How the immune system works Source: http://www.aidsmap.com Information on the human immune system, including a description of immune cells and antibodies, and how the immune system's components work together to combat infection.

How the immune system works .......................................................... 1 SUMMARY: HOW THE IMMUNE SYSTEM WORKS.............................................. 2 WHAT IS THE IMMUNE SYSTEM? .............................................................. 3 IMMUNE CELLS .................................................................................. 4 Phagocytic cells........................................................................... 4 Dendritic cells ............................................................................. 5 Lymphocytes .............................................................................. 5 B-lymphocytes ............................................................................ 5 T-lymphocytes ............................................................................ 6 CD4 and CD8 T lymphocytes......................................................... 6 Memory, naive and activated T-cells .............................................. 7 Natural killer cells........................................................................ 7 ANTIGENS AND ANTIBODIES ................................................................... 7 RECOGNISING ANTIGENS ...................................................................... 8 Human leukocyte antigens (HLAs) ................................................. 9 IMMUNE RESPONSES............................................................................ 9 Bacteria ..................................................................................... 9 Intracellular bacteria ................................................................. 10 Viruses .................................................................................... 10 Fungi ....................................................................................... 10 CYTOKINES AND CHEMOKINES .............................................................. 10

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Summary: How the immune system works •

The human immune system protects the body against foreign objects, such as micro-organisms. It is made of many different cells that are spread throughout the body, each playing different roles and moving about the body as needed.

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There are two major types of cells in the blood. The most common are red blood cells or erythrocytes, which carry oxygen to the body tissues, and carry away carbon dioxide. The other group are white blood cells, or leukocytes. The leukocytes are the immune cells.

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Some white blood cells recognise specific foreign organisms to which the body has been exposed in the past. These specific immune cells are called lymphocytes. Other white blood cells are non-specific and can attack a range of different foreign organisms, including neutrophils, eosinophils and natural killer cells.

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There are two different types of lymphocytes. B-lymphocytes (sometimes just called B-cells) produce antibodies. An antibody is a protein that can lock onto a distinct part of a specific foreign organism. When this happens, the antibody signals to other immune cells to attack the organism.

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T-lymphocytes (sometimes just called T-cells) are called different names depending on the molecules on their surface.

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CD4 cells (also known as CD4 T-lymphocytes, or T-helper cells) play a coordinating role in the immune system. They help B-lymphocytes identify foreign organisms (which they produce antibodies against). They also secrete substances that enable CD8 cells to reproduce. CD4 cells also activate macrophages (see below) to kill certain organisms, including many causes of AIDS diseases. When HIV destroys CD4 cells, all these parts of the immune system are disrupted.

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CD8 cells (also known as CD8 T-lymphocytes or cytotoxic T-cells) attach themselves to body cells identified as abnormal, notably cells that have been infected by viruses, and kill them.

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Natural killer cells (or NK cells) attack tumour cells and virusinfected cells in a similar way to lymphocytes. But while each lymphocyte can only recognise and attack cells infected