IL17A augments autophagy in Mycobacterium tuberculosis-infected monocytes from patients with active tuberculosis in association with the severity of the disease.
Accordingly, we examined the impact of individual versus combined neutralization of TNF-α and IL-17A in a mouse model of rheumatoid arthritis (collagen-induced arthritis) and the concomitant susceptibility to infections that are likely to manifest as side effects of blocking these cytokines (oral candidiasis or tuberculosis).
All mice showed strong antibody responses to the InsB protein, and splenocytes stimulated with InsB showed strong IFN-γ and IL-17 responses and a weak IL-2 response, all of which have been implicated in disease expression and used for the immunodiagnosis of TB.
As IL-27 limits optimal antimycobacterial protection by inhibiting IL-17A production, blocking of IL-27R-mediated signaling may represent a strategy for improving vaccination and host-directed therapy in tuberculosis.
By analyzing the cellular responses to mycobacterial antigens in patients who had latent tuberculosis with or without filarial infection, we were able to demonstrate that filarial infection coincident with M. tuberculosis infection significantly diminishes M. tuberculosis-specific Th1 (interleukin [IL]-12 and IFN-gamma) and type 17 T helper (Th17; IL-23 and IL-17) responses related to increased expression of cytotoxic T lymphocyte antigen (CTLA)-4 and programmed death (PD)-1.
Impairment in TNF, IL-1β, and IL-17 production upon stimulation with mycobacterial antigens may contribute to the increased susceptibility to M. tuberculosis infection observed in HTLV-1 infected individuals.
In addition, studies on the human macrophage methylation profiles from the patient cohorts indicated that the methylation rate of IL17 family members and related genes were significantly altered in patients with active MTB infections.
In contrast, SNPs in the proinflammatory IL17A and IL17F genes (rs2275913 and rs763780, respectively), found previously to correlate with the disease occurrence in Chinese population, were not significantly associated with tuberculosis in the Croatian population.
It is concluded that 4-1BB has the potential to be used as a biomarker to identify MAIT cells with enhanced IFN-γ and IL-17 responses that might be associated with tuberculosis infection control.
Metabolites from anaerobic bacterial fermentation may, therefore, increase TB susceptibility by suppressing IFN-γ and IL-17A production during the cellular immune response to M. tuberculosis.
Mice immunized with BCG expressing low levels of LTAK63 (rBCG-LTAK63<sub>lo</sub>) showed higher Th1 cytokines and IL-17 in the lungs, and when challenged intratracheally with Mycobacterium tuberculosis displayed a 2.0-3.0 log reduction in CFU as compared to wild type BCG.
Moreover, <i>Mtb</i>-Ag-stimulated PBMCs from TB carrying the C allele produced the lowest levels of IFNG, the highest level of IL17A, and the minimum proliferation indexes as compared to TT TB, suggesting a relationship between the C allele and tuberculosis severity.
Mucosal T-helper cells producing IFN-γ (Th1) and IL-17 (Th17) are important for protecting against tuberculosis (TB), but the mechanisms by which DCs generate antigen-specific T-helper responses during Mtb infection are not well defined.
Our objective was to analyze, in an in vitro model, the influence of Infliximab on the granulomatous reactions and on the production of antigen-specific cytokines (TNF-α, IFN-γ, IL-12p40, IL-10 and IL-17) from beads sensitized with soluble Bacillus Calmette-Guérin (BCG) antigens cultured in the presence of peripheral blood mononuclear cells (PBMC) from TB patients.
Our results show that TB(+)HIV(+) pleurisy results in significantly reduced frequency of CD4(+)IL-17(+)RORC(+)STAT3(+) Th17 cells compared to TB(-)HIV(-)ex vivo (p = 0.0054) and was confirmed in conditioned media studies in vitro (p = 0.0001).
Our results suggest that the TT genotype of IL-17Ars3748067 might be a risk factor for TB in Asians; the A allele, as well as the AG and AA+AG genotypes of the rs2275913 polymorphism, might be protective against TB in Caucasians.
Our studies highlight the potential value of targeting the IL-17-CXCL13 pathway rather than the IFNγ pathway as a new strategy to improve mucosal vaccines against TB.
Overall, our findings demonstrated that the AA genotype from the IL-17Ars2275913 SNP is positively associated with protection to active tuberculosis but related to higher disease severity in the Argentinean population.