Autoimmune Arthritis Through Indoleamine-2,3-Dioxygenase Expressing Dendritic Cells and the Nuclear Factor, Erythroid 2-Like 2 Antioxidant Pathway. J Inflamm (Lond) 12:53
Davis, Laurie S (2015) BiP, From Putting Out Fires to Fanning the Flames in Rheumatoid Arthritis. Arthritis Rheumatol 67:1147-50
Xiao, Feng; Waldrop, Shar L; Bronk, Steve F et al. (2015) Lipoapoptosis induced by saturated free fatty acids stimulates monocyte migration: a novel role for Pannexin1 in liver cells. Purinergic Signal 11:347-59
Ireland, Sara J; Monson, Nancy L; Davis, Laurie S (2015) Seeking balance: Potentiation and inhibition of multiple sclerosis autoimmune responses by IL-6 and IL-10. Cytokine 73:236-44

Showing the most recent 10 out of 42 publications