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Om een idee te geven van wat ik nu leer:
Citaat:
T Cells And Cellular Immunity
T cells mature, acquire functional repertoires, and learn the concept of self in the thymus. The thymus accomplishes dual tasks of positive selection (clones that recognize Ag/MHC are allowed to proliferate, mature, and emigrate to the periphery) and negative selection (clones that react to self as if foreign are eliminated). The exact cellular and molecular mechanisms of this selection are not fully known.
During fetal development, the T-stem cell, derived from bone marrow, moves to the thymus, where it matures and learns the concept of self. The process of thymic selection occurs, and mature lymphocytes are allowed to leave the thymus; they are found in peripheral blood and in lymphoid tissues. All mature T cells express CD4 or CD8 in a mutually exclusive fashion.
T-Helper Cells
T cells that express CD4 are generally referred to as T-helper (TH) lymphocytes. These cells can be subdivided into two major categories, depending on their function, response to various cytokines, and ability to secrete cytokines. The current thinking is that TH cells start as precursor cells that make IL-2. On initial stimulation, these cells develop into THO cells, which can secrete several cytokines, including IFN-, IL-2, IL-4, IL-5, and IL-10. Depending on the cytokine available, THO cells can develop into either TH1 or TH2 cells, with IFN- and IL-12 favoring the development of TH1 and IL-4 and IL-10 favoring the development of TH2. TH1 and TH2 differ in the profile of the cytokines they secrete: TH1 cells secrete IFN-, whereas TH2 cells secrete IL-4, although both secrete several other cytokines (eg, IL-3, GM-CSF, TNF-) equally well. In general, TH1 favors the promotion of cellular immunity, whereas TH2 favors the promotion of humoral immunity.
The delineation of TH1 and TH2 responses has changed the thinking about the relationship of the immune system to disease. An immune response should be not only vigorous but also appropriate to the infection or disease. Perhaps the best example of this strategy is leprosy, in which it is now believed that a TH1 response results in tuberculoid leprosy, whereas a TH2 response results in lepromatous leprosy. In addition, a TH1 response may aggravate autoimmune disease, whereas a TH2 response favors the secretion of IgE and the development of atopy.
T-Suppressor/Cytotoxic Cells
T cells that express CD8 are less well characterized than TH subsets, although it appears that they too can be divided into two types depending on the cytokines they secrete, with the segregation being identical to CD4 subsets. It has been suggested that the lymphocyte types be called type 1 and type 2 (T1, T2) rather than TH1 and TH2, because the same subdivision can be seen in CD8 cells.
Cytotoxic T cells (TC) refer to Ag-specific MHC-restricted cytotoxic T lymphocytes (CTL--see below). Both CD4 and CD8 cells can function as CTL, depending on whether class II or class I MHC is recognized, respectively. Several kinds of cytotoxic or killer cells are also recognized; only some of them express CD8 or CD4 markers.
Killer Cells
Identification of each kind (of several) depends on MHC restriction, requirements for sensitization, target specificities, and responses to cytokines. Although macrophages can be cytotoxic, such toxicity is nonspecific and results from activation by some cytokines. The various types of killer cells can be simplified into MHC-restricted (eg, CTL) and MHC-nonrestricted (eg, NK cells). Neither kind requires Ab, complement, or phagocytosis to kill the target cell; instead, they deliver the lytic signal through the target cell membrane after establishing intimate cell-to-cell contact.
MHC-restricted killers:
Cytotoxic T lymphocytes (CTL) are killer cells generated only on specific sensitization either against cells that express foreign MHC products (allogeneic) or against autologous cells--provided these cells have been modified by viral infection or a chemical hapten (syngeneic). The life of a CTL has 3 phases: A precursor cell can become cytotoxic on appropriate stimulation; an effector cell has differentiated and can lyse its appropriate target; and a memory cell, quiescent and no longer stimulated, is ready to become an effector upon restimulation with the original cells. Intact cells are the most potent stimulators of CTL generation; soluble Ag is ineffective except under certain conditions. As mentioned above, Ag is processed and a fragment is embedded in the Ag-presenting groove of the MHC. It is now possible to identify the peptides that have a perfect fit for various MHC haplotypes. If such peptides are used for stimulation, they can embed in the MHC and thus stimulate a T-cell response.
