Exposure-Response Analyses of the Effects of Venetoclax, a Selective BCL-2 Inhibitor, on B-Lymphocyte and Total Lymphocyte Counts in Women with Systemic Lupus Erythematosus.
Some cytokines and proteins associated with cell survival and proliferation, such as BAFF, APRIL, IL6 and BCL2, have been found to be elevated both in SLE and lymphoma.
The safety, tolerability, and pharmacodynamics of the selective Bcl-2 inhibitor venetoclax (ABT-199) were assessed in women with systemic lupus erythematosus.
Our results indicate that imbalanced STAT5 phosphorylation, which is related to Bcl2 and Ki-67 expression, may confer survival and proliferative advantage to T<sub>con</sub> over aT<sub>reg</sub> and could represent a possible marker of SLE disease severity.
Furthermore, treatment of NZB/NZW mice with ABT-199, a selective oral inhibitor of Bcl-2, prolonged survival and prevented proteinuria and development of TII in a lupus prevention model.
We therefore sought to determine if the Bcl-2 gene is involved in SLE by studying members of a large cohort of Mexican SLE patients (n = 378) and 112 Swedish simplex families.
To determine whether 7 candidate genes, including tumor necrosis factor receptor II, bcl-2, CTLA-4, interleukin-10 (IL-10), CD19, Fcy receptor type IIA (CD32), and IL-1 receptor antagonist, may contribute to susceptibility to systemic lupus erythematosus (SLE) in the Italian population.
To evaluate the clinical impact of this polymorphism, the frequency of bcl-2 polymorphism was investigated in 221 children with insulin-dependent diabetes mellitus (IDDM), 237 adults with autoimmune disease (105 with rheumatoid arthritis, 57 with systemic lupus erythematosus, 55 with Sjögren's syndrome, and 20 others), and 290 healthy Japanese children and adults.
In human SLE, genes of early components of complements as well as many polymorphic genes (including the MHC class II and class III, FcgammaR, mannose-binding protein, IL-6, Bcl-2, and IL-10 genes) have been associated with SLE or LN by population-based case-control or within-case studies.
This raises the possibility that the increased expression of bcl-2 seen in lymphoid cells from SLE patients may be of intrinsic genetic origin rather than being secondary to the auto-reactive process.
Although the occurrence of circulating T lymphocytes with abnormally high bcl-2 expression is not specific for SLE, it is evidence for a dysregulation of lymphocytic programmed cell death in this autoimmune disease.