Wu B, Huang C, Kato-Maeda M et al.IL-9 is associated with an impaired Th1 immune response in patients with tuberculosis. Clin Immunol 126:202-210

ArticleinClinical Immunology 126(2):202-10 · March 2008with9 Reads
DOI: 10.1016/j.clim.2007.09.009 · Source: PubMed
Although a defective Th1 response has been demonstrated in patients infected with Mycobacterium tuberculosis (Mtb), the mechanisms leading to this defect are not well understood. To study the immune response to Mtb infection, we stimulated PBMC from individuals with latent tuberculosis infection (LTBI) or patients with tuberculosis (TB) with the Mtb specific antigen early secretory antigenic target-6 (ESAT-6). mRNAs for a panel of cytokines were measured using quantitative real-time PCR (qPCR). PBMC from TB patients exhibited low levels of IFN-gamma, IL-12alpha, IL-12beta, and IL-23 mRNA but high levels of IL-9 mRNA. Sera from TB patients blocked the differentiation and function of dendritic cells from TST negative (TST-) donors. Exogenous IL-9 reduced IFN-gamma mRNA expression in PBMC from LTBI by 30% (n=4) and neutralization of IL-9 restored the IFN-gamma mRNA expression in PBMC from TB patients by 66% (n=8). Thus, increased expression of IL-9 may contribute to the development of TB.
    • "Recently, Romagnoli et al. demonstrated that ESAT-6 is involved in the ability of Mtb to escape the human DC phagosome [14]. Also, ESAT-6 is known to induce the PBMC of tuberculosis-bearing patients to produce IFN-γ and chemokines [15]–[16]. Furthermore, recombinant DNA vaccine encoding ESAT-6 elicits a strong Th1 response in mice [17]. Vaccination with a fusion protein composed of ESAT-6 and Antigen 85B, a protein belonging to the Mtb Antigen 85 complex [18], activates DCs and Th1/Th17 cell responses in mouse models [19]–[21]. "
    [Show abstract] [Hide abstract] ABSTRACT: The limited efficacy of the BCG vaccine against tuberculosis is partly due to the missing expression of immunogenic proteins. We analyzed whether the addition to BCG of ESAT-6 and HspX, two Mycobacterium tuberculosis (Mtb) antigens, could enhance its capacity to activate human dendritic cells (DCs). BCG showed a weak ability to induce DC maturation, cytokine release, and CD4(+) lymphocytes and NK cells activation. The addition of ESAT-6 or HspX alone to BCG-stimulated DC did not improve these processes, whereas their simultaneous addition enhanced BCG-dependent DC maturation and cytokine release, as well as the ability of BCG-treated DCs to stimulate IFN-γ release and CD69 expression by CD4(+) lymphocytes and NK cells. Addition of TLR2-blocking antibody decreased IL-12 release by BCG-stimulated DCs incubated with ESAT-6 and HspX, as well as IFN-γ secretion by CD4(+) lymphocytes co-cultured with these cells. Moreover, HspX and ESAT-6 improved the capacity of BCG-treated DCs to induce the expression of memory phenotype marker CD45RO in naïve CD4(+) T cells. Our results indicate that ESAT-6 and HspX cooperation enables BCG-treated human DCs to induce T lymphocyte and NK cell-mediated immune responses through TLR2-dependent IL-12 secretion. Therefore ESAT-6 and HspX represent good candidates for improving the effectiveness of BCG vaccination.
    Full-text · Article · Oct 2013
    • "These new findings further underscore a link between IL-9 and IL-17 and suggest that this link is particularly strong in patients with unstable angina, potentially reflecting up-regulation of IL-9R in T cells from these patients. However, IL-9 may also possess anti-inflammatory properties by enhancing the function of regulatory T cells [22] and by suppressing IL-12 production in certain antigen presenting cells [29]. Moreover, of relevance to stroke, IL-9 has been shown to protect cortical neuron from cell death by anti-apoptotic mechanisms [30], and further studies are clearly needed to elucidate the net effect of IL-9 levels in atherosclerotic disorders. "
    [Show abstract] [Hide abstract] ABSTRACT: Atherosclerosis is a chronic inflammatory disorder that involves a range of inflammatory mediators. Although interleukin (IL)-9 has been related to inflammation, there are at present no data on its role in atherosclerosis. Here we have examined IL-9 and IL-9 receptor (IL-9R) systemically and locally in patients with coronary and carotid atherosclerosis. Plasma IL-9 was quantified by enzyme immunoassay and multiplex technology. IL-9 and IL-9R mRNA were quantified by real-time RT-PCR, and their localization within the lesion was assessed by immunohistochemistry. THE MAIN FINDINGS WERE: (i) Patients with carotid atherosclerosis had significantly raised IL-9 plasma levels compared with healthy controls (n = 28), with no differences between asymptomatic (n = 56) and symptomatic (n = 88) patients. (ii) On admission, patients with acute ST-elevation myocardial infarction (STEMI) (n = 42) had markedly raised IL-9 plasma levels which gradually declined during the first week post-MI. (iii) T cells and monocytes from patients with unstable angina (n = 17) had increased mRNA levels of IL-9 as compared with controls (n = 11). (iv) Carotid plaques (n = 68) showed increased mRNA levels of IL-9 and IL-9R compared to non-atherosclerotic vessels (n = 10). Co-localization to T cells (IL-9 and IL-9R) and macrophages (IL-9) were shown by immunohistochemistry. (v) IL-9 increased IL-17 release in peripheral blood mononuclear cells from patients with unstable angina (n = 5) and healthy controls (n = 5) with a particularly enhancing effect in cells from the patient group. Our findings show increased IL-9 levels in different atherosclerotic disorders both systemically and within the lesion, suggesting a role for the IL-9/IL-9R axis in the atherosclerotic process, potentially involving IL-17 mediated mechanisms. However, the functional consequences of these findings should be further investigated.
    Full-text · Article · Aug 2013
    • "Third, immunosuppressive cytokines (IL-10, IL-13, TGF-β, etc.) produced by Th2 cells and infected macrophages act on macrophages in an autocrine or paracrine fashion, and thereby down-regulate the production of RNIs and ROIs and responsiveness to macrophage-activating cytokines such as TNF-α and IFN-γ [12] [76] [80]. In addition, It has recently been reported that blood levels of IL-9, which is presumably produced by Th2 cells, was elevated in TB patients compared with persons with latent MTB infection and that IL-9 reduced IFN-γ mRNA expression in peripheral blood mononuclear cells because of inhibition of Th1 cell differentiation [81]. These events lead to suppression of the bactericidal/bacteriostatic activity of host macrophages against mycobacterial pathogens. "
    [Show abstract] [Hide abstract] ABSTRACT: In the advanced stages of mycobacterial infections, host immune systems tend to change from a Th1-type to Th2-type immune response, resulting in the abrogation of Th1 cell- and macrophage-mediated antimicrobial host protective immunity. Notably, this type of immune conversion is occasionally associated with the generation of certain types of suppressor macrophage populations. During the course of Mycobacterium tuberculosis (MTB) and Mycobacterium avium-intracellulare complex (MAC) infections, the generation of macrophages which possess strong suppressor activity against host T- and B-cell functions is frequently encountered. This paper describes the immunological properties of M1- and M2-type macrophages generated in tumor-bearing animals and those generated in hosts with certain microbial infections. In addition, this paper highlights the immunological and molecular biological characteristics of suppressor macrophages generated in hosts with mycobacterial infections, especially MAC infection.
    Full-text · Article · May 2012
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