Type 1 Cytokines and the Pathogenesis of Tuberculosis

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T cells contribute to defense against infections by producing specific patterns of cytokines, which can be broadly divided into type 1 cytokines, including interferon  and interleukin 2 (IL-2), and type 2 cytokines, including IL-4 and IL-5. Interferon  contributes to protective immunity against intracellular pathogens by activating macrophages to more effectively eliminate these organisms. IL-12 and IL-18 are macrophage products that strongly favor development of type 1 cytokine responses.

Immune defenses against Mycobacterium tuberculosis are mediated primarily by T cells, and interferon  is essential for protective immunity. Mice with a targeted deletion of the interferon  gene are highly susceptible to tuberculosis (1, 2) and patients with defective receptors for interferon  or IL-12 have markedly increased susceptibility to severe infections with Mycobacterium bovis BCG and other mycobacteria (3).

At the site of disease in patients with tuberculosis, interferon  and IL-12 concentrations are higher than those in other inflammatory conditions (4). Why does this not protect against tuberculosis? One possibility is that macrophages fail to respond to interferon , because of genetic host defects or effects mediated by M. tuberculosis. Subtle abnormalities in interferon  receptor expression may reduce interferon  responsiveness in patients with tuberculosis, as in patients with severe disease from nontuberculous mycobacteria (3). Alternatively, M. tuberculosis itself can inhibit signal transduction by interferon  in macrophages, preventing the downstream effects that eliminate mycobacteria (7). Another explanation for the development of tuberculosis despite elevated type 1 cytokine levels is that such levels are present too late in the course of infection to prevent development of disease. In the early phases of infection, when the host-pathogen interactions are most critical, interferon  levels may be reduced in patients who subsequently develop tuberculosis, whereas these levels may be elevated in persons who become healthy tuberculin reactors. Unfortunately, ethical and logistical considerations have precluded evaluation of the early local cytokine response.

The systemic cytokine response in tuberculosis can be assessed by measuring serum cytokine levels. Interferon  concentrations in serum and plasma of patients with tuberculosis are elevated, compared with those in healthy persons who were recently infected with M. tuberculosis (8). In this issue of the American Journal of Respiratory and Critical Care Medicine, Yamada and colleagues confirm and extend these observations, demonstrating that serum IL-18 and interferon  concentrations are higher in patients with tuberculosis than in healthy control subjects (9). There was a positive correlation between IL-18 and interferon  concentrations in tuberculosis patients, suggesting that IL-18 contributes to interferon  production.

Although serum interferon  and IL-18 concentrations are elevated in patients with tuberculosis, peripheral blood mononuclear cells produce less interferon  and IL-18 when stimulated in vitro with M. tuberculosis antigens, compared with findings in healthy tuberculin reactors (10). How can these contradictory findings be reconciled? We believe that the increased IL-18 and interferon  serum levels in patients with tuberculosis reflect leakage of these cytokines from tissue sites into the circulation. In contrast, reduced interferon  production by M. tuberculosis-stimulated peripheral blood cells is due to sequestration of interferon -producing cells at the site of disease, combined with systemic immunosuppression. Several findings support this view. First, higher serum IL-18 and interferon  levels are found in tuberculosis patients with advanced disease (8, 9), and interferon  levels decrease as patients improve during therapy (8, 14). Because type 1 cytokine concentrations at the diseased site are probably highest in patients with severe disease and marked inflammation, and because local cytokine levels are likely to decline during treatment, the findings described above are consistent with leakage of cytokines from the site of disease into serum. Second, in patients with pleural tuberculosis, interferon  concentrations and the percentage of cells that produce interferon  in response to M. tuberculosis are much higher in pleural fluid than in blood (15). Therefore, sequestration of interferon -producing cells at the diseased site probably contributes to reduced interferon  production by peripheral blood cells. Third, there is systemic inhibition of type 1 cytokine responses in patients with tuberculosis, independent of cellular sequestration. Monocytes from patients with tuberculosis produce increased amounts of the immunosuppresive cytokine transforming growth factor , and neutralization of transforming growth factor  enhances M. tuberculosis-induced interferon  production (11). In addition, peripheral blood cells from tuberculosis patients express more IL-4 mRNA than do cells from healthy tuberculin reactors (16), and IL-4 is a potent inhibitor of type 1 responses.

Although interferon  and IL-18 are believed to contribute to effective immunity to tuberculosis, Yamada and coworkers found highest serum levels of these cytokines in patients with severe disease, high fever, and extensive radiographic infiltrates (9). These clinical findings show that type 1 cytokines, while necessary for protective immunity, can also mediate immunopathology. Similar findings are observed in malaria, in which interferon  is essential for protection, but high serum levels of this cytokine are found in patients with severe disease (17). The double-edged sword of type 1 cytokines mandates caution in considering their use in pharmacologic doses as immunotherapy in tuberculosis. Although interferon  showed limited benefit in some patients with multidrug-resistant tuberculosis (18), type 1 cytokines have the potential to cause uncontrolled inflammation and life-threatening adverse events.

Yamada and colleagues comment briefly on the conflicting results in different studies of the cytokine response in tuberculosis. For example, M. tuberculosis antigen-stimulated peripheral blood cells from patients with tuberculosis produced high (12, 19) or normal (4, 11) levels of IL-4 and IL-10, and the same authors have reported conflicting results in different populations (11, 12)! While different culture conditions in vitro may explain some discrepancies, we believe that they result primarily from differences in the intrinsic immune response of patient populations. First, malnutrition unrelated to tuberculosis can markedly affect cytokine production (20). Second, asymptomatic parasitic infections in patients with tuberculosis can upregulate type 2 cytokines and inhibit the type 1 cytokine response (21). Third, the severity of tuberculosis can affect the cytokine response, as shown by Yamada and by others (16, 22). Fourth, the cytokine response changes during therapy, so that results obtained in the early phases of treatment differ from those obtained later (10, 12). Investigators should consider these factors in designing and interpreting future studies to understand the relationship between type 1 cytokines and the pathogenesis of tuberculosis.

Center for Pulmonary and Infectious, Disease Control, Departments of Medicine, Cell Biology,and Immunology, University of Texas Health Center, Tyler, Texas

Acknowledgments: Supported in part by the National Institutes of Health (AI27285), the Center for Pulmonary and Infectious Disease Control, and the Cain Foundation for Infectious Disease Research. Peter F. Barnes holds the Margaret E. Byers Cain Chair for Tuberculosis Research.

	References

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