Association of B Lymphocyte Stimulator (BLyS) gene polymorphisms with systemic lupus erythematosus (SLE)

Professor Lau, Yu Lung   (Principal Investigator (PI))

Professor Lau Wallace Chak Sing   (Co-Investigator)

12

2006-09-01

70000

Association of B Lymphocyte Stimulator (BLyS) gene polymorphisms with systemic lupus erythematosus (SLE)

BLyS, gene polymorphisms, systemic lupus erythematosus

Allergy/Immunology

200607176061

Small Project Funding

2006

Completed

Systemic lupus erythematosus (SLE ) is a complex, multifactorial autoimmune disease that is characterized by the production of various autoantibodies. Dysregulated T cell-dependent induction of autoreactive B cells is considered to play a critical role in the development of SLE (1). The etiology and pathogenesis of SLE remain unclear, but the increased concordance rate in monozygotic twins, familial aggregation and high heritability suggested that the genetic factor is involved in the development of SLE (2-4). BLyS (BAFF, TALL-1, THANK, zTNF-4 and TNFSF-13B) (NCBI gene ID: 10673) is one of the proteins controlling B cell homeostasis, tolerance and malignancy (5-8). It is critical for B cell survival and maturation. Excessive BLyS production has been shown to trigger severe autoimmune diseases in mice resembling SLE and Sjögren’s syndrome (SS) (9-12). BLyS is expressed by various types of cells including neutrophils, monocytes, macrophages, dendritic cells, follicular dendritic cells (FDCs) in germinal centres (GCs), activated T cells, malignant B cells and CD34+ cells from cord blood (13-20). Messenger RNA for BLyS is found in a variety of tissues, and its levels seem to be relatively constant, suggesting that the production rates for BLyS may be quite stable (21). Several pieces of evidence have suggestd that BLyS may be a candidate gene of SLE. BLyS is encoded on human chromosome 13q34 and murine chromosome 8 (5,7,22). As determined by previous genome-wide screening, this region is a susceptible locus of SLE (LOD score = 2.50) (23) Several polymorphisms have been identified in the human BLyS gene (24). These include four single nucleotide polymorphisms (SNPs) in the promoter region, -1283G/A, -871C/T, -514T/C and -353G/C and one SNP in the intron 1, IVS1-45C/G. Transgenic mice overexpressing BLyS have been well-studied (9-11). In general, BLyS overexpression creates a state of immune hyperreactivity that is skewed primarily towards peripheral B cell activation and terminal differentiation, including increased mature B cells in the periphery, enlarged lymphoid organs and spleens, and hypergammaglobulinemia with autoimmune-like manifestations, including anti-DNA antibodies and Ig-deposition in the kidneys leading to glomerulonephritis with proteinuria and decreased lifespan. In addition, a disproportional increase in the MZ B cells, and the presence of rheumatoid factors have been reported (9). Mice models for SLE, which include the NZBWF1 and the Fas-dependent MRL/lpr mice, were found to have elevated levels of circulating BLyS, which increases during disease progression (10, 25). In SLE patients, BLyS level is found to be elevated and fluctuate during the course of SLE (26). Significantly elevated serum BLyS levels correlated with higher levels of anti-dsDNA antibody titers among SLE patients has also been reported (27-28). In addition, the association of SNPs of BLyS, -1283G/A, -871C/, -514T/C, -353G/C and IVS1-45C/G, with SLE and RA has been demonstrated in a case-control study using 156 SLE patients, 221 RA patients and 227 healthy controls (24). It was found that -871TT genotype was over-represented in SLE patients with anti-Sm antibody (P = 0.082) and the -871 T allele was associated with higher BLyS mRNA level (P = 0.010). As pathogenesis of SLE involves the break of tolerance of B cells, whereas BLyS is essential for B cell survival when B cells progress from transient T1 to transitional T2 stages, MZ B cell formation, differentiation of MZ B cells, stable GC formation, proper humoral responses and immunoglobulin switch and T cell response. We hypothesize that BLyS is a candidate gene of SLE and we aimed to identify whether the BLyS gene polymorphisms are associated with SLE and disease phenotypes in our population. We also aimed to investigate the correlation between these BLyS gene polymorphisms and their circulating levels. Reference: Please refer to attachment [06-CRCG-BLyS-Reference.doc]