T Cell - B Cell Collaboration in the Immune Response to Infection - Essay Example

T CELL - B CELL COLLABORATION IN THE IMMUNE RESPONSE TO INFECTION Word Count: 1737 Immune System Overview: The chief function of the immune system isto protect the body from infections by invading pathogenic microorganisms like viruses, bacteria and fungi (Levinson, 2004). It has a huge range of cells and chemical substances at hand to identify and destroy an infinite number of foreign intruders (Dowshen, 2007).It differentiates foreign molecules from local ones and starts a suitable reaction, comprising of a range of cells, to counteract its harmful effects and bring the state of the body back to normal. (Kuby, 1996) The interesting part about the immune system is the stimulation of a memory response which activates the same reaction in a very short time. (Lee Evatt, 1990) Classification: The entry of a foreign pathogen is resisted by reactions of both innate and acquired immunity. The one comprises of the skin as an anatomic barrier; temperature, pH, oxygen, etc. as physiologic barriers; ingestion of pathogens as an endocytic barrier, and inflammatory barriers. It is referred to as "non-specific" because it generally attempts to stop the spread of all types of invaders. (Kuby, 1996) The latter type consists of two categories: cell-mediated immunity and antibody-mediated (humoral) immunity. It is the stronger one of the two types but takes several hours or even days to become fully activated. It is referred to as "specific" because it responds differently to every other foreign pathogen. (Hariharan, 2006) Cellular Basis of Immunity Introduction: Lymphocytes, a class of White Blood Cells, are a vital part of the acquired immune system, being responsible for the whole reaction. They are produced in the primary lymphoid organs and then migrate to the secondary lymphoid organs where they recognize antigens of foreign bodies by the help of membrane receptors specific to the antigens. Two major classes of lymphocytes take part in the acquired immunity: B-Cells (B lymphocytes) and T-Cells (T lymphocytes). (Alberts, Bray, Lewis, Raff, Roberts, Watson, 1994), (Linnemeyer, 1993) 1) T-Cells: Origin Precursors of T-cells originate in the foetal liver and yolk sac during the embryonic life, and migrate to the bone marrow after birth. The stem cells then enter the thymus by chemo taxis and develop into T-cells which are later specialized into CD4+ (helper) cells or CD8+ (cytotoxic) cells. (UNC-SOM, 2004) Maturation On entering the thymus, T-cell precursors (prothymocytes) develop into T-cells that indicate both CD4 and CD8 molecules on their membranes and then later continue to indicate either CD4 or CD8 molecules. The cells having antigen receptors for self proteins are destroyed by aptosis (programmed cell death). This prevents autoimmunity. On the other hand, the cells having antigen receptors that do not react with self MHC proteins are also killed as this causes the definite selection of T-cells that do react with MHC proteins. (Stadnyk, 2007) Functions of the MHC proteins include positive selection of T-cells as well as presentation of foreign body antigens to them. (NIAID, 2003) General Function The Helper T-cells activate lymphocytes called macrophages and other T-cells involved in the immune response, and aid B-cells in producing antibodies by alerting them and determining the type of antibody to be produced. (NIAID, 2003) 2) B-Cells: Origin Precursors of B-cells migrate from the foetal liver to the bone marrow where they remain and undergo maturation throughout the adult life. They do not require thymus for their development. (Levinson, 2004) Maturation Development of B-cells takes place in two phases: antigen-independent phase & antigen-dependent phase. In the 1st phase, stem cells of the marrow differentiate into B-lineage and progenitor B-cells. The progenitor B-cells proliferate into precursor B-cells which requires the microenvironment supplied by the surrounding stroma. Cells of the stroma release numerous cytokines, most importantly IL-7, which help in the maturation process. Further specialization of a pre B-cell converts it into an immature B-cell by light-chain gene arrangement. Continued development of immature B-cells causes expression of both IgD and IgM, thus forming mature B-cells. The 2nd phase takes place in the secondary lymphoid organs such as spleen and lymph nodes. Mature B-cells divide into memory and plasma cells on antigen activation, by the clonal selection theory, which refers to the selection of the B-cell that best fits the antigen receptor. Memory cells undergo changes in the membrane immunoglobulin, often showing two isotypes, while plasma cells produce antibodies. (Gordon; Rothenberg, 1998) General function The plasma cells are responsible for the formation of antibodies that act on the foreign bodies, while memory cells start the secondary immune response (response to invasion by the same pathogen, some days or weeks after the primary invasion), and so are a long-term protection from the pathogen. They react rapidly, compared to the virgin cells dividing into plasma cells and more memory cells. (Doug, 2006) B-Cells & T-Cells in an Immune Response T-CELLS Classification of Helper T-Cells: The previously mentioned functions of helper T-cells are performed by the following two classes of CD4 cells: 1) Th-1 Cells: release IL-2 which aids in the activation of cytotoxic T-cells and macrophages, and helps in the initiation of delayed hypersensitivity response in conjunction with gamma interferon. Thus it is useful in counteracting intravascular pathogens. 2) Th-2 Cells: release IL-4, CD40L, IL-5 and IL-6 which stimulate the activation and differentiation of antigen-binding B-cells. Thus they are useful in counteracting with extra cellular pathogens and parasites. (Harrington; Hatton; Mangan, 2005) Factors favouring production of Th-1 cells over Th-2 cells: 1) IL-12 produced by macrophages increases the number of Th-1 cells thus promoting the delayed hypersensitivity response. 