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Th2 cytokines in susceptibility to tuberculosis
1Centre for Infectious Diseases and International Health (CIDIH), University College, London, UK. g.rook@ucl.ac.uk
Current Molecular Medicine
|May 17, 2007
Summary
Tuberculosis (TB) susceptibility in developing countries is linked to immune responses. Blocking the Th2 component, rather than just enhancing the Th1 response, may be key for effective vaccines where Bacillus Calmette et Guérin (BCG) often fails.
Area of Science:
- Immunology
- Infectious Diseases
- Vaccinology
Background:
- Tuberculosis (TB) remains a major global health challenge, particularly in developing countries where the Bacillus Calmette et Guérin (BCG) vaccine shows limited efficacy.
- Immune responses in these regions, characterized by a mixed IFN-gamma (Th1) and Th2 response to mycobacterial antigens, differ from those in areas with high BCG effectiveness.
- A pre-existing IL-4 (Th2) component appears to hinder immunity during active TB, especially after high-dose M. tuberculosis (Mtb) challenge.
Purpose of the Study:
- To investigate the immunological factors contributing to differential susceptibility to tuberculosis (TB) in developing countries.
- To understand why the BCG vaccine is less effective in these specific geographical and immunological contexts.
- To identify potential targets for novel TB vaccines tailored to populations where BCG fails.
Main Methods:
- Review and synthesis of existing data on immune responses (IFN-gamma, IL-4, IL-13, TNF-alpha) in individuals and animal models from developing countries.
- Analysis of the role of IL-4 and IL-13 in modulating Th1-mediated immunity and macrophage function.
- Examination of mechanisms by which IL-4 impacts antimicrobial activity, cell apoptosis, iron availability, and regulatory T cell proliferation.
Main Results:
- A background Th1 response may offer protection against low-dose Mtb challenge, but a pre-existing IL-4 response can impede immunity, particularly at higher challenge doses.
- IL-4 (and IL-13) can impair Th1 immunity by promoting alternative macrophage activation, reducing TNF-alpha-mediated apoptosis, decreasing iNOS activity, and increasing intracellular iron availability for Mtb.
- IL-4 also drives immunopathology through increased TNF-alpha toxicity and pulmonary fibrosis, and promotes the proliferation of FOXP-3+ regulatory T cells.
Conclusions:
- Effective TB vaccines for developing countries may require strategies that actively block the detrimental Th2 (IL-4/IL-13) immune responses, in addition to enhancing the Th1 response.
- Understanding and counteracting the suppressive effects of IL-4 is crucial for developing vaccines that confer protection in diverse populations.
- Targeting the Th2 component could overcome the limitations of current BCG vaccination strategies in high-incidence regions.
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