Tuberculosis in Africa: Learning from Pathogenesis for Biomarker Identification  Stefan H.E. Kaufmann, Shreemanta K. Parida  Cell Host & Microbe  Volume 4, Issue 3, Pages 219-228 (September 2008) DOI: 10.1016/j.chom.2008.08.002 Copyright © 2008 Elsevier Inc. Terms and Conditions

Figure 1 From the Site of Action in the Lung to Biomarkers in the Peripheral Blood The figure depicts the major pathologic and protective mechanisms in the lung during latent Mtb infection and active TB disease. In addition, the picture indicates determination of immunologic, transcriptomic, and metabolomic biomarkers. Cell Host & Microbe 2008 4, 219-228DOI: (10.1016/j.chom.2008.08.002) Copyright © 2008 Elsevier Inc. Terms and Conditions

Figure 2 Three Steps to T Cell Activation The figure shows three critical steps toward T cell activation and polarization. (1) T cells recognize antigen not in its natural form; rather the antigen is presented by reference structures encoded by the major histocompatibility complex (MHC). Antigens that reside in phagosomes are presented by MHC-II molecules to CD4 T cells. Because Mtb resides in phagosomes, this is the main antigen presentation/recognition pathway in TB. Antigens in the cytosol are loaded onto MHC-I molecules that present their antigens to CD8 T cells. Unconventional T cells comprising γδ T cells and CD1-restricted T cells are activated during Mtb infection, as well. Human γδ T cells recognize small molecules containing pyrophosphate residues, also termed phospholigands. The CD1-restricted T cells recognize mycobacterial glycolipids in the context of CD1 molecules. (2) CD4 T cells can be further subdivided into different T helper (Th) cells according to their cytokine expression pattern. The Th1 cells are critical for protection against TB. They typically produce interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), lymphotoxin (LT), interleukin (IL)-2, and granulocyte-macrophage colony-stimulating factor (GM-CSF). The Th2 cells stimulate humoral immune responses via secretion of IL-4 and IL-5. The Th17 cells produce IL-6, IL-17, IL-21, and IL-22, which probably contribute to early protection. The regulatory T cells (Treg) produce tumor growth factor beta (TGF-β) and IL-10, which suppress immune responses. Cytokines are also important for polarization of CD4 Th cells. Thus, IL-12, IL-18, and IFN-γ promote Th1 cell development; IL-33 together with IL-4 and IL-25 induce Th2 cell development; TGF-β, together with IL-6, promotes Th17 cell polarization in mice and TGF-β and IL-21 do so in humans, and TGF-β together with vitamin A derivates (retinoic acid, RA) favors Treg cell maturation. (3) For complete activation, T cells need to be costimulated by surface molecules. Many of these molecules belong to the B7 family. Thus, interactions of CD28 on T cells with B7.1 and/or B7.2 on antigen-presenting cells (APCs) promote T cell stimulation as do interactions of the inducible T cell costimulator (ICOS) on activated T cells with ICOSL (B7.h) on APCs. Other mechanisms are inhibitory such as interactions of B7.1 and B7.2 with CTLA-4 and interactions with PD-1 on activated T cells with PD-L on APCs. Cell Host & Microbe 2008 4, 219-228DOI: (10.1016/j.chom.2008.08.002) Copyright © 2008 Elsevier Inc. Terms and Conditions