Overexpression of BclXL in B Cells Promotes Th1 Response and Exacerbates Collagen-Induced Arthritis

Abstract

B cells play a pathogenic or regulatory role in many autoimmune diseases through production of autoantibodies, cytokine production, and Ag presentation. However, the mechanisms that regulate these B cell functions under different autoimmune settings remain unclear. In the current study, we found that when B cells overexpress an antiapoptotic gene, BclXL, they significantly increased production of IFN-γ and enhanced Th1 response. Consistently, Bcl-xL transgenic mice developed more severe and sustained collagen-induced arthritis due to the enhanced Th1 response. The production of autoantibodies in BclXL transgenic mice was comparable to that in wild-type mice. Thus, our results indicate a novel role of BclXL in regulating B cell functions and immune responses. In patients with rheumatoid arthritis, arthritogenic B cells often up-regulate BclXL expression, which may not only render B cells resistant to apoptosis but also alter the ability of the autoreactive B cells to produce cytokines and modulate the inflammatory response. This may have therapeutic implications if BclXL expression can be down-regulated in autoreactive B cells.

HSF1-mediated BAG3 Expression Attenuates Apoptosis in 4-Hydroxynonenal-treated Colon Cancer Cells via Stabilization of Anti-apoptotic Bcl-2 Proteins

“…5C). However, in HSF1-and BAG3-silenced cells, the LC 50 of HNE was reduced to 25 M. Also, treating cells with 45 M HNE for 24 h induced caspase 3 cleavage in both HSF1-and BAG3-silenced cells, but not in the nontransfected or control siRNA-transfected cells (Fig. 5D), confirming that HSF1 siRNA and BAG3 siRNA both sensitize RKO cells to apoptosis to a similar degree.…”

Aberrant Reactive Oxygen and Nitrogen Species Generation in Rheumatoid Arthritis (RA): Causes and Consequences for Immune Function, Cell Survival, and Therapeutic Intervention

“…Similarly, primary murine B cells that are genetically predisposed to overexpress Bcl-x L show elevated production of IFN-g and mediate an enhanced TH1 response. Bcl-x L transgenic mice also develop more severe and sustained collagen-induced arthritis than wild-type mice (314). Finally, an increased number of cells are positive for Bcl-2 in the RA synovium when compared to that of the osteoarthritic synovium where the frequency of Bcl-2 positive cells correlated with the extent of synovial hyperplasia and inflammation (229).…”

Bcl-xL is required for the development of functional regulatory CD4 cells in lupus-afflicted mice following treatment with a tolerogenic peptide

“…Bcl-xL also plays a role in the development, differentiation, and clonal selection of B cells [5,6]. Transgenic expression of Bcl-xL or Bcl-2 in murine B cells was shown to modify the repertoire of B cells and to result in the production of pathogenic antibodies and the development of autoimmune diseases including systemic lupus erythematosus (SLE) and the exacerbation of collagen-induced arthritis [7][8][9]. In contrast, when Bcl-2 was transgenically expressed in T cells, the mice were found to be long-lived and without evidence of autoimmunity, and they were also resistant to the development of collagen-induced arthritis and SLE [10][11][12].…”