Análisis de Precios

Animal model work has proved the existence of separate types of lymphocytes which may mediate DTH and/or a protective immune response separately. Different lymphocyte surface markers investigatyed in this study included CD4, CDS, HLA-DR and CD30 on CD3 T cells; CDS on yS-T cells; and CD23 on CD 19 B cells. These surface markers have been described in chapter 6. Lymphocytes which have previously met mycobacterial antigens may develop different surface markers confirming their long term memory cell status. These memory cells differentiate and expand following subsequent encounter with mycobacteria depending on: 1) site of reaction 2) degree of

mycobacterial load 3) type of antigens processed 4) milieu of different cells and cytokines involved.

Different cells are likely to be involved at different stages of the immune response. Some cells are equipped with multiple functions such as secreting different cytokines or lysing other cells. These different means of attacking M.tuberculosis might offer considerable advantages to the host. However, selection of the wrong mechanism of defence o r malfunction of a particular cell type could also result in a harm ful rather than a protective réponse. A coordinated communication is required between macrophages and T cells for an effective anti­ mycobacterial response.

Immune cells are responsible for mediating different types of immune responses. As pathogenic mycobacteria cause chronic inflammation, cell- mediated immunity (CMI) rather than humoral immunity provides the main form of immune defence. In CMI, T cells are the main inducers and regulators of the adaptive immune responses, while macrophages are the main effectors. The major dilemma in antimycobacterial defence, is the capacity of mycobacteria to survive as persistors inside macrophages.

MACROPHAGES

Mycobacteria are found mainly inside macrophages and relatively few polymorphonuclear cells in vivo. The chronic persistence of mycobacteria is probably responsible for their ingestion by longer-lived macrophages rather than granulocytes such as neutrophils and eosinophils which have shorter life-spans. Macrophages have powerful mechanisms to attack intracellular parasites such as reactive oxide

intermediates (ROI), proteases and acidic conditions inside lysosomes. They also possess machinery to process antigens inside phagosomes and present them to T cells. T cells can further activate macrophages to kill mycobacteria. T cells can also directly lyse macrophages if the latter are unable to control mycobacterial growth.

T CELLS

All the T cells in peripheral circulation have CD3 molecules. The CD3 molecule is involved in signal transduction and T cell activation. There are different subsets of T cells such as CD4, CDS, CD4 CD8 and y8-T cells. They differ in their antigen recognition as well as their effector responses such as cytolysis and cytokine production. CD4 T cells are generally believed to be the main regulators of CMI as they are the main lymphocytes responding to antigen-presenting cells. Reduction in absolute numbers of CD4 T cells is seen in some conditions associated with impaired CMI such as HIV infection. This phenomenon is also seen in HIV-negative TB patients.

CD4 and CDS T cells differ in the manner in which they recognise antigens. CD4 T cells recognise their antigens in association with M HCn (major histocompatibility class II) receptors on the antigen-presenting cells such as macrophages. CDS T cells recognise their antigens in association with MHCI receptors which are present on all nucleated cells. Antigens presented with MHCII or MHCI molecules are processed differently which has important consequences for the survival of

M.tuberculosis. Antigens associated with MHCII receptors are processed in endosomes whereas MHCI-associated antigens are processed in the cytoplasm.

Mycobacteria are usually killed in the endosomes. However,

M.tuberculosis has been known to produce ammonia which increases the normally acidic pH of lysosomes, inhibits lysosomal fusion and allows the bacilli to escape out of phagosomes into the cytoplasm. In such instances, CD8 T cells would be activated via MHCI receptors. The presence of M.tuberculosis in the cytoplasm could be a sign of ineffective immune response in itself, therefore recruitm ent of CDS T cells probably leads to a more vigorous and drastic response. A subset of CDS T cells, called cytotoxic T cells, have granules stored with potent enzymes. These enzymes can lyse impotent macrophages and their contents.

CD4 CD8 T cells can have a(3 or yô TCRs. 90% of peripheral blood T ; I cells have a(3- TCRs whereas 10% have yô- TCRs. yô T cells recognise I receptors independent of MHC restriction. yd-T cells have limited recognition ability and a restricted pattern (Tsukaguchi et al, 1995). Their receptors are believed to be less specific in their recognition. The proportion of yô-T cells is raised in the uterus, tongue, intestinal épithélia and skin where they have are responsible for immunological surveillance. yÔ-T cells are usually the first cells to arrive at the site of infection especially in the epithelial and mucosal surfaces. This might allow the yÔ-T cells to respond quicker than CD4 and CD8 T cells and thus be very important in the primary response. They are also believed to recognise common and non-specific antigens such as HSPs without MHC restriction. However, they do not form memory cells and their roles might be limited in subsequent reactions. yô-T cells have also been found to have different anatomical distributions to other T cells, fo r example, their numbers are increased at mucosal surfaces.

OTHER LYMPHOCYTES

Other lymphocytes such as large granular lymphocytes (LGL) including natural killer (NK) cells and lymphokine-activated killer (LAK) cells are believed to attack abnormal or stressed autologous cells. B cells and plasma cells are responsible for humoral response. Granulocytes such as neutrophils, basophils and eosinophils are responsible for the innate immune response including acute inflammation.