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A large international team has honed in on the fragment of the complement receptor that decreases the risk for lupus. This has allowed them to offer a plausible explanation for why B cells target certain regions of double-stranded DNA after encountering debris from dying cells.
Zhao J, Giles BM, Taylor RL et al. Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA. Ann Rheum Dise (2014) Published online first Sept. 1. doi:10.1136/annrheumdis-2014-205584. Open access.
Researchers have identified a functional variant in the gene for complement receptor 2 (CR2/CD21) as the explanation for a significantly decreased risk of systemic lupus erythematosus (SLE) in some individuals.
Previously in a mouse model of SLE, the researchers identified CR2 as a candidate gene for SLE susceptibility, due to its products’ unique structural and functional alterations.
Subsequent research showed that a common three single-nucleotide polymorphism (SNP) CR2 haplotype was associated with a 1.54 increased risk for lupus development in some Caucasian and Chinese families affected with lupus. They found another set of SNPs associated with decreased risk for lupus.
In their new study, the researchers fine-mapped the region spanning CR2 in 15,750 subjects from four ancestral groups: European Americans, African Americans, Asians, and Hispanics. Their aim was to identify a possible causal variant or variants for these associations with SLE, and to develop new hypotheses concerning the role of CR2 in disease development.
In three of the four ancestral groups, they found that one allele of rs1876453 in the gene coding for CR2 was associated with a decreased risk for SLE. Stratifying these population-based data by various clinical manifestations of lupus, they found the presence of this allele most strongly associated with reduced levels of highly specific autoantibodies that target double-stranded DNA (dsDNA). These autoantibodies are present in preclinical, active, and severe SLE, are highly specific for SLE, and can predict its onset and exacerbation.
The researchers found that the allele has long-range effects on genes involved in lupus pathogenesis. It alters the formation of multiple DNA-protein complexes in B cells--including one called CTCF, known as the master regulator of chromatin organization, which regulates gene expression.
The allele also increased B cell expression of complement receptor 1 (CR1), which has an inhibitory role in B-cell activation, suggesting a “plausible mechanism” for how it alters susceptibility to SLE.
In people less susceptible to lupus, they propose, the increased expression of CR1 triggered by this allele may help to tolerize dsDNA-specific B cells to apoptotic debris coated with complement, either preventing SLE or helping to modify its course. The researchers predict “broad implications for the management of patients with this disease.”