RESUMO
The role of pro-inflammatory cytokines in systemic lupus erythematosus (SLE) remains somewhat controversial. Several studies have shown increased production of TNF alpha and IL-6 in patients with SLE. Increased production of IL-6, TNF alpha, and IL-1 soluble receptors have also been reported. This finding is provocative because the soluble receptors have the capacity to act as antagonists. Several other inflammatory disorders are also associated with increased production of soluble TNF alpha receptors suggesting that this may be a general compensatory mechanism designed to down-regulate inflammation. The recent identification of an SLE disease susceptibility locus near the TNFR2 locus (TNFR p75) suggested the hypothesis that genetically driven differences in soluble TNFR2 production could play a role in the genetic susceptibility to SLE. We therefore characterized the frequency of a genetic polymorphism in the 3' untranslated region of the TNFR2 gene in Caucasoid SLE patients and geographically matched controls. No difference in the gene frequency of the two base-pair polymorphism in SLE patients compared to controls was found, nor was there any association with any particular clinical phenotype.
Assuntos
Antígenos CD/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Polimorfismo Genético , Receptores do Fator de Necrose Tumoral/genética , Regiões 3' não Traduzidas , Alelos , Estudos de Casos e Controles , Frequência do Gene , Humanos , Fenótipo , Receptores Tipo II do Fator de Necrose TumoralRESUMO
A microsatellite repeat polymorphism was identified in the 3' flanking region of the human ETS1 gene. Sequencing revealed two CA repeat segments in close proximity. Seven different alleles comprising various combinations of CA repeat units were identified in a healthy control population. Because ETS1 plays a role in lymphocyte development and function, apoptosis, and inflammation, we examined whether any of these polymorphisms were associated with a systemic inflammatory condition, systemic lupus erythematosus (SLE). Inheritance of this disease is polygenic and a recent genome-wide screen for SLE susceptibility loci revealed linkage with chromosome 11q14-23, the region in which the ETS1 gene lies. This region has also been identified as a general autoimmune susceptibility region. None of the seven distinct ETS1 alleles appeared statistically more frequently in SLE patients than controls, however, two alleles were associated with particular clinical manifestations. Allele 1 is associated with discoid lesions and allele 7 is associated with vasculitis. While this polymorphism does not directly affect the coding region of ETS1, it may be a marker for overexpression of a particular isoform or inheritance of another polymorphism which does affect function. These data suggest that ETS1 may be involved in the phenotypic expression of systemic lupus erythematosus.
Assuntos
Lúpus Eritematoso Sistêmico/genética , Fenótipo , Polimorfismo Genético/genética , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição/genética , Alelos , Distribuição de Qui-Quadrado , Mapeamento Cromossômico , Primers do DNA/química , Frequência do Gene , Humanos , Lúpus Eritematoso Sistêmico/patologia , Repetições Minissatélites , Dados de Sequência Molecular , Proteína Proto-Oncogênica c-ets-1 , Proteínas Proto-Oncogênicas c-etsRESUMO
Interferon-gamma is a cytokine which is believed to play a role in both the susceptibility and pathogenesis of lupus. To determine whether genetic variants might influence the development of this polygenic autoimmune disease, we analyzed the gene frequency of eight different alleles in controls and patients with SLE. Ninety-nine controls and 136 patients with systemic lupus erythematosus were genotyped for a CA repeat in the first intron of the interferon-gamma gene. There were no statistically significant differences in the allele frequencies between patients and controls suggesting that these polymorphic variants do not influence susceptibility. We then examined whether any of these alleles were associated with specific clinical manifestations. Allele 1 was associated with gastrointestinal lupus while allele 6 was associated with more severe lupus. Allele 2 appeared to be protective for arthritis. This suggests that genetic variation in interferon-gamma expression might influence the disease course.
Assuntos
Interferon gama/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Polimorfismo Genético/genética , Alelos , Baltimore/epidemiologia , Repetições de Dinucleotídeos/genética , Repetições de Dinucleotídeos/imunologia , Predisposição Genética para Doença , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Repetições de Microssatélites/genética , Repetições de Microssatélites/imunologia , Philadelphia/epidemiologiaRESUMO
OBJECTIVES: Systemic lupus erythematosus (SLE) is a polygenic disorder of dysregulated inflammation. Numerous specific candidate genes have been identified and most relate to the handling of immune complexes or antigen presentation. This is consistent with the classic finding of immune complex deposition in affected end organs. We wished to examine combinatorial effects of polymorphic variants of genes involved in immune complex clearance in susceptibility to lupus. METHODS: This study examined the occurrence of polymorphisms in genes which encode proteins known to be involved in immune complex handling and clearance. Each polymorphic variant of a complement protein (C2, mannose binding protein and C4), complement receptor (CR1) or Fc receptor (FcgammaRIIA and FcgammaRIIIA) gene is known to affect function adversely. One hundred and sixty SLE patients and 212 control subjects were genotyped using polymerase chain reaction methods. RESULTS: We found an increasing association of SLE with increasing numbers of gene defects. Combinations of severe defects in FcgammaRIIA and FcgammaRIIIA were particularly deleterious for both African American and Caucasian patients, even though only one defective variant was individually statistically significantly associated with SLE. CONCLUSIONS: The results of the study suggest that genes may interact in ways that either synergize or modify the effect of a single genetic effect and imply that association studies must be interpreted within the genetic background of the populations.
Assuntos
Complexo Antígeno-Anticorpo/metabolismo , Lúpus Eritematoso Sistêmico/genética , Polimorfismo Genético , População Negra , Proteínas do Sistema Complemento/genética , Feminino , Frequência do Gene , Humanos , Modelos Logísticos , Lúpus Eritematoso Sistêmico/etnologia , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Razão de Chances , Reação em Cadeia da Polimerase , Estudos Prospectivos , Receptores de IgG/genética , População BrancaRESUMO
Quantitation of cytokine production is a valuable adjunct to standard immunologic assays in defining several pathologic processes. Nevertheless, there is little agreement about which tissues should be assayed, which type of assay should be performed, and which stimulation protocol should be used. As these types of assays enter the clinical arena, there is need for standardization. There is also a need to maximize the amount of information which may be derived from a single sample. We compared secreted interleukin 4 (IL-4), IL-2, IL-6, tumor necrosis factor alpha (TNF-alpha), and gamma interferon proteins as measured by enzyme-linked immunosorbent assay with intracellular cytokine production (IL-2 and gamma interferon) as detected by flow cytometry and quantitative competitive PCR for IL-2, IL-4, TNF-alpha, and gamma interferon mRNA and cDNA. Results from unstimulated cells and cells stimulated with phorbol myristate acetate, phytohemagglutinin, and phorbol myristate acetate plus phytohemagglutin were compared. All three methodologies detected significant stimulation of cytokine production. The combination of phytohemagglutinin and phorbol myristate acetate was overall the most-potent stimulus.