| Themes > Science > Life Sciences > General Biology > Immunology > The Immune System & Its Effector Mechanisms > The Human Immune System & The Immune Response > The Immune response to infection and AIDS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
As explained in preceding lectures different pathogens live in different micro-environments and have different life cycles. Immune responses to these pathogens have to be appropriate for the micro-environment and life cycle of a pathogen. Figure 7.1 lists examples of common pathogens and the body compartments they colonize during their life cycle (sites of infection). Some pathogens appear at more than one site. Viruseó for example replicate in the cytosol, but in most cases have to pass through the extracellular space to infect other cells. The figure also illustrates that the effector mechanisms that is needed and used depends on the site the pathogen occupies. Table 7.1 gives an overview of effector mechanisms used for the clearance of a primary infection and protection during subsequent re-infection. The table illustrates that immune responses to pathogens are not uniform. Different pathogens require and trigger different responses ranging from humoral to cellular. The humoral responses can be further subdivided depending as to what antibody isotype is required (and used) and the cellular responses as to being CD8+ and/or Th1 type CD4+. Sometimes, these responses are polarized. For example, the response is either predominantly humoral and controlled by Th2 T-cells or predominantly cellular and controlled by Th1 T-cells. In many cases however, a mixture of responses is triggered. Many viruses elicit strong CD8+ T cell responses and strong, high affinity antibody responses at the same time. This seems plausible as most viruses need to cross the extracellular space in order to infect new cells. During this phase in their life cycle viruses are accessible to antibodies. Th1 and Th2 responses can also occur simultaneously despite the fact that the cytokine products secreted by both are mutually inhibitory. One possible explanation for this apparent paradox is that antigen-driven responses are highly compartmentalized by antigen. Thus, all antigen-specific cellular interactions are mediated by either membrane bound molecules or, when mediated by cytokines, these are released on a polar fashion thus preventing "spill over" to cells of unrelated specificity. Effector mechanisms used to clear primary infection / protect against re-infection
____________________ ++/++ good clearance of primary infection / good protection against subsequent re-infection +/+ fair clearance of primary infection / fair protection against subsequent re-infection ?/(+) unknown role in clearance of primary infection / only transient protective effect against re-infection - no effect Immunological memory The clonal selection theory was the earliest convincing attempt to explain the nature of immunological memory. As explained earlier, it postulated that immunological memory is based on the antigen driven expansion of clones that are specific for that antigen. The increased number of antigen specific cells was thought to be the main reason for the faster and stronger memory response. It has since become clear that not only numbers of antigen specific cells, but also their responsiveness contribute to immunological memory. Thus, "memory cells" respond more quickly to antigenic stimulation, have a lower activation threshold. Immunological memory has to be redefined in another important way. As outlined above, adaptive immune responses and consequently immunological memory differ widely depending on the effector mechanisms used for protection against re-infection with a particular pathogen. Thus, there are different forms of immunological memory, such as T cell memory, B cell memory, and memory based on elevated antibody titers. Immunological memory is long lasting. It is not clear how immunological memory is maintained. Two opposing theories are being discussed. One postulates that once clonal expansion has occurred, increased numbers of T (or B) cells with increased responsiveness persist for a long time even in the absence of antigen. The other postulates that small amounts of antigen need to persist in the host in order to continually stimulate antigen specific cells. This discussion is complicated by the fact that the two groups tend to use different definitions of immunological memory. The former defines as immunological memory any measurable alteration of the biological status of the host (T cell activation status, number of antigen specific T cells, antibody titers etc.) and the latter uses a more restrictive definition, immunological memory meaning protection from re-infection. It is not surprising that the requirements for the second, more stringent definition are more difficult to meet (e.g. require persistence of antigen). Inappropriate immune responses Although immune responses are often mixed, containing both a Th1 and Th2 component, highly polarized responses do occur and, if inappropriate, can lead to failure to clear the infectious pathogen. The following paragraph describes an infectious disease that takes very different clinical forms depending of whether an appropriate or an inappropriate polarized immune response is initiated. The response to Mycobacterium leprae Mycobacterium