Allogeneic CTL can be readily generated in vitro on culture of normal lymphocytes with irradiated allogeneic stimulator cells that differ across all or part of the MHC barrier. Allogeneic CTL can also be generated in vivo on transplantation of an organ derived from a donor whose MHC products differ from those of the recipient and probably play an important role in organ transplant rejection. Successful generation of CTL requires two signals: the antigenic signal (stimulator cells) and the amplification signal (cytokines). Efficient action of these two signals requires APCs, TH, and TC precursors. The amplification signal is mediated by cytokines that act in tandem; the most important are IL-1, IL-2, and IL-4. Other cytokines (including IL-6, IL-7, IL-10, and IL-12) are believed to be involved in CTL generation, at least in vitro.
Another kind of CTL that is important in eliminating certain intracellular pathogens (especially virally infected cells) is the so-called Ag-specific CTL (syngeneic CTL). Syngeneic CTL recognize only target cells that express the Ag used for sensitization in association with MHC. Such CTL are generated against autologous cells provided the cells have been "modified" by viral infection or chemical haptens. Expression of viral products, or haptens, on the cell surface in association with MHC triggers a cascade of cell differentiation and cytokine release and response similar to the allogeneic CTL. Both allogeneic and syngeneic CTL use the TCR/CD3 complex for target cell recognition.
MHC-nonrestricted killers:
Unlike CTL, natural killer (NK) cells do not require sensitization to express their killer function. NK cells constitute 5 to 30% of normal peripheral blood lymphocytes. NK cells are lymphocytes, but they do not belong to the T- or B-cell lineages. Therefore, NK cells do not express sIg or TCR/CD3 on their surface. The surface markers that best characterize NK cells are CD2+, CD3-, CD4-, and CD56+, with a subset being CD8+. NK cells will kill certain autologous, allogeneic, and even xenogeneic tumor cells regardless of whether these targets express MHC; indeed, they may preferentially kill target cells that express little or no class I MHC. Susceptibility to killing by NK cells can be reduced if the target cell is induced to increase its MHC expression (eg, by transfection or by IFN).
This apparent inhibition of NK killing activity by class I MHC expression led to the identification of several class I MHC receptors on the surface of NK cells. These receptors are structurally different from the TCR and are generally referred to as killer cell inhibitory receptors (KIR). While engagement of MHC by the TCR on T cells leads to T-cell activation, engagement of the MHC by most KIR leads to inhibition of NK activity, although there are some KIR that can lead to activation. KIR have also been identified on T cells. This presents an interesting enigma: T cells have different receptors (TCR/CD3 and KIR) for the same molecule (class I MHC) but with opposing effects. What decides whether a T cell will be activated or inhibited is not well known, and the outcome may vary depending on the T-cell clone.
NK cells have long been thought to be important in tumor surveillance because they can kill some tumor target cells and because most tumors lack MHC expression. NK cells also kill some virally infected cells and some bacteria (eg, Salmonella typhi). The Ag-recognition structure of NK cells remains elusive.
In addition to their killing property, NK cells can secrete several cytokines, IFN- and GM-CSF (granulocyte-macrophage colony-stimulating factor) in particular. NK cells may be the most potent source of IFN-. By secreting IFN-, NK cells can influence the adaptive immune system by favoring the differentiation of TH1 and inhibiting the differentiation of TH2.
