In humans and in mice, control of the intracellular pathogen, Mycobacterium tuberculosis (Mtb), requires IFN-γ. Although the adaptive immune response results in production of substantial amounts of IFN-γ in response to Mtb, the immune response is unable to eradicate the infection in most cases. We have previously reported evidence that Mtb inhibits macrophage responses to IFN-γ, suggesting that this may limit the ability of IFN-γ to stimulate macrophages to kill Mtb. We have also observed that uninfected macrophages, adjacent to infected macrophages in culture, exhibit decreased responses to IFN-γ. Here we report that IL-6 secreted by Mtb-infected macrophages inhibits the responses of uninfected macrophages to IFN-γ. IL-6 selectively inhibits a subset of IFN-γ-responsive genes at the level of transcriptional activation without inhibiting activation or function of STAT1. Inhibition of macrophage responses to IFN-γ by IL-6 requires new protein synthesis, but this effect is not attributable to suppressor of cytokine signaling 1 or 3. These results reveal a novel function for IL-6 and indicate that IL-6 secreted by Mtb-infected macrophages may contribute to the inability of the cellular immune response to eradicate infection.
Rationale: Among patients with nontuberculous mycobacterial lung disease is a subset of previously healthy women with a slender body morphotype, often with scoliosis and/or pectus excavatum. We hypothesize that unidentified factors predispose these individuals to pulmonary nontuberculous mycobacterial disease. Objectives: To compare body morphotype, serum adipokine levels, and whole-blood cytokine responses of patients with pulmonary nontuberculous mycobacteria (pNTM) with contemporary control subjects who are well matched demographically. Methods: We enrolled 103 patients with pNTM and 101 uninfected control subjects of similar demographics. Body mass index and body fat were quantified. All patients with pNTM and a subset of control subjects were evaluated for scoliosis and pectus excavatum. Serum leptin and adiponectin were measured. Specific cytokines important to host-defense against mycobacteria were measured in whole blood before and after stimulation. Measurements and Main Results: Patients with pNTM and control subjects were well matched for age, gender, and race. Patients with pNTM had significantly lower body mass index and body fat and were significantly taller than control subjects. Scoliosis and pectus excavatum were significantly more prevalent in patients with pNTM. The normal relationships between the adipokines and body fat were lost in the patients with pNTM, a novel finding. IFN-g and IL-10 levels were significantly suppressed in stimulated whole blood of patients with pNTM. Conclusions: This is the first study to comprehensively compare body morphotype, adipokines, and cytokine responses between patients with NTM lung disease and demographically matched controls. Our findings suggest a novel, predisposing immunophenotype that should be mechanistically defined.Keywords: leptin; adiponectin; pectus excavatum; scoliosis; Marfan syndrome Chronic lung disease due to nontuberculous mycobacteria (NTM) is a growing public health concern (1-3). Recent studies estimate the incidence in the United States to be five to six cases per 100,000 and as high as 15.5 cases per 100,000 in persons over 50 years of age (3-5). Because the duration of symptomatic NTM lung disease is often years, the prevalence of disease is estimated to be 10 to 40 cases per 100,000 (1).In the United States, the most common NTM species associated with lung disease are Mycobacterium avium complex (MAC), Mycobacterium kansasii, and Mycobacterium abscessus. Although NTM are widespread in water and soil (6, 7), relatively few persons develop disease. Thus, intact immunity is likely pivotal for protection against NTM.Chronic lung disease is the most common form of NTM infection, manifested by two main radiographic patterns: (i) an upper lobe fibrocavitary pattern that occurs mostly in men with underlying lung disease such as chronic obstructive pulmonary disease (COPD) and (ii) a nodular-bronchiectasis pattern that often involves the right middle lobe and lingula and which appears to be more common in women with no clear risk factors (8)...
Rationale: Microarray technology is widely employed for studying the molecular mechanisms underlying complex diseases. However, analyses of individual diseases or models of diseases frequently yield extensive lists of differentially expressed genes with uncertain relationships to disease pathogenesis. Objectives: To compare gene expression changes in a heterogeneous set of lung disease models in order to identify common gene expression changes seen in diverse forms of lung pathology, as well as relatively small subsets of genes likely to be involved in specific pathophysiological processes. Methods: We profiled lung gene expression in 12 mouse models of infection, allergy, and lung injury. A linear model was used to estimate transcript expression changes for each model, and hierarchical clustering was used to compare expression patterns between models. Selected expression changes were verified by quantitative polymerase chain reaction. Measurements and Main Results: A total of 24 transcripts, including many involved in inflammation and immune activation, were differentially expressed in a substantial majority (9 or more) of the models. Expression patterns distinguished three groups of models: (1) bacterial infection (n 5 5), with changes in 89 transcripts, including many related to nuclear factor-kB signaling, cytokines, chemokines, and their receptors; (2) bleomycin-induced diseases (n 5 2), with changes in 53 transcripts, including many related to matrix remodeling and Wnt signaling; and (3) T helper cell type 2 (allergic) inflammation (n 5 5), with changes in 26 transcripts, including many encoding epithelial secreted molecules, ion channels, and transporters. Conclusions: This multimodel dataset highlights novel genes likely involved in various pathophysiological processes and will be a valuable resource for the investigation of molecular mechanisms underlying lung disease pathogenesis.
We have used transgenic mouse models to examine the mechanisms of tolerance in CD4(+) T lymphocytes to soluble, systemic and cell-associated, tissue-restricted self-antigens. Anergy to an islet antigen, as a model of a tissue antigen, is dependent on the inhibitory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4), and tissue-restricted autoimmunity is inhibited by regulatory T lymphocytes. Anergy to a circulating systemic antigen can occur independently of CTLA-4 signals, and it is induced primarily by a block in proximal receptor-initiated signals. CD4(+)CD25(+) regulatory T cells are generated in response to both forms of self-antigens, but the induction is much more efficient with the tissue antigen. Receptor desensitization can be induced by the systemic antigen even in the absence of regulatory T cells, but tolerance can be broken by immunization much more easily if these cells are absent. Deletion of mature T cells is striking with the systemic antigen; there is little evidence to support peripheral deletion as a mechanism of tolerance to the tissue antigen. Thus, both distinct and overlapping mechanisms account for unresponsiveness to different forms of self-antigens. These results establish a foundation for searching for genetic influences and pathogenic mechanisms in organ-specific and systemic autoimmune diseases.
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