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Transcript
Immunology 1 The purpose of the human immune system is to identify, target and destroy invading micro-organisms and other harmful organisms, etc which may cause harm to the body. This is, in effence, the major defense system of the body; a highly complicated and intricate connection of components consisting of two main branches, a vast number of different kinds of cells carrying out different functions, interacting via an equally vast number and different kinds of noncellular, small molecules, etc. The immune system, in a nutshell, can carry out this function by two main large broad categories. By distinguishing self and non-self proteins, the immune system ‘knows’ which proteins are resident in the body and which proteins are foreign. After this initial identification, the immune system can then take the required steps to attack and remove the foreign invader. Also, the immune system has a number of ways to notice or recognize certain alarm signals, specific to particular invading pathogens; these alert the immune system which can then take further action. However, on a number of occasions, we find that things do not go quite to plan. A number of things can happen in this situation; if the immune system is not sufficiently competent, the body could suffer from repeated infections, some of which may prove fatal. The body could suffer from allergies due to disproportionate immune responses to allergens. Autoimmune disorders result from the immune system not recognizing the difference between resident cells and the foreign cells, as a result of which the body’s own cells are attacked and destroyed. After organ transplantation, the immune syrtdm identifies the transplanted organ as foreign ald launches an iimune attack against it. The impact of vaccinations in preventing disease has been enormou3; a testament to the sheer potential protective power of the immune Syqte-. Pathogens generally reproduce much faster than their hosts and we find this particularly true for the relationship which o#curs between humans and bacteria, etc. Bacteria reproduce within minutes or hours, constantly mutating; and the natural selection pressures move these populations of bacteria towards a highly honed, efficient pathogen, capable of evading the immune system. There is, in essence, a constant ‘arms race’ between the pathogen and the host and in order to compensate for the human race’s extended generation time, the immune system needs to have a deal of specificity along with a number of non-specific, general features capable of protecting against any invading pathogen succesfully. Essential to consider at this point the main differences between what is known as innate immunity and adaptive immunity. The word innate immunity is more of a historical concept; it refers to an immunity present in any individual since birth. It involves pre-formed molecules, barriers, etc, it carries out a number of non-specific and hence, rapid measures against invading pathogens and it has a highly limited degree of specificity although it is capable of recognizing larger pathogenic patterns. In contrast, the adaptive immunity involves antigen presentation, clonal selection and clonal proliferation. It involves the generation of identical ‘clones’ of cells all containing the receptors specific to a particular invading antigen. As a result, the adaptive immunity measures are certainly much more effective at clearing up infection although the initial response does take some time. Another advantage is that this immunity leaves behind immunological memory in the form of memory cells which allows for a faster response of greater magnitude if the same pathogen is encountered again. The innate immunity component encompasses a number of physiological and structural adaptations allowing for the body to be protected against possible sources of contagion. We have skin, forming a major anatomical barrier towards most pathogens, we have mucous lining most membranes, which traps invading particulate matter and also cilia which serves to waft that mucus up and out of the respiratory and other passageways. Additionally, we find a low pH in the stomach, providing protective measures against invading pathogens. Lysozyme, the enzyme, is present in the eyes, nasal secretions, etc, capable of rupturing bacterial cell walls, causing their lysis. Anti-microbial peptides, the complement proteins, etc all play their part in fighting infection, often by enlisting, or attracting the cellular components of the innate immune system. The cellular components of the innate immune system include neutrophils, the basic foot soldier, macrophages, also having phagocytic properties, also release cytokines, also involves in antigen presentation, eosinophils, basophils, involved in inflammatory