Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The TNF-like ligand BAFF/BLyS is a potent survival factor for B cells. It binds three receptors: TACI, BCMA, and BR3. We show that BR3 signaling promotes processing of the transcription factor NF-kappaB2/p100 to p52. NF-kappaB2/p100 cleavage was abrogated in B cells from A/WySnJ mice possessing a mutant BR3 gene, but not in TACI or BCMA null B cells. Furthermore, wild-type mice injected with BAFF-neutralizing BR3-Fc protein showed reduced basal NF-kappaB2 activation. BR3-Fc treatment of NZB/WF1 mice, which develop a fatal lupus-like syndrome, inhibited NF-kappaB2 processing and attenuated the disease process. Since inhibiting the BR3-BAFF interaction has therapeutic ramifications, the ligand binding interface of BR3 was investigated and found to reside within a 26 residue core domain. When stabilized within a structured beta-hairpin peptide, six of these residues were sufficient to confer binding to BAFF.
 ...
PMID:BAFF/BLyS receptor 3 binds the B cell survival factor BAFF ligand through a discrete surface loop and promotes processing of NF-kappaB2. 1238 44

A paradigm shift in our understanding of autoimmune disease pathology is underway; B cells are now considered to play a central role in disease pathogenesis. Targeting B cells may prove to be an effective route for the development of novel therapeutics. BLyS, a member of the TNF family of cytokines, is an essential survival factor for B cells. Constitutive BLyS overexpression in mice leads to an autoimmune phenotype similar to lupus nephritis. Clinically, BLyS is elevated in patients with systemic autoimmune diseases including rheumatoid arthritis and systemic lupus erythematosus. BLyS ablation results in a block of B cell development in which mature B cells are absent. BLyS binds to three receptors, BR3, TACI and BCMA. Analysis of the receptors suggests that the major pro-survival signals are mediated by BR3, while TACI is involved in negative signaling. BCMA is required for survival of long-lived plasma cells. BLyS signaling results in upregulation of anti-apoptotic bcl-2 family members. In animal models of autoimmune disease, BLyS antagonists reduce disease severity and delay disease progression. BLyS is an attractive target for antagonism in autoimmune diseases. Multiple approaches are being taken to antagonize BLyS including a fully human antibody and soluble BLyS receptors. These approaches are currently being tested in clinical trials.
 ...
PMID:BLyS--an essential survival factor for B cells: basic biology, links to pathology and therapeutic target. 1528 3

B lymphocyte stimulator (BLyS), also known as B cell-activating factor, is a key positive regulator of B cell homeostasis, and elevated levels of BLyS have been observed in systemic lupus erythematosus (SLE) patients. Given that anti-chromatin auto-antibodies are one of the hallmarks of SLE, we examined the role of BLyS and its receptors in the regulation of anti-chromatin B cells. We demonstrate that exogenous BLyS treatment leads to an increase in B cell numbers, particularly anti-chromatin B cells; yet, their localization in the spleen and auto-antibody production remain unaffected. We also examined transmembrane activator and CAML interactor (TACI), BLyS receptor 3 (BR3) and B cell maturation antigen expression on anti-chromatin B cells before and after receiving T cell help. Interestingly, in the absence of T cell help, TACI expression is greater on immature anti-chromatin B cells compared with immature Tg(-) B cells, whereas BR3 levels are comparable. After receiving T cell help, the anti-chromatin B cells that have differentiated into short-lived plasma cells no longer express BR3 but retain TACI. These data suggest a novel role for TACI in anti-chromatin B cell homeostasis and differentiation.
 ...
PMID:The role of BLyS/BLyS receptors in anti-chromatin B cell regulation. 1736 93

Rabbits are widely used for vaccine development, and investigations of human infectious and autoimmune diseases such as Systemic Lupus Erythematosus (SLE). For these applications, we cloned, sequenced and expressed rabbit B-cell Activating Factor (BAFF), and localized BAFF in cells and tissues of the rabbit immune system. The rabbit homolog of the human BAFF binding site (miniBR3 peptide) within the BAFF-specific receptor BR3 was synthesized. This 26-residue core domain binds to recombinant rabbit BAFF protein. Flow cytometric analyses using purified recombinant rabbit BAFF combined with real-time PCR findings revealed that BAFF detected on peripheral blood B-cells from normal rabbits is probably complexed to BAFF receptors rather than produced by the B-cells. BAFF was detected in developing appendix of young rabbits by immunohistochemical staining suggesting that BAFF plays a role during the period following birth when rabbit B-cell development and pre-immune antibody repertoire diversification and selection is occurring.
 ...
PMID:Expression and localization of rabbit B-cell activating factor (BAFF) and its specific receptor BR3 in cells and tissues of the rabbit immune system. 1912 39

