6533b82bfe1ef96bd128d75d

RESEARCH PRODUCT

Relevance of gamma interferon, tumor necrosis factor alpha, and interleukin-10 gene polymorphisms to susceptibility to Mediterranean spotted fever.

subject

description

Several studies have demonstrated that cellular immunity plays a critical role in the protective immune response against Rickettsia conorii. Immune CD4+ and CD8+ T cells are both involved in the control of rickettsial infection (38). Perivascular infiltrated CD4+ and CD8+ T lymphocytes, macrophages, and natural killer cells produce chemokines and cytokines that activate endothelial rickettsicidal activities. Infected human cells, including endothelial cells, hepatocytes, and macrophages, activated by gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β), kill intracellular rickettsiae by one or a combination of three mechanisms, involving nitric oxide synthesis, hydrogen peroxide production, and tryptophan degradation (17). Moreover, clearance of rickettsiae requires activated cytotoxic CD8+ T cells, which eliminate the remaining infected cells by inducing apoptosis (26, 41, 42). The acute phase of Mediterranean spotted fever (MSF) is characterized by significantly increased serum levels of IFN-γ, TNF-α, IL-10, and IL-6 compared to the levels found during the convalescent phase of the disease or in healthy controls (10, 40). The IFN-γ levels sharply drop within the second week of the disease, whereas TNF-α, IL-10, and IL-6 gradually decrease, reaching normal levels after the third week of infection (40). The dramatic changes in the cytokine production pattern clearly indicate their role in the immunomodulation of the response against the microorganism, and differences in cytokine production seem to influence the extent and severity of the disease (26). On the other hand, the degree of cytokine expression depends not only on the type and intensity of the stimulation but also on host genetic factors, such as polymorphisms located in coding and regulatory regions of cytokine genes (6). Cytokine single nucleotide polymorphisms (SNPs) are important potential tools for genetic prediction of disease susceptibility (22). This genetic variability might be responsible for different rates of susceptibility to infectious diseases or rates of development of severe complications (28). Associations of TNF-α and/or IL-10 gene polymorphisms with cerebral malaria, mucocutaneous leishmaniasis, lepromatous leprosy, and increased mortality for meningococcus meningitides have been reported by different groups (1, 9, 19, 30, 39). Similar results have been obtained for IL-1 gene cluster (5, 21) and IFN-γ (25, 31) polymorphisms in studies of genetic susceptibility to tuberculosis. In the present study, we aimed at genotyping the SNPs of the promoter regions of TNF-α −308G/A (rs1800629) and IL-10 −1087G/A (rs1800896), −824C/T (rs1800871), and −597C/A (rs1800872) and the IFN-γ T/A SNP at position +874 (rs2430561) in a group of Sicilian patients affected by MSF, taking into account the role that these cytokines might play in the immune response against R. conorii infection (26).