Antibody-Dependent Cell-Mediated Cytotoxicity
NK cells express CD16, a receptor for IgG-Fc (see Antibody Structure, below), and can use this receptor to mediate another kind of MHC-nonrestricted killing. Ab-dependent cell-mediated cytotoxicity (ADCC) depends on the presence of Abs that recognize a target cell (ADCC specificity is therefore conferred by the specificity of the Ab). Upon binding its Ag, the Ab's Fc region is exposed and will bind its receptor on the NK cell to form a bridge. Once the bridge is formed, a poorly understood lytic signal is delivered to the target cell, resulting in its demise.
An interesting form of ADCC is the so-called reverse ADCC. Certain killer cells, including MHC-restricted CTL, that express CD3 on their surface can lose specificity in the presence of anti-CD3 Abs. Anti-CD3 binds to its ligand on the surface of the killer cell, leaving its Fc portion free to bind to target cells expressing Fc receptors. Again, once a bridge is formed, the lytic signal is delivered to the Fc-bearing target cell. Some forms of ADCC may prove useful for targeting tumor cells in vivo as a form of immunotherapy.
MHC-Nonrestricted T Killers
In addition to the NK cells that are CD3- TCR- CD56+, another subset is CD3+ CD56+ and can express CD2, CD5, and CD8. Most are TCR-, although some TCR- clones have been identified. This subset can mediate some spontaneous NK-like activity and can augment such activity after stimulation with IL-2. Another subset of T cells (CD3+ TCR- CD4- CD8- CD56- CD16-) can be cytotoxic, although most are clones or cell lines. It remains to be seen whether freshly isolated lymphocytes of this phenotype are spontaneously cytotoxic.
Lymphokine-Activated Killers
Some lymphocytes cultured with IL-2 develop into potent lymphokine-activated killers (LAK) capable of killing a wide spectrum of tumor target cells as well as autologous lymphocytes that have been modified by culture, some viruses, or haptens. LAK are viewed as a phenomenon rather than a unique lymphocyte subset. LAK precursors are heterogeneous but can be divided into two major categories: NK-like and T-like. It is generally agreed that the classic NK cells constitute the major LAK precursors in the peripheral blood, but this may not be true in extravascular tissues.
Tests of Cellular Immunity
Minimal quantitative evaluation of cellular immunity should include lymphocyte counts, T-cell subset numbers (CD3, CD4, CD8), and NK cell numbers by fluorescence analysis. Qualitative evaluation includes delayed-type hypersensitivity (DTH) skin tests and the following in vitro tests: (1) proliferation in response to soluble Ag, to anti-CD3 Ab, and to allo-Ag; (2) the lytic activity of NK cells both spontaneously and after stimulation with IL-2 or IFN; (3) ability to elaborate cytokines with emphasis on IFN-, TNF-, IL-2, and IL-4; and (4) ability to generate MHC-restricted CTL. Further analysis will depend on the results of these tests. Comprehensive testing of cellular immunity is limited to research laboratories.
DTH skin tests establish the normalcy of some aspects of the cellular immune system. However, they do not test the status of CD8 cells, virgin CD4 cells, NK cells, and APCs other than Langerhans' cells. For example, a patient can have a complete absence of NK cells and yet have a normal DTH. Thus, while a negative DTH skin test indicates an abnormal cellular immunity, the reverse is not true (see Immune Networks, below).
DTH skin tests should be read at 48 h. An earlier response could be due to an Arthus reaction (which starts 4 to 6 h after the test and can be present up to 24 h). An Arthus reaction is due to the presence of Ab that binds to the injected Ag, resulting in immune complex formation, complement activation, and neutrophil chemotaxis. The cellular infiltrate in an Arthus reaction consists mostly of neutrophils, while the infiltrate in DTH is composed of mononuclear cells. The DTH response begins to resolve after 48 h, and if one reads the skin test at 72 h, a borderline positive reaction (> 5 mm induration) may appear negative.