B-cell activation factor belonging to the tumor necrosis factor family (BAFF) is a major contributor to survival of B lymphocytes during development and maturation. A relationship between circulating BAFF levels and disease activity has been reported in patients with the autoimmune disease Systemic Lupus Erythematosus (SLE). Clinical trials targeting BAFF or its receptors are currently in progress. In order to further characterize a rabbit (Oryctolagus cuniculus) model of SLE, we investigated the expression of BAFF and its receptors in non-inbred, pedigreed rabbits derived from breeding and selection based on autoantibody responses. We immunized rabbits related to previous groups that developed autoantibodies and inflammatory responses after immunizations with peptides synthesized on multiple antigen-branched polylysine backbones. Blood and sera collected before immunization and after boosts were used for health monitoring, analyses of serum autoantibody responses by ELISA and immunofluorescence. Peripheral blood mononuclear cells (PBMC) were studied by flow cytometry and were the source of mRNA for quantitative PCR analyses. We hypothesized that BAFF mRNA expression and serum BAFF levels measured indirectly through BAFF receptor binding might increase in autoantibody-producing rabbits. Immunized rabbits developed elevated levels of leucocyte populations, anti-nuclear, anti-dsDNA and other autoantibodies. BR3 mRNA levels in total PBMC decreased and BAFF levels remained low and unchanged in most immunized rabbits. By flow cytometry, percentages of BAFF positive cells decreased. Percentages of transmembrane activator and CAML interactor (TACI) decreased in most rabbits from all the immunized groups. The rabbit is an important model for human autoimmune and infectious diseases, and a high quality draft rabbit genome assembly was recently completed. Human disease models developed in non-inbred pedigreed animals are better able to reflect the complexities of diseases such as SLE with familial patterns of inheritance. Although no consistent pattern of elevated expression of BAFF mRNA or protein was found in the rabbits studied, the data collected and reported here build upon previous data to refine understanding of a rabbit model of SLE.
 ...
PMID:Investigations of a rabbit (Oryctolagus cuniculus) model of systemic lupus erythematosus (SLE), BAFF and its receptors. 2004 Nov 51

The study was promoted to probe into the effect of BLyS on the activity of peripheral B lymphocytes mediated by BLyS receptors in patients with systemic lupus erythematosus (SLE). Thirty new-onset patients having fulfilled the American College of Rheumatology (ACR) revised criteria for the diagnosis of SLE. Twenty age-matched healthy volunteers were recruited for this study. Peripheral blood samples were used to analyze the expression of BLyS protein and related receptors (BR3, TACI), to detect peripheral B cell subpopulations of different phases. Clinical disease activity was evaluated according to the systemic lupus erythematosus disease activity index (SLEDAI-2000). The percentage of CD19(+)CD5(+), CD19(+)CD27(+), CD19(+)CD38(+) and total CD19(+) in the peripheral blood is significantly higher in SLE patients than that in healthy controls (p < 0.01). BLyS concentrations and TACI expression are up-regulated in SLE patients (p < 0.01) while BR3 showed no differences between the two groups (p > 0.05). BLyS concentrations and TACI MFI both showed positive correlation with SLEDAI (r(2) = 0.391, p < 0.001, r(2) = 0.339, p = 0.001), whereas BR3 expression showed no relationship with SLEDAI. The disorders of peripheral B cell subsets maybe reflect the effect of BLyS on the activity of peripheral B lymphocytes mediated by BLyS receptors. The significant up-regulation of BLyS and its receptors, especially TACI may serve as a target for the treatment of SLE.
 ...
PMID:The effect of BLyS on the activity of peripheral B lymphocytes mediated by BLyS receptors in patients with systemic lupus erythematosus. 2333 87

The objective of the present study was to investigate the role of Toll-like receptor (TLR)-9 in B lymphocyte stimulating factor (BLyS)-induced systemic lupus erythematosus (SLE) in mice. The anti-double stranded (ds)DNA antibody titer, levels of complement proteins (C3 and C4), interleukin (IL)-10 and the disease activity [assessed by the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level] were measured. A total of 21 transgenic female mice (aged 8-10 weeks and weighing 30-40 g) expressing the Epstein-Barr virus membrane antigen, BLLF1, were studied. Mice were randomly divided into the control, the BLyS inhibition and the TLR-9 inhibition groups, with 7 mice in each group. Mice in the blank control group received intraperitoneal injections of normal saline, mice in the BLyS inhibition group received intraperitoneal injections of anti-BR3 monoclonal antibody (5,000 ng/day) and mice in the TLR-9 inhibition group received intraperitoneal injections of anti-human TLR-9 antibody (250 ng/day). The treatment regimens continued for 10 days, followed by the collection of peripheral venous blood. The relative levels of TLR-9 mRNA were measured by reverse transcription-quantitative polymerase chain reaction. Furthermore, the BLyS protein concentration and IL-10 levels were measured by ELISA. TLR-9 mRNA, BLyS, IL-10, anti-dsDNA antibody titer, C3, C4, ESR and CRP levels of the blank control group were significantly higher than those of the other two groups (P<0.05). The differences in comparison of these indexes between the BLyS inhibition and TLR-9 inhibition groups were not statistically significant (P>0.05), with the exception of TLR-9 mRNA and BLyS. In conclusion, the TLR-9 signaling pathway may be important for BLyS-induced SLE, and regulation of the inflammatory immune level.
 ...
PMID:Toll-like receptor-9 is involved in the development of B cell stimulating factor-induced systemic lupus erythematosus. 2938 7