leprae, like Mycobacterium tuberculosis, grows in macrophage vesicles. The appropriate response is macrophage activation by specific Th1 cells. When macrophages are activated by Th1 cells, they can kill the organisms in endosomes. Not all individuals develop a Th1 response, some develop a Th2 response instead. It is now becoming clear that this polarization of responses is the reason for the existence of two different forms of leprosy, known as tuberculoid leprosy and lepromatous leprosy. Patients with the tuberculoid form develop a Th1 response with macrophage activation but little antibody production. As a consequence, few live bacteria are found in tissues. Although macrophage activation leads to some damage to peripheral nerves, the disease proceeds slowly and the patient usually survives. Patients with lepromatous leprosy develop a Th2 response and high levels of antibodies. Because these antibodies cannot reach the intracellular bacteria, they proliferate abundantly, causing extensive tissue damage and eventual death of the patient. Pathogens subverting normal immune responses There are many examples of pathogens that evade immune responses. This is achieved in many different ways. Certain bacteria produce superantigens that activate many T cells simultaneously and thereby overwhelm the host's immune system. One of the most prominent examples are staphylococcal enterotoxins and toxic shock syndrome toxin-1. These toxins form a bridge between the MHC molecule and T cell receptors thereby activating them regardless of their specificity. Some viruses can bind intracellular MHC molecules before they travel to the cell surface, thereby preventing presentation of viral peptides by these MHC molecules. The most prominent example of a virus that escapes normal host response is the virus that causes acquired immunodeficiency syndrome (AIDS). The response to the human immunodeficiency virus (HIV) The human immunodeficiency virus (HIV) is the causative agent of the acquired immunodeficiency syndrome (AIDS). HIV infects CD4+ T-cells and macrophages which leads to functional impairment of both. The structural components of the virus are illustrated in Figure 7.2. For an understanding of how HIV causes immunodeficiency, it is necessary to understand the life cycle of this virus. The life cycle if HIV The life cycle of HIV in CD4+ T cells is illustrated in Figure 7.3 and involves the following steps: 2) The virus envelop fuses with the cell membrane allowing the genome of the virus to enter the cytosol. 3) Reverse transcriptase copies viral RNA into double stranded DNA (cDNA). 4) The cDNA coding for viral proteins enters the nucleus and is integrated into the infected cell's own DNA. Transcription does not occur until the T cell is activated. Until then, the virus is not reproducing actively. It is a "provirus". 5) T cell activation induces low level transcription of provirus producing viral RNA. 6) Multiple splicing of viral RNA allows translation of early genes tat and rev. 7) Tat amplifies transcription and rev increases transport of singly spliced of unspliced viral RNA to the cytoplasm. 8) The late proteins Gag, Pol and Env are translated and assembled into virus particles that bud from the cell. Gag and pol mRNAs are translated to give long polypeptide chains that contain both protein sequences fused together. Individual proteins (Gag and Pol) have to be produced by viral proteases. The product of the env gene (gp160) has to be cleaved by host proteases to give gp120 and gp40. The most successful drug therapies of HIV developed so far are inhibitors of step 3 (Reverse transcriptase inhibitors such as AZT) and inhibitors of step 8, cleavage of polyproteins into functional viral proteins by viral proteases (protease inhibitors). It is thought that the functional impairment of CD4+ T-cells allows the virus to survive in the host. This phase of the infection may take many years. During this time the patient has few symptoms, if any, but is able to infect other individuals. Later during the infection CD4+ T-cells are not only functionally impaired, but destroyed. The depletion of CD4+ T-cells brings about the immunodeficiency syndrome known as full blown AIDS. Figures 7.4 and 7.5 show the time course of disease progression in a population of HIV infected individuals and the a typical time course of disease progression within one individual. It is not known with certainty what cases the functional impairment of CD4+ T-cells and their destruction later. Several alternative hypotheses have been proposed: Possible mechanisms for the loss of CD4+ T-cell function: HIV replication is stimulated when the infected T-cell gets activated. Therefore, memory cells are lost preferentially. 2) HIV gp120 crosslinks CD4, produces a negative signal and prevents T-cell activation. 3) HIV infects APCs. APCs either die as a consequence of being infected or are killed by CD8+ T-cells. 4) The virus itself eventually kills the infected CD4+ T-cell. 5) Infected CD4+ T-cells are killed by virus specific CD8+ T-cells. As a result of the lack of CD4+ T cells AIDS patients become susceptible to a number of opportunistic infections which eventually causes the death of the patient. Some of the more common infections are listed in Table 7.2. Table 7.2 Common infections and malignancies in AIDS patients
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