ABSTRACT
Lymphotoxin-alpha (LT-alpha or LTA) is an inflammatory cytokine that is involved in the organization and maintenance of the inflammatory process and in the arrangement of cells at the site of inflammation. These features suggest an important role in the development of chronic Chagas' disease, especially the cardiac form. The objective of this study was to evaluate LT-alpha genetics and its biological role in chronic Chagas' disease. A total of 284 subjects were studied. The LT-alpha single-nucleotide polymorphism (+252) was analyzed by the polymerase chain reaction-restriction fragment length polymorphism and expression by enzyme-linked immunosorbent assay in culture supernatants and in individual T lymphocytes by flow cytometry. The risk of developing the cardiac form was 2.8 times higher among carriers of genotype GG and 2.4 times among carriers of genotype GA when compared to subjects carrying genotype AA. Seropositive subjects carrying the G allele produced significantly higher levels of LT-alpha. The cytokine was mainly expressed by CD8(+) T lymphocytes in the absence of any stimulus and after stimulation with the Trypanosoma cruzi antigen. This study provides genetic and biological evidence for an important role of LT-alpha in the development of the cardiac form of Chagas' disease.
Subject(s)
Chagas Cardiomyopathy/genetics , Lymphotoxin-alpha/genetics , Polymorphism, Single Nucleotide , Adult , Aged , Aged, 80 and over , Antigens, Protozoan/immunology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/parasitology , Case-Control Studies , Chagas Cardiomyopathy/epidemiology , Chagas Cardiomyopathy/immunology , Chagas Cardiomyopathy/parasitology , Female , Gene Expression Regulation/genetics , Gene Expression Regulation/immunology , Humans , Lymphotoxin-alpha/immunology , Male , Middle Aged , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , Trypanosoma cruzi/immunologyABSTRACT
TNF-alpha plays an important role in trypanocidal mechanisms and is related to tissue injury. This cytokine has been detected in the heart of human chagasic patients where it is associated with tissue damage. This study investigated whether TNF-alpha levels and the presence of genetic polymorphisms are associated with the presence of T. cruzi infection and/or with the development of the cardiac form in chronic chagasic patients. Genomic DNA of 300 subjects from an endemic area was extracted and analyzed by PCR using specific primers. TNF-alpha was assayed in culture supernatants by ELISA. An association was observed between the absence of the TNF-238A allele and negative serology. Furthermore, seropositive individuals carrying the TNF-238A allele produced significantly higher TNF-alpha levels without stimulation (p=0.04) and after stimulation with LPS (p=0.007) and T. cruzi antigens (p=0.004). The present results suggest that the polymorphism at position -238 influences susceptibility to infection and that this allele is associated with higher TNF-alpha production in seropositive individuals.