No abstract

Objectives-There is an enrichment of immune response genes that are subject to copy number variations (CNVs). However, there is limited understanding of their impact on susceptibility to human diseases. CC chemokine ligand 3 like-1 (CCL3L1) is a potent ligand for the HIV coreceptor, CC chemokine receptor 5 (CCR5), and we have demonstrated previously an association between CCL3L1-gene containing segmental duplications and polymorphisms in CCR5 and HIV/AIDS susceptibility. Here, we determined the association between these genetic variations and risk of developing systemic lupus erythaematosus (SLE), differential recruitment of CD3+ and CD68+ leukocytes to the kidney, clinical severity of SLE reflected by autoantibody titres and the risk of renal complications in SLE.Methods-We genotyped 1084 subjects (469 cases of SLE and 615 matched controls with no autoimmune disease) from three geographically distinct cohorts for variations in CCL3L1 and CCR5.Results-Deviation from the average copy number of CCL3L1 found in European populations increased the risk of SLE and modified the SLE-influencing effects of CCR5 haplotypes. The CCR5 human haplogroup (HH)E and CCR5-32-bearing HHG*2 haplotypes were associated with an increased risk of developing SLE. An individual's CCL3L1-CCR5 genotype strongly predicted the overall risk of SLE, high autoantibody titres, and lupus nephritis as well as the differential Conclusion-CCR5haplotypes HHE and HHG*2 strongly influence the risk of SLE. The copy number of CCL3L1 influences risk of SLE and modifies the SLE-influencing effects associated with CCR5 genotypes. These findings implicate a key role of the CCL3L1-CCR5 axis in the pathogenesis of SLE.

Interleukin-1 beta (IL-1b) exerts a range of inflammatory and immunomodulatory activities that are important in host defense and autoimmune response. The IL-1b gene, located on chromosome 2 (2q13), is polymorphic. The influence of its polymorphism on 355 patients with autoimmune rheumatic diseases was examined. To this effect, 172 patients with rheumatoid arthritis (RA), 114 with systemic lupus erythematosus (SLE), and 69 with primary Sjö gren's syndrome (pSS) were studied. The control group consisted of 392 matched healthy individuals. Genotyping of IL-1b single-nucleotide polymorphisms (SNPs) at positions À511 (C/T) and þ 3953 (C/T) was performed by the polymerase chain reaction-restriction fragment length polymorphism technique. In addition, levels of IL-1b were measured by immunoassay in supernatants of lipopolysaccharide (LPS)-stimulated and nonstimulated peripheral blood monocytes (PBM) obtained from 19 homozygous individuals for the three most common IL-1b likely haplotypes, all belonging to the control group. Allele þ 3953T was protective for SLE (odds ratio (OR) ¼ 0.57, 95% confidence intervals (CI) ¼ 0.34-0.88, P ¼ 0.01) as was the haplotype À511C þ 3953T (OR ¼ 0.43, 95%CI ¼ 0.25-0.74, pc ¼ 0.006). The latter was associated with a lower LPS-stimulated-PBM IL-1b secretion. Results suggest that IL-1b polymorphism influences the susceptibility to acquire SLE in our population. The protective association might be explained by the observed inhibitory effect of IL-1b þ 3953T allele on the secretion of IL-1b under inflammatory circumstances.