Examining a paradox in the pathogenesis of human pulmonary tuberculosis: Immune activation and suppression/anergy

G. Vanham, Z. Toossi, C. S. Hirsch, R. S. Wallis, S. K. Schwander, E. A. Rich, J. J. Ellner

Research output: Contribution to journalReview articlepeer-review

67 Scopus citations

Abstract

Protective immunity against Mycobacterium tuberculosis (MTB) in animal models is based on cell-mediated immunity (CMI), involving bi-directional interactions between T cells and cells of the monocyte/macrophage (MO/MA) lineage. Key factors include MO-derived interleukin (IL)-12 and tumor necrosis factor (TNF)-α as well as T cell derived IL-2 and interferon (IFN)-γ. These cytokines appear particularly crucial in the induction of MA-mediated elimination of mycobacteria. Several lines of evidence indicate that similar mechanisms are operating in humans. During active pulmonary tuberculosis (PTB), signs of both immune depression and immune activation are concomitantly present. Decreased tuberculin skin test reactivity in vivo and deficient IFN-γ production by MTB-stimulated mononuclear cells in vitro are observed. On the other hand, the serum levels of several cytokines, including TNF, and other inflammatory mediators are increased and circulating MO and T cell show phenotypic and functional evidence of in vivo activation. In this review, we will discuss the evidence for three models, which could explain this apparent paradox: 1. Stimulation of the T cell-suppressive function from MO/MA; 2. Intrinsic T cell refractoriness, possibly associated with tendency to apoptosis (programmed cell death), and 3. Compartmentalization and redistribution of immune responses to the site of disease. The opportunistic behavior of MTB during human immunodeficiency virus (HIV) infection can be explained by suppression of type-1 responses at the level of antigen-presenting cells, CD4 T cells and effector macrophages. The ominous prognostic significance of intercurrent PTB during HIV infection seems primarily due to prolonged activation of HIV replication in macrophages. Supportive immune therapy during PTB could aim at correcting the type-1 deficiency either by IFN-γ inducers (e.g. IL-12, IL-18) or by neutralizing the suppressive cytokines transforming growth factor β (TGF-β) and IL-10. Alternatively, inflammatory over-activity could be reduced by neutralizing TNF. Finally, anti-apoptotic therapies (e.g. IL-15) might be considered.

Original languageEnglish (US)
Pages (from-to)145-158
Number of pages14
JournalTubercle and Lung Disease
Volume78
Issue number3-4
DOIs
StatePublished - Jan 1 1997
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Pulmonary and Respiratory Medicine

Fingerprint Dive into the research topics of 'Examining a paradox in the pathogenesis of human pulmonary tuberculosis: Immune activation and suppression/anergy'. Together they form a unique fingerprint.

Cite this