2) Adjuvants promote production of cytokines like IL-12 and thus enhance the formation of Th-1 cells. 3) Lipoproteins of bacteria stimulate "toll-like receptors" on the macrophage which causes release of IL-12 thus promoting formation of Th-1 cells. (Farrar; Asnagli; Murphy, 2002) Role of cytokines: 1) IL-1 activates B and T cells, and induces production of IL-2. 2) IL-2 promotes growth of helper and cytotoxic T-cells, and acts in conjunction with IL-4 to promote growth of B-cells. 3) IL-4 and IL-5 enhance growth and differentiation of B cells, respectively. IL-4 also increases the Th-2 subset of helper T cells, which produce IL-4 & IL-5. on the other hand, IL-5 promotes production of IgA and aids in the synthesis and activation of the eosinophils. 4) IL-10 and IL-12 are responsible for the controlled production of Th-1 cells. IL-12 helps in the development of Th-1 cells, while IL-10 suppresses their development by restriction of gamma interferon formation. The relative quantity of IL-4, IL-10 and IL-12 directs the differentiation of Th-1 and Th-2 cells, and thus stimulates either humoral or cell-mediated immunity. (Levinson, 2004) The signalling of the cytokine receptors takes place by the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. In this pathway, after the ligand binds to the cytokine receptor, the intracellular non-receptive JAK tyrosine kinase molecules become active and auto-phosphorylate and Trans-phosphorylate each other and their receptors. The SH2 part of the cytosolic STAT proteins recognizes the residual phosphor-tyrosine and move towards the nucleus. There they bind to a specific DNA recognition sequence and stimulate the transcription of the required gene. (Zeidler, 2000), (Bromberg, 2002), (Kisseleva, 2002) Activation: Helper T cells need to recognize an antigen-MHC class II protein complex on the membrane of antigen-presenting macrophages or dendritic cells (in order to be activated. IL- 1 formed by the macrophages is required for the activation of both types of T cells. In addition, for helper T cells, B7 protein on the antigen-presenting cell must bind with CD28 protein and release of IL-2 by the helper T cell, which binds to its receptor on the same cell and further activates it. For the cytotoxic T cell to be activated, its receptor binds to an MHC class I protein instead, presented to it by a virus-infected cell. Along with that, the IL-2 produced by the helper T cell the virus-infected cell. (NCI, n.d) Figure 1: T cell activation (NIH, 2003) Line of Action: The functions of T cells are divided into the following categories: Effector functions: are carried out primarily by cytotoxic T cells, which destroy virus-infected and tumor cells, but helper T cells also have a little part in them. In order to kill an infected cell, cytotoxic T cells need to get cytokine stimulation from a helper T cell. The helper T cells recognize the viral antigens on the class II protein of a macrophage and release IL-2 which induces production of more cytotoxic T cells. These cells inject perforins and granzymes to kill the infected cell. They also activate caspases that cause aptosis and thus, cell death. Delayed hypersensitivity is brought about by Th-1 cells and macrophages. In this response, the CD4 cells produce interleukins while the macrophages are the absolute effectors. (Levinson, 2004) Regulatory functions: (described with the function of B cells) B-CELLS Activation & Line of Action: Antigen binds to membrane IgD or IgM and cross links adjacent immunoglobulins. The immunoglobulins aggregate forming patches, and move to one pole of the cell forming a cap. The cap is ingested resulting in the surfacing of epitopes bound with class II MHC proteins. The CD4 cell identifies this complex and releases IL-2, IL-4, and IL-5 that induce growth and development of the B cell. (Levinson, 2004) In the presence of a thymus dependent antigen (requires participation of helper T-cells), apart from recognition of the epitope by the T cell receptor, and the binding of the antigen to the immunoglobulin, another signal is required for the activation of the B cell; binding of the CD40L on the T cell to the CD40 on the B cell that is necessary for the class switching from IgM to IgG and the formation of other classes. (Lane, 1988), (Levinson, 2004) In the presence of a thymus independent antigen (does not require helper T-cells), those that are multivalent, the additional signal is the binding of the antigen to toll-like receptors for the release of IL-2, or extensive cross linking due to the multivalent property of the antigen. In the thymus dependent response, all classes of antibodies are made, such as IgA, IgG, IgE, IgM, etc, while in the thymus independent response, IgM is the antibody chiefly formed. This shows that interleukins formed by the helper T cells are used for class switching. Furthermore, the thymus dependent response produces memory B cells while thymus independent does not. Thus a secondary immune response does not occur in the thymus independent response. Figure 2: B cell activation (NIH, 2003) Due to the formation of memory cells by the aid of helper T cells, a secondary immune response occurs when the same pathogen strikes again some time (months or years later). Thus, the same antibodies are produced, but more rapidly. Each time the same antigen strikes the antibody, it binds the antigen more strongly. This is due to somatic hypermutation, that is; mutations occurring in the DNA sequence that codes for the antigen receptor. These altered plasma cells are thus selected more forcibly and more often, by the antigen, to be part of the antibody production. This is known as affinity maturation. (Kuby, 1996) Works Cited 1) Activation of T-Cells. (n.d). 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