Sle2 on mouse chromosome 4 is a strong recessive locus associated with lupus nephritis in the NZM2410 model. Other groups have identify other SLE-associated loci in the centromeric half of this chromosome. Congenic analysis has showed that Sle2 is associated with B cell hyperactivity resulting in producing of polyclonal IgM antibodies, in vivo and in vitro hyper-responsiveness, increased B7.2 expression, and enlargement of the Bl1 population. Characterization of polycongenic strains combining Sle1, -2. and -3 has shown that Sle2 is necessary for full disease expression, and that, in combination of Sle3, Sle2 results in highly penetrant non-pathogenic hyaline and mesangial renal lesions that might constitute an accelerating factor for lupus nephritis. Using the congenic dissection approach, and following the steps that we are following in the functional and genetic dissection of the role of telomeric chromosome 4 in SLE pathogenesis. To achieve this goal, we have produced a series of 10 sub-congenic strains covering the area. We will use these strains in two specific aims: 1) We will assess whether the various phenotypes associated with Sle2 result from a single or several loci and generate a high resolution genetic map of these loci. The immunological defects and gene expression profile associated with each of these loci will be established. 2) We will determine the contribution of these loci to SLE pathogenesis by combining the corresponding sub-intervals to either Sle3 or the Sle1/Sle3 combination to reconstitute the Sle2/Sle3 or Sle1/Sle2/Sle3 immunopathology, respectively. Preliminary results indicate that the elevated B7.2 expression, but not increased Bl1 compartment, is associated with increased pathogenicity. These experiments are a necessary step towards the identification of the SLE-susceptibility genes on mouse chromosome 4. A high resolution genetic map that leads to the physical map and ultimate cloning of the gene cannot be constructed without a solid evaluation of the number of loci and their associated defects. Finally, the understanding of their relative contribution to the disease process will establish priorities for gene identification.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI039824-07
Application #
6502357
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2001-09-01
Project End
2002-08-31
Budget Start
Budget End
Support Year
7
Fiscal Year
2001
Total Cost
Indirect Cost
City
Dallas
State
TX
Country
United States
Zip Code
75390
Luo, Wei; Mayeux, Jessica; Gutierrez, Toni et al. (2014) A balance between B cell receptor and inhibitory receptor signaling controls plasma cell differentiation by maintaining optimal Ets1 levels. J Immunol 193:909-920
Cuda, Carla M; Misharin, Alexander V; Gierut, Angelica K et al. (2014) Caspase-8 acts as a molecular rheostat to limit RIPK1- and MyD88-mediated dendritic cell activation. J Immunol 192:5548-60
Dozmorov, Igor; Dominguez, Nicolas; Sestak, Andrea L et al. (2013) Evidence of dynamically dysregulated gene expression pathways in hyperresponsive B cells from African American lupus patients. PLoS One 8:e71397
Gutierrez, Toni; Mayeux, Jessica M; Ortega, Sterling B et al. (2013) IL-21 promotes the production of anti-DNA IgG but is dispensable for kidney damage in lyn-/- mice. Eur J Immunol 43:382-93
Cuda, Carla M; Agrawal, Hemant; Misharin, Alexander V et al. (2012) Requirement of myeloid cell-specific Fas expression for prevention of systemic autoimmunity in mice. Arthritis Rheum 64:808-20
Wang, Andrew; Guilpain, Philippe; Chong, Benjamin F et al. (2010) Dysregulated expression of CXCR4/CXCL12 in subsets of patients with systemic lupus erythematosus. Arthritis Rheum 62:3436-46
Gutierrez, Toni; Halcomb, Kristina E; Coughran, Alanna J et al. (2010) Separate checkpoints regulate splenic plasma cell accumulation and IgG autoantibody production in Lyn-deficient mice. Eur J Immunol 40:1897-905
Jacob, Chaim O; Zhu, Jiankun; Armstrong, Don L et al. (2009) Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus. Proc Natl Acad Sci U S A 106:6256-61
Wang, Andrew; Fairhurst, Anna-Marie; Tus, Katalin et al. (2009) CXCR4/CXCL12 hyperexpression plays a pivotal role in the pathogenesis of lupus. J Immunol 182:4448-58
Fairhurst, Anna-Marie; Mathian, Alexis; Connolly, John E et al. (2008) Systemic IFN-alpha drives kidney nephritis in B6.Sle123 mice. Eur J Immunol 38:1948-60

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