IMMUNE NETWORKS
The immune system operates as a whole, and no one component operates autonomously. In any immune response, the components function in concert, in tandem, or in conflict, as exemplified by the ability of the immune system to eliminate microorganisms. Extracellular microorganisms (most encapsulated bacteria) need only to be phagocytosed to be digested; however, intracellular microorganisms (eg, mycobacteria) are readily ingested, but cannot be digested unless the macrophage receives an activation signal.
The strategy to eliminate extracellular microorganisms is therefore directed toward phagocytosis, which is facilitated by opsonization (coating of a microorganism with Ab and/or complement products). Because most phagocytes have receptors for the Fc portion of Ab and for C3 products, the presence of these molecules on a bacterium facilitates its adherence and ingestion. This "simple" immune response depends on successful Ab synthesis, activation of the complement cascade, and an intact phagocytic system. Abs are made by B cells, yet B cells are subject to help and suppression by T cells. In addition, phagocytes are recruited by chemotactic factors, some of which are made by T cells.
The strategy to eliminate some intracellular microorganisms that infect phagocytes involves activation of host cells, which then become "armed" and able to kill these organisms in a nonspecific fashion. The ability to activate macrophages is at the heart of the typical delayed-type hypersensitivity (DTH) reaction, and the DTH skin test is an excellent example of the various cascades involved in a given immune response. The premise of a DTH skin test is that intradermal injection of an Ag to which the patient has been previously exposed leads to local induration within 48 h. The intricate network involved in such a response is illustrated in Fig. 146-2. Upon injection, Langerhans' cells in the skin take up Ag, process it, and present it (complexed with class II MHC) to a CD4+ cell that was previously exposed to the Ag (ie, a long-lived memory cell). Once the CD4+ cell engages the Ag/MHC complex, it expresses IL-2 receptors and releases several cytokines (eg, IFN-, IL-2, and lymphocyte and macrophage chemotactic factors). IFN- induces the endothelial cells to increase their expression of adhesion molecules, thus facilitating the egress of lymphocytes and macrophages through the endothelial barrier. IL-2 and IFN- also act as proliferation/differentiation signals, allowing T-cell memory clones and the newly arrived T cells to expand. Once macrophages reach the injection site, they are prevented from leaving by migration-inhibiting factors (MIF) that are secreted by the activated T cells. IFN- and GM-CSF, both of which are secreted by the T cells, then act as macrophage-activating factors (MAF). The activated macrophages now are "armed" and can kill intracellular organisms and any bystander tumor cells.
Activated macrophages secrete IL-1 and TNF-, which potentiate the secretion of IFN- and GM-CSF, increase the expression of adhesion molecules on endothelial cells, and allow these cells to secrete tissue factor, which triggers the coagulation cascade, ending in fibrin deposition. Concomitantly, the activated lymphocytes secrete macrophage procoagulant-inducing factor (MPIF), which allows the expression of macrophage procoagulant activity (MPCA) on the activated macrophages; MPCA also activates the coagulation cascade resulting in fibrin deposition. Fibrin deposition is responsible for the induration seen with DTH skin tests.
The DTH pathway is important to eliminating microorganisms that infect phagocytes. Some microorganisms (eg, viruses) may infect cells that lack the lytic machinery and thus cannot be activated to mediate intracellular killing. Such pathogens are eliminated by CTL. On infection with a virus, cells will express viral Ag on their surface in association with MHC. This virus/MHC complex will stimulate the generation of syngeneic CTL that will then kill the cells expressing this complex. Depending on whether the viral product is associated with class I or II MHC, the CTL will belong to the CD8 and CD4 subsets, respectively. As discussed above, the association with either MHC class depends on the Ag-processing pathway used; eg, most CTL generated against measles and herpes simplex virus belong to the CD4 subset. In influenza virus infection, the CTL directed against the nucleoprotein Ag are CD8, while those directed against the hemagglutinin Ag are CD4.
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Niet om op te scheppen, maar gewoon om een idee te geven van wat ik dan zoal leer.
Vraag me af of iemand dat herkent, en zoja... MSN?  
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27-10-2003, 18:58
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