The purpose of this proposal is to identify the genes responsible for the S/e2 lupus-associated phenotypes in the NZM2410 murine model, and to characterize the mechanisms by which these genes contribute to lupus pathogenesis. Consequently, S/e2, a genetic locus that affects B cell development and function, plays a major role in autoimmune pathogenesis. We have recently identify three independent S/e2 regions, Sle2a, Sle2b, and S/e2c, that affect the size of the B-1a cell pool, but only two of them, S/e2a and Sle2b contribute to autoimmune pathogenesis. S/e2 affects the number of perC B-1acells through multiple mechanisms, which could be mediated independently through each of the three S/e2 loci. Finally, our long-time collaborator Dr. Chandra Mohan (UTSW) has shown that S/e2 mediates a breach of tolerance using the 56R anti-DNA heavy chain transgenic model. Based on these recent results and on the strategy that we have been using to characterize the Sle1 genes, we propose the three following aims to identify the S/e2 genes: 1. To generate high resolution genetic maps of the S/e2a. Sle2b, and S/e2c loci. We will produce B6.S/e2 congenic recombinant sub-strains and screen them for increased perC B-1a cell pool. This process will be iterated until each locus has been mapped to a < 0.5 cM critical interval. In addition, we will monitor the co- segregation of the B-1a phenotype with the contribution to lupus pathogenesis using an interaction mapping approach between each of the S/e2 loci with other SLE susceptibility loci. 2. To characterize the phenotypes associated with each of the 3 S/e2 loci. Concurrent with the genetic mapping effort, we will refine the phenotypic definition of each S/e2 locus.
This aim has the dual goal of elucidating the mechanisms by which these loci contribute to disease mechanisms, and facilitating the selection of candidate genes for Aim 3. To accomplish this goal, we will 1) assign each of the mechanisms by which S/e2 increases the B-1a cell pool to specific S/e2 loci, 2) compare the gene expression profile of perC B-1a cells expressing each S/e2 locus, and 3) determine which of the three S/e2 loci is responsible for the loss of tolerance to nuclear antigens using the 56R model. 3. To identify the genes corresponding to S/e2a. Sle2b, and S/e2c.
Aims 1 and 2 will provide a list of positional and functional candidate genes for each of the S/e2 loci. Sequence and expression polymorphisms between the B6 and the B6.S/e2 congenic strains will be systematically characterized for these genes. The functionality of these polymorphisms relative to B cell functions will be then evaluated between the congenic strains. Congruity between the presence of a functional polymorphism and location within the critical interval will provide strong evidence that the NZM2410 allele of this specific gene is responsible for the corresponding SLE susceptibility phenotype.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI068965-03
Application #
7344836
Study Section
Special Emphasis Panel (ZRG1-HAI-K (08))
Program Officer
Johnson, David R
Project Start
2006-02-15
Project End
2011-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
3
Fiscal Year
2008
Total Cost
$342,998
Indirect Cost
Name
University of Florida
Department
Pathology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Xu, Zhiwei; Morel, Laurence (2015) Contribution of B-1a cells to systemic lupus erythematosus in the NZM2410 mouse model. Ann N Y Acad Sci 1362:215-23
Xu, Z; Croker, B P; Morel, L (2013) The combination of two Sle2 lupus-susceptibility loci and Cdkn2c deficiency leads to T-cell-mediated pathology in B6.Fas(lpr) mice. Genes Immun 14:373-9
Niu, Haitao; Fang, Guoqiang; Tang, Yiting et al. (2013) The function of hematopoietic stem cells is altered by both genetic and inflammatory factors in lupus mice. Blood 121:1986-94
Lantow, Margareta; Sivakumar, Ramya; Zeumer, Leilani et al. (2013) The granulocyte colony stimulating factor pathway regulates autoantibody production in a murine induced model of systemic lupus erythematosus. Arthritis Res Ther 15:R49
Potula, Hari-Hara S K; Xu, Zhiwei; Zeumer, Leilani et al. (2012) Cyclin-dependent kinase inhibitor Cdkn2c deficiency promotes B1a cell expansion and autoimmunity in a mouse model of lupus. J Immunol 189:2931-40
Potula, Hari-Hara S K; Morel, Laurence (2012) Genetic variation at a Yin-Yang 1 response site regulates the transcription of cyclin-dependent kinase inhibitor p18INK4C transcript in lupus-prone mice. J Immunol 188:4992-5002
Zeumer, L; Sang, A; Niu, H et al. (2011) Murine lupus susceptibility locus Sle2 activates DNA-reactive B cells through two sub-loci with distinct phenotypes. Genes Immun 12:199-207
Xu, Zhiwei; Cuda, Carla M; Croker, Byron P et al. (2011) The NZM2410-derived lupus susceptibility locus Sle2c1 increases Th17 polarization and induces nephritis in fas-deficient mice. Arthritis Rheum 63:764-74
Xu, Zhiwei; Potula, Hari-Hara S K; Vallurupalli, Anusha et al. (2011) Cyclin-dependent kinase inhibitor Cdkn2c regulates B cell homeostasis and function in the NZM2410-derived murine lupus susceptibility locus Sle2c1. J Immunol 186:6673-82
Xu, Zhiwei; Vallurupalli, Anusha; Fuhrman, Christopher et al. (2011) A New Zealand Black-derived locus suppresses chronic graft-versus-host disease and autoantibody production through nonlymphoid bone marrow-derived cells. J Immunol 186:4130-9