No association between E- and L-selectin genes and SLE: soluble L-selectin levels do correlate with genotype and a subset in SLE.

Altered function of selectin glycoprotein adhesion molecules may modulate severity and organ-specific manifestations of autoimmune and inflammatory disease via changes in leukocyte trafficking. Serum concentrations of selectin molecules have been suggested as useful biomarkers in systemic lupus erythematosus (SLE). We identified increased levels of soluble L-selectin (sL-selectin), but not soluble E-selectin (sE-selectin) in 278 European-Caucasian lupus patients compared to 230 healthy siblings (P=0.002). sL-selectin levels were markedly elevated in patients with IgG antiphospholipid autoantibodies (P=0.002), suggesting that perhaps sL-selectin defines a subgroup of lupus with vasculopathy. sL-selectin level was also influenced by two L-selectin polymorphisms: 665C>T, F206L in the epidermal growth factor-like domain (P=0.015) and rs12938 in the 3'-untranslated region (P=0.06). Having shown increased sL-selectin levels in lupus patients, we used genetics to investigate whether this was a secondary phenomena or the result of an underlying genetic mechanism. The inheritance of nine single-nucleotide polymorphisms (SNP) spanning the selectin locus was tested in 523 UK simplex SLE families. No association with SLE, or related phenotypes, was evident with any single SNP, or haplotype in family-based tests of association. Selectin polymorphisms are, therefore, unlikely to be independent factors in SLE susceptibility.

The genetics of systemic lupus erythematosus.

BACKGROUND: There is a genetic predisposition to human systemic lupus erythematosus (SLE). The genes that contribute to susceptibility are, for the most part, unknown. The introduction of new gene mapping techniques has opened the way to explore lupus genetics on a genome-wide basis. METHODS: Microsatellites are simple sequence repeats widely distributed throughout eukaryotic genomes. They exhibit length variation. This polymorphism can be exploited to provide a panoply of genome-wide markers. Thereby, loci linked with lupus have been mapped in lupus-prone mouse strains and in recently published studies in multi-case human families. RESULTS: More than 20 non-MHC (major histocompatibility complex) loci have now been linked with murine lupus. Nine non-MHC loci have been corroborated in human SLE. Some of the mouse intervals are syntenic with human loci raising the tantalizing possibility of common susceptibility genes. Although we await the results of formal gene identification, functional studies in back-cross and congenic analyses indicate that, in the mouse at least, disease genes act at multiple levels in disease development. CONCLUSIONS: A large number of genes are involved in the pathogenesis of SLE. The data also suggest that even the MHC contribution is multiple. Having mapped disease loci, geneticists now face the task of closing down on the actual aetiological alleles and demonstrating how they might operate. This undertaking will add significantly to our understanding of disease development.

Prevalence of CD8+ T-cell expansions in relation to age in healthy individuals.

Clonal CD8+ T-cell expansions have been identified in the peripheral blood of healthy adults and occasionally in children. These expansions are often large, yet their etiology is unknown. This study evaluated the relationship between age and the prevalence of these expansions in a healthy population (n = 147) aged 9 months to 85 years. Expansions were determined using immunofluorescence staining with monoclonal antibodies to different T-cell receptor (TCR)-variable regions. The overall prevalence was 13.6% and increased linearly with age as follows: 0% for 9-month-olds, 2.7% for 4- to 12-year-olds, 13.3% for 20- to 30-year-olds, 20.7% for 35- to 50-year-olds, and 33.4% for 65- to 85-year-olds. Multiple expansions were observed only in the oldest group. Certain TCR-variable regions appeared to be preferentially utilized by these expansions, which suggests a response to a particular antigenic stimulus. Childhood illness and vaccination histories did not provide insight into the etiology of these expansions. Age was the only measured factor that was associated with these expansions.