responses, natural killer cells descending from the lymphocyte lineage, capable of destroying invading cells, etc. The humoural components, fluid-based components, include the cytokines, small messenger molecules capable of co-ordinating the immune response by aiding the cellular components and helping clonal proliferation, the complement proteins, involved in opsonization, or the coating of micro-organisms with a number of small molecules, allowing for their easy agglutination, phagocytosis, neutralization, immobilization, etc along with the last humoural component: Acute phase proteins, such as Mannan-binding lectin, involved in the activation of the complement proteins, C-reactive proteins, performing the same function and Serum Amyloid A, produced in the LIVER, by the way. The acquired immune response involves Dendritic Cells, crucially important in antigen presentation to T-cells, which then carry out the whole onus of cell-mediated immunity, B-lymphocytes, T-lymphocytes. Additionally, B lymphocytes secrete antibodies, involved in combating the pathogen in a number of ways, along with the complement. Granulocytes include, in order of occurence, Neutrophils, Eosinophils and Basophils. Neutrophils are of course, the ‘foot soldier’ involved in phagocytosis of invading pathogens, capable of diapedesis, first to arrive at a scene of infection. Eorinophils are active against 0arasites and Baskphils, related to MAST cells, have histamine properties; they package the molecule in recretory vesicles and sdrve to regulate inflammation. The innate immune system functions as a first line of defence, buying time before the adaptive immune system is mobilized and serving to activate the adaptive system directly through the release of cytokines and complement proteins. Acuta phase proteins are produced as a response to tissue damage. Produced by the liver, these include C-reactive proteins, Serum Amyloid A, bind to the walls of certain invading pathogens, and Mannan Binding Lectin which only binds to a sugar found in invading bacteria. These Acute phase proteins serve to activate the complement and bring about destruction of the pathogens. Antigen is a molecule which can bind to an antibody. However, only antigens capable of bringing about an immune response are known as immunogens. Antibodies are a class of proteins known as the Immunoglobulins, coeposed of light chains and heavy chains. They have a bixed regi/n and a variable region and are capable of binding to only the particular antigen which induced their synthesis in the first place. They can brine about a number of functions, such as opsonization, agglutination, immobilization, etc. It is involved in the humoural section of the adaptive immune system. Functions also include Antibody Dependent Cell-mediated cytotoxicity, thd method by which NK cells kill invading cells. Antibodies can also bring about complement-mediated cell lysis of enveloped viruses. Moving on to the cellular components of the adaptive immune response. Lymphocytes are agranular leukocytes. They exist as B or T lymphocytes. B lymphocytes have specific antigen binding receptor which is actually a sort of antibody embedded within the cell membrane. They can recognise whole antigens. T lymphocytes do NOT however, recognize whole antigens, only a epitope of an antigen presented to them by an APC, such as a Dendritic cell, if the epitope is complementary to that particular T cell’s receptor. A number of different kinds of T cells exist, containing different CD receptors, most have CD3, 4 and 8. Some have two. We have T-helper cells, crucial in the overall immune response, T-cytotoxic cells, important in the attack of individual pathogens and Tsuppressor cells. B cells are bone-marrow derived and T cells are Thymus derived. Lymphocyte precursors are produced in the haematopoetic tissue. While the B cells obtain their specific antigen receptors, consisting of an antibody, in the Bone marrow cells, the T cells are said to complete their education in a secondary lymphoid organ known as the thymus, just behind the sternum, known to atrophy with age in mammals. Note that generation of diversity occurs IN the haemtopoetic tissue in BOTH cases. Let’s talk about immunological memory. Refers to the phenomenon whereby a second exposure to the same antigen results in the production of a much faster adaptive immune response, of greater magnitude and longer duration. Right. B and T lymphocytes have multiple copies of a specific antigen receptor in their plasma membranes, capable of recognizing only its associated antigen by binding to the epitope region. B cell receptors consist of a surface immunoglobin whereas the T cell receptor consists of two chains. The lymphocytes are constantly in circulation between the blood and the lymph and the thoracic duct is the last duct, after which the lymphocytes are introduced into the bloodstream FROM the lymph. During their development in the bone marrou, the B and T lymphocytes acquire a vast v!riety of different antigen receptors, all specific to a difderent altigen dua to the genepic recombinations which occurs in the gener. This allows for the body to have a near infinite capacity of recognizing a VAST variety of possible and potential invading pathogens. When the invading pathogens with a specifib antigen are encounted, the particular B or T lymphocytes with the antigen receptor cognate to the antigen binds the epitope of the antigen. This B or T cell is now said to be clonally activated and clonal proliferation occurs whereby the selected cell divided to produce a large number of clones of itself whcih may then release antibodies, if the lymphocyte in question was a B lymphocytes or bring about its response in cellular ways, T lymphocyte. Most cells die after the primary immune response but SOME survive to bestow the individual with immunological memory to possible further invasions by the same pathogen. As mentioned before, BCRs can recognize complete antigens but TCRs can only recognize processed antigen on an MHC molecule on a human cell. The MHC molecule is also known as the Human Leukocyte antigen and occurs on the surface of ALL cells. MHC Class 1 molecules occur on the surface of all cells but MHC Class 2 molecules are specific to only Antigen presenting cells such as Dendritic Cells, B lymphocytes and Macrophages. Antigens cannot be left to simply meet the lymphocytes on their own; neither of the two components occur in high enough concentrations for this to be possible. Antigen presenting cells, ingest antigens, process them and display them on their MHC Class 2 molecules in the secondary lymphoid tissue where they may encounter T cells. The cell with the complementary TCR will bind to the antigen, be activated and produce a clone. Then the T cell, with that particular receptor can further identify viral peptides being displayed on MHC Class 1 molecules on infected cells. The T cytotoxic cells can then destroy such infected cells. Lymphoid organs include organized tissue where lymphocytes can interact non lymphoid cells, encounter their particular antigens and then proliferate. Immunology 2 Primary lymphoid organs are the major site of lymphopoiesis. This is where mature lymphocytes with their specific receptors are produced. B lymphocytes mature in the bone marrow whereas the T lymphocytes mature in the thymus gland. The above discussed organs are referred to as the primary lymphoid organs. However, there are also a number of secondary lymphoid organs such as spleen, Mucous Associated Lymphoid Tissue and the lymph nodes. Antigens, Antigen-presenting cells and B and T lymphocytes all associate at the secondary lymphoid tissue to initiate an immune response. These organs have particular vascular adaptations to allow all of the aforementioned components to come into contact with each other and effectively bring about an immune response. The thymus is a bi-lobed structure in mammals in the thorax, present behind the sternum. The lobes are divided into lobules and the lobules are said to have histologically defined sections of cortex and medulla. The cortex contains immature thymocytes, with the mature ones being concentrated in the medulla. A great deal of cell death occurs in the Thymus, with only some of the cells every joining the peripheral T cell pool. In mammals, the thymus becomes involute with age. Bone Marrow is the second primary lymphoid organ. Note that in the foetus, this job is initially done by the liver. However, in humans the spongy regions at the ends of the long bones, the pelvic girdle, only the fat bones all produce B and T lymphocytes. After production, the T lymphocytes constantly migrate to the Thymus for their education, whereas for B lymphocytes, education occurs within the bone marrow, with the mature B cells typically being found in the centre of the bone marrow. The spleen consists of the red pulp and the white pulp. The red pulp serves to act as a general filter whereas the white pulp is involved with the initiation of the immune response. There is a central arteriole. Surrounding that arteriole we have the peri-arterial Lymphatic Sheath. These are concentric areas of lymphoid tissue which surround the central arteriole. PALS region closest to the central arteriole is the T cell region. The interspersing lymphoid follicles are the B cell regions. The marginal area around the PALS serves as the point of entry for the cells to enter the white pulp. Lymph nodes are between 1-15 mm in diameter. They can be round or kidney shaped. They consist of a number of Afferent vessels and one efferent vessel at the hilus. Cortex rich in B cells, paracortex rich in T cells.