In Vitro Synthesis of Interferon-γ, Interleukin-4, Transforming Growth Factor-β and Interleukin-1β by Peripheral Blood Mononuclear Cells from Tuberculosis Patients: Relationship with the Severity of Pulmonary Involvement

Abstract

Given the role of cell-mediated immune responses in resistance to mycobacteria, we sought to analyse whether there was a relationship between the severity of pulmonary tuberculosis (TB) and lymphocyte proliferation as well as in vitro cytokine production. To achieve this, 25 untreated TB patients showing mild (n = 5), moderate (n = 9) or advanced (n = 11) pulmonary disease, and 12 age-matched healthy controls (mean+/-SD, 37+/-14.5 years) were studied. Peripheral blood mononuclear cells were cultured for 5 days with 10 microg/ml whole, sonicated Mycobacterium tuberculosis (WSA) or 2.5 microg/ml Concanavalin A (Con A). Supernatants were collected on day 4, from cultures grown with or without WSA, for measurement of interferon-gamma (IFN-gamma), interleukin (IL)-4, IL-1beta and transforming growth factor-beta (TGF-beta). Antigen-specific proliferation was found to be reduced among patients and more profound in those with advanced disease who also displayed a depressed response to Con A. Patients with mild TB showed a preferential production of IFN-gamma over IL-4, gave the highest level of IFN-gamma synthesis upon specific antigen stimulation and showed increased levels of IL-1beta production. Findings in patients with moderate TB appeared compatible with a mixed production of IFN-gamma and IL-4 coexisting with a higher synthesis of TGF-beta, by comparison to patients with mild TB. Advanced disease showed the highest IL-4 and TGF-beta production, with IFN-gamma synthesis readily noticeable, yet decreased in comparison with the other patient groups. Differences in cytokine response according to the amount of lung involvement suggest a role for such mediators in the immunopathogenesis underlying the distinct clinical forms of pulmonary TB, that is a predominant T helper Th)1-like or Th2-like activity in mild or in progressive TB, respectively.

Patients with Multidrug-Resistant Tuberculosis Display Impaired Th1 Responses and Enhanced Regulatory T-Cell Levels in Response to an Outbreak of Multidrug-ResistantMycobacterium tuberculosisM and Ra Strains

“…Low in vitro Th1 responses to different M. tuberculosis antigens have been observed in MDR-TB patients, such as impaired IFN-␥ production (4,16,25,26,33) and increased IL-4 production by CD4 ϩ T cells stimulated by a lipid extract of H37Rv (50). Likewise, in our study, both MDR-TB and S-TB patients showed an impaired expression of IFN-␥ in CD4 ϩ and CD8 ϩ T cells, irrespective of the tested strain; therefore, this might be ascribed to the altered Th1/Th2 profile characteristic of advanced disease (13). In contrast to the work of McDyer et al (33), we found diminished IFN-␥ expression in MDR-TB patients, in spite of their normal CD4 ϩ counts of Ͼ500/l.…”

Differential Production of Systemic and Intralesional Gamma Interferon and Interleukin-10 in Nodular and Ulcerative Forms of Buruli Disease

“…Indeed, systemic IFN-␥ production was also lower and IL-10 production was higher in patients with the ulcerative form than in patients with the nodular form of Buruli disease. Such differential expression of cytokines in different clinical forms of a mycobacterial disease is reminiscent of what has been described for tuberculosis (8) and leprosy (32).…”

Model for Immune Responses to Mycobacterium avium Subspecies paratuberculosis in Cattle

“…This shift in the predominant immune response is often associated with progression to clinical disease. A similar phenomenon has been linked to clinical disease associated with mycobacterial infections in other species, including mice and humans (2,25). The mechanisms responsible for loss or reduction of type 1-like responses to mycobacteria, including M. avium subsp.…”