The IL-17A rs2275913 single nucleotide polymorphism is associated with protection to tuberculosis but related to higher disease severity in Argentina.

Mycobacterium tuberculosis (Mtb) causes nearly 10 millions of new tuberculosis disease cases annually. However, most individuals exposed to Mtb do not develop tuberculosis, suggesting the influence of a human genetic component. Here, we investigated the association of the rs2275913 SNP (G → A) from IL-17A and tuberculosis in Argentina by a case-control study. Furthermore, we evaluated in vitro the functional relevance of this SNP during the immune response of the host against Mtb and analyzed its impact on clinical parameters of the disease. We found an association between the AA genotype and tuberculosis resistance. Additionally, within the healthy donors population, AA cells stimulated with a Mtb lysate (Mtb-Ag) produced the highest amounts of IL-17A and IFN-γ, which further support the genetic evidence found. In contrast, within the tuberculosis patients population, AA Mtb-Ag stimulated cells showed the lowest immunological parameters and we evidenced an association between the AA genotype and clinical parameters of disease severity, such as severe radiological lesions and higher bacilli burden in sputum. Overall, our findings demonstrated that the AA genotype from the IL-17A rs2275913 SNP is positively associated with protection to active tuberculosis but related to higher disease severity in the Argentinean population.

Neutrophil elastase treated dendritic cells promote the generation of CD4(+)FOXP3(+) regulatory T cells in vitro.

We have previously shown that neutrophilic elastase converts human immature dendritic cells (DCs) into TGF-ß secreting cells and reduces its allostimulatory ability. Since TGF-ß has been involved in regulatory T cells (Tregs) induction we analyzed whether elastase or neutrophil-derived culture supernatant treated DCs induce CD4(+)FOXP3(+) Tregs in a mixed lymphocyte reaction (MLR). We found that elastase or neutrophil-derived culture supernatant treated DCs increased TGF-ß and decreased IL-6 production. Together with this pattern of cytokines, we observed a higher number of CD4(+)FOXP3(+) cells in the MLR cultures induced by elastase or neutrophil-derived culture supernatant treated DCs but not with untreated DCs. The higher number of CD4(+)FOXP3(+) T cell population was not observed when the enzymatic activity of elastase was inhibited with an elastase specific inhibitor and also when a TGF-ß1 blocking antibody was added during the MLR culture. The increased number of CD4(+) that express FOXP3 was also seen when CD4(+)CD25(-) purified T cells were cocultured with the TGF-ß producing DCs. Furthermore, these FOXP3(+) T cells showed suppressive activity in vitro. These results identify a novel mechanism by which the tolerogenic DCs generated by elastase exposure contribute to the immune regulation and may be relevant in the pathogenesis of several lung diseases where the inflammatory infiltrate contains high numbers of neutrophils and high elastase concentrations.