Amerindian ancestry in Argentina is associated with increased risk for systemic lupus erythematosus.

Previous studies have demonstrated that in admixed populations, West African ancestry is associated with an increased prevalence of systemic lupus erythematosus (SLE). In the current study, the effect of Amerindian ancestry in SLE was examined in an admixed population in Argentina. The Argentine population is predominantly European with approximately 20% Amerindian admixture, and a very small (<2%) contribution from West Africa. The results indicate that Amerindian admixture in this population is associated with a substantial increase in SLE susceptibility risk (Odds Ratio=7.94, P=0.00006). This difference was not due to known demographic factors, including site of collection, age and gender. In addition, there were trends towards significance for Amerindian ancestry influencing renal disease, age of onset and anti-SSA antibodies. These studies suggest that populations with Amerindian admixture, like those with West African admixture, should be considered in future studies to identify additional allelic variants that predispose to SLE.

Both risk alleles for FcgammaRIIA and FcgammaRIIIA are susceptibility factors for SLE: a unifying hypothesis.

The aim of this study was to analyze in families with SLE for the presence of linkage and the structure and transmission of haplotypes containing alleles for the low-affinity Fcgamma receptors. The Fcgamma receptor polymorphisms FcgammaRIIA-131R/H, FcgammaRIIIA-176F/V and FcgammaRIIIB-NA1/2 and a polymorphism in the FcgammaRIIB gene were genotyped with RFLP, allele-specific PCR or pyrosequencing. Individual SNPs and haplotypes were tested for linkage in multicase families and for association using contingency tables, transmission disequilibrium test and affected family-based control groups in Swedish and Mexican single-case families. No linkage or association could be detected using the FcgammaR polymorphisms in the multicase families. However, an association was found for both FcgammaRIIA-131R and IIIA-176F alleles in the single-case families, but not for IIIB or IIB. Allelic association to SLE was found for a haplotype that included both risk alleles, but not in haplotypes where only one or the other was present. We propose that FcgammaRIIA-131R and FcgammaRIIIA-176F are both risk alleles for SLE transmitted primarily, but not exclusively on a single major haplotype that behaves functionally in a situation similar to that of compound heterozygozity.

Association analysis with microsatellite and SNP markers does not support the involvement of BCL-2 in systemic lupus erythematosus in Mexican and Swedish patients and their families.

We have described suggestive linkage between microsatellite markers within the cytogenetic region 18q21-23 and SLE, a region where linkage with other autoimmune diseases has also been detected. The Bcl-2 gene located within this region, is a candidate gene because of its role in apoptosis, a physiological mechanism that could be deregulated in autoimmune disease. Furthermore, several studies have found abnormalities of Bcl-2 expression in SLE patients. We therefore sought to determine if the Bcl-2 gene is involved in SLE by studying members of a large cohort of Mexican SLE patients (n = 378) and 112 Swedish simplex families. Using a microsatellite marker and two single nucleotide polymorphisms located within the gene, we were unable to detect association between Bcl-2 and SLE in either population. We also tested whether combinations of alleles of the Bcl-2 and IL-10.G microsatellites would increase the risk for SLE. Our results do not support such hypothesis. Our findings suggest that linkage between SLE and the 18q21-23 region is due to a gene other than Bcl-2.

Frontiers of SLE: review of the 5th International Congress of Systemic Lupus Erythematosus, Cancun, Mexico, April 20-25, 1998.

OBJECTIVE: To review the recent advances in clinical and experimental research in systemic lupus erythematosus (SLE). METHODS: Review of the 5th International Congress of SLE that took place in Cancun, Mexico, on April 20-25, 1998. RESULTS: The main topics presented at the conference are summarized. These include new findings about the genetics of SLE due to fine mapping of the patients' genes and lupus mouse models, the nucleosome as a major autoantigen in SLE, serving as an immunogen for pathogenic T helper and B cells and contributing to the development of lupus nephritis, abnormalities of apoptosis as a cause of SLE, and apoptotic mechanisms as a cause of autoimmunization. Other topics included the pathophysiologic role of anti-endothelial cell antibodies in lupus with central nervous system involvement, vasculitis, the thrombotic diathesis associated with the antiphospholipid syndrome, induction of endothelial cell apoptosis and its regulation by the idiotypic network, the penetration of antinuclear antibodies to the cytoplasm and nucleus and the subsequent interaction with cellular organelles, and new aspects in the antiphospholipid syndrome, including animal models of the disease and the importance of antibodies to beta-2-glycoprotein-I and prothrombin. Advances in the clinical aspects of SLE included clinical manifestations, diagnosis, pregnancy and neonatal SLE, infections, hormones, and treatment. Additionally, four "Lectures of A Lifetime," entitled (1) What causes lupus? (2) From natural autoimmunity to autoimmune disease; (3) The idiotypic network and SLE; and (4) Late-stage morbidity and mortality in SLE-the role of accelerated atherosclerosis were presented. CONCLUSIONS: Recent advances provide new insights into the pathogenesis of SLE, as well as hope for novel therapeutic modalities and diagnostic measures. These offer the possibility of improving life quality and decreasing mortality from the disease and its complications.

Genetic analysis of the contribution of IL10 to systemic lupus erythematosus.

OBJECTIVE: To study the contribution of the IL10 gene to the susceptibility to systemic lupus erythematosus (SLE). METHODS: Analysis by fluorescent-semiautomated genotyping of a dinucleotide repeat located in the promoter region of the IL10 locus (microsatellite G). RESULTS: No significant difference was found in the frequencies of the microsatellite alleles of 330 Mexican patients with SLE compared to 368 controls from the same population. Two-point linkage analyses were carried out using 13 Mexican, 13 Swedish, and 8 Icelandic families with 2 or more cases with SLE. No linkage was revealed between IL10 and SLE, using a variety of parameter settings. CONCLUSION: Our results do not support that the IL10 gene contributes to the susceptibility to SLE in the populations we studied.

A comparison of genome-scans performed in multicase families with systemic lupus erythematosus from different population groups.

Systemic lupus erythematosus is a disease of unknown etiology. Multiple genetic factors are believed to be involved in its pathogenesis. In addition, and due to genetic heterogeneity, these factors and/or their combinations may be different in different ethnic groups, while some might be shared between populations. We have performed genome scans in multicase families from three different population groups, two from Northern Europe, with a high degree of homogeneity, and the third from a recently admixed population of Mexican Mestizos. Although our family material is relatively small, the results presented here show that using family sets from well defined populations are sufficient to detect susceptibility loci for SLE. Our results also reveal the chromosomal regions most likely to contain susceptibility genes for SLE.

Participation of the Bcl-2 and Fas molecules in experimental apoptosis of spleen B lymphocytes.

BACKGROUND: Homeostasis in the immune system is based on equilibrium between rates of cell renewal and cell death. Failure of elimination of undesirable autoreactive B cell clones may lead to autoimmune disorders. OBJECTIVE: To assess the participation of the Bcl-2 and Fas molecules in the regulation of B lymphocyte death. METHODS: We used two strains of mice known to have deficient mechanisms of apoptosis, namely the transgenic C57BL/6-E mu-bcl-2-22 expressing the bcl-2 transgene on B cells, and the C57BL/6-lpr/lpr mutant, lacking the expression of a functional Fas molecule. Both strains develop a systemic lupus erythematosus-like disease with serum autoantibodies and splenomegaly. We induced apoptosis by three different treatments: dexamethasone,gamma irradiation and hyperthermia. The proportion of cells in apoptosis was determined with the TUNEL method. RESULTS: Radiation or hyperthermia induced apoptosis was inhibited more effectively by having the lpr mutation than the proto-oncogene bcl-2, but the latter conferred higher resistance to apoptosis by dexamethasone. CONCLUSIONS: Our findings suggest that the role of molecules regulating cell death may relate to the stimuli used to induced apoptosis, and that both the lpr mutation and the overexpression of the proto-oncogene bcl-2 protect B cells from apoptosis induced by the three treatments tested.

T lymphocyte subsets, suppressor and contrasuppressor cell functions, and production of interleukin-2 in the peripheral blood of rheumatic fever patients and their apparently healthy siblings.

We studied CD4 and CD8 T cell subsets, suppressor cell function, production of IL-2, and immune contrasuppressor cell activity in 21 patients with rheumatic fever (RF), both at the time of their first acute episode and 3 months later (recovery phase). As controls we studied their healthy sibling nearest in age, as well as age- and sex-matched unrelated normal subjects. In the acute phase we found CD4+ T cells to be high, concanavalin A-induced suppression to be low, and production of IL-2 to be significantly decreased, as compared to the normal unrelated controls. The addition of contrasuppressor cells (VV+) to cell cocultures resulted in an increase in proliferation by mononuclear cells (MNC) in response to streptococcal M antigen but not to C carbohydrate antigen. In the recovery phase, CD4+ T cells became normal, CD8+ T cells rose above normal, and the suppressor cell functions (concanavalin-A-induced and spontaneously expanded), as well as the production of IL-2, fell further. Siblings were found to have increased CD8+ T cells and decreased production of IL-2, as compared to the unrelated controls. These findings indicate that important immunoregulatory disturbances occur during the acute phase of rheumatic fever, some of which persist, accentuate, or change during the recovery phase. The findings in siblings could be related either to streptococcal infection or to a familial immunoregulatory aberration.