Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Effects of Altering Fli1 Levels in Lupus T Cells on Disease Expression and T Cell Function in the MRL/Lpr Mouse Model.
Basher1, Fahmin, Bunni1, Marlene, Amani1, Zainab, Zhang2, Xian, Nowling2, Tamara K.
The Ets factor Fli1 is implicated as a key modulator of lupus disease expression. Over-expressing Fli1 in healthy mice, results in the development of an autoimmune kidney disease similar to that observed in lupus. Lowering the global levels of Fli1 in two lupus mouse models significantly improved disease and prolonged survival. Lowering the levels of Fli1 in hematopoietic cells in MRL/lpr lupus mice resulted in significantly improved kidney disease. The cell type mediating this protective effect is unknown. We have analyzed the effects of reducing Fli1 levels in lupus T cells on disease expression using an adoptive transfer model and on T cell function in kidney infiltration, proliferation and apoptosis assays.
T cells were isolated from spleens of MRL/lpr Fli1+/+ and Fli1+/- mice. Fli1+/+ T cells were transferred into MRL/lpr Fli1+/- mice and Fli1+/- T cells were transferred into Fli1+/+ mice. As a control, Fli1+/+ T cells and Fli1+/- T cells were also transferred into Fli1+/+ and Fli1+/- mice, respectively. All donors and recipients were 7 weeks old. Urine and blood were collected at 2, 4, 8 and 12 weeks after transfer. ELISAs were performed to measure proteinuria and serum anti-GBM, anti-dsDNA and Ig levels. Proliferation was measured by CFSE staining and apoptosis by AnnexinV staining following stimulation with PMA and ionomycin. T cell subsets infiltrating the kidney were analyzed by flow cytometry.
Transferring Fli1+/+ T cells into Fli1+/- mice does not significantly increase the urine albumin levels of the Fli1+/- mice but transfer of Fli1+/- T cells into Fli1+/+ mice decreases the levels of urine albumin compared to controls. Similarly, Fli1+/+ mice that received Fli1+/- T cells had significantly decreased serum IgG levels (p=0.026) but Fli1+/- mice that received Fli1+/+ T cells did not have a significant increase in IgG levels compared to controls. Additionally, MRL/lpr Fli1+/- mice have significantly fewer numbers of total T cells infiltrating the kidney compared to MRL/lpr Fli1+/+ mice at 14 weeks of age (p=0.017). Specifically, MRL/lpr Fli1+/- had both decreased percentages and numbers of CD4+ T cells (p<0.004) and activated/memory CD3+ T cells (p<0.02). However, no significant differences were observed in proliferation or apoptosis between MRL/lpr Fli1+/+ and Fli1+/- T cells.
These results suggest that reducing Fli1 levels in T cells may have specific effects on autoantibody production. Because transferring Fli1+/- T cells into Fli1+/+ mice resulted in reduced urine albumin and serum IgG levels and transferring of Fli1+/+ into Fli1+/- mice did not significantly increase urine albumin and serum IgG levels, it suggests that T cells with reduced Fli1 levels may be playing a regulatory role to suppress Fli1+/+ pathogenic T cells. In addition, the results of the kidney infiltration analyses suggest Fli1 also may play a role in T cell migration, proliferation, apoptosis and/or differentiation. However, our results indicate Fli1 does not significantly affect proliferation or apoptosis of lupus T cells following mitogenic stimulation. The role of Fli1 on T cell differentiation and regulatory function are currently being explored.
To cite this abstract, please use the following information:
Basher, Fahmin, Bunni, Marlene, Amani, Zainab, Zhang, Xian, Nowling, Tamara K.; Effects of Altering Fli1 Levels in Lupus T Cells on Disease Expression and T Cell Function in the MRL/Lpr Mouse Model. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2363