Promoter haplotypes of the interleukin-10 gene influence proliferation of peripheral blood cells in response to helminth antigen

Abstract

Since interleukin (IL)-10 is a key mediator of immunosuppression, and immunosuppression is considered an important element of helminth infection, we studied variants of the putative IL-10 gene promoter in 337 individuals from 130 families heavily exposed to infection by the tissue nematode Onchocerca volvulus. As shown by transmission disequilibrium tests, variants of the IL-10 promoter at positions -1082(G/A), -819(C/T), and -592(C/A) in the haplotype of ATA were significantly associated with high peripheral blood cell (PBC) proliferative responses to O. volvulus antigen (OvAg). No associations were observed using phytohemagglutinin-induced PBC proliferation or with qualitative or quantitative phenotypes of onchocerciasis or onchocerciasis-related skin disease. The findings are compatible with the hypothesis that the ATA haplotype causes a decrease in IL-10 production by OvAg-reactive type-1 regulatory T-lymphocytes, thereby alleviating the suppression of other T cells. To our knowledge, this is the first time that an influence of IL-10 promoter variants is shown on the adaptive immune response.

Immunoepidemiological Profiling of Onchocerciasis Patients Reveals Associations with Microfilaria Loads and Ivermectin Intake on Both Individual and Community Levels

“…High levels of IL-10 have been described in onchocerciasis patients presenting the hyporeactive form of infection [7], [16], [17], [24], [45]. To analyze whether IL-10 responses were altered in a-MF individuals, isolated PBMCs were stimulated with either αCD3/αCD28 (Figure 5A) or filarial antigen preparations (Figures 5B–D).…”

“…Humans display a substantial inter-individual variability and the intensity of IL-10 secretion has been linked to inherited polymorphisms [51]. Interestingly, Timman et al determined that certain promoter haplotypes of IL-10 influence filarial-specific proliferation responses of PBMC from O. volvulus individuals [45] which correlates with studies showing that IL-10 neutralization reverses hypo-responsive T cells ex vivo [24]. Although such findings provide insight into genetic predispositions that could determine the outcome of infection, the analysis performed in our current study demonstrated that all infected patients produced more IL-10 upon classical T cell activation or filarial-specific re-stimulation.…”

Sodium fluoride (NaF) causes toxic effects on splenic development in mice

“…TGF-β can promote survival of activated T cells, and enhance Th1 cell differentiation in the presence of IFN-γ in vitro [43]. IL-10, as an immunosuppressive cytokine, has an essential role in the establishment of peripheral tolerance to allergens and protects the host from exaggerated inflammatory responses to pathogens as well as autoimmune diseases [44], and can also inhibit T-cell proliferation and cytokine production [45, 46]. Decreased TGF-β protein expression levels and increased IL-10 protein expression levels imply that T cell and B cell numbers and activities are decreased.…”

Cytokine polymorphisms in the Th1/Th2 pathway and susceptibility to non-Hodgkin lymphoma

“…26,27 In our haplotype analysis, we determined that SNPs either in the promoter or in linkage disequilibrium (LD) with those tested in our study, were associated with risk for NHL. It is notable that the same IL10 promoter haplotypes have been associated with a number of immune-mediated diseases, including progression of HIV infection and autoimmune diseases such as lupus erythematosus, graft-versushost disease following marrow transplantation, and asthma, providing supportive evidence that common genetic variation in the IL10 genes could influence disease susceptibility further.…”

“…The SNPs analyzed in this study were chosen on the basis of prior functional data and previous association studies [15][16][17][18][20][21][22][23][24][25][26][27][28] or to help characterize the haplotype structure of the gene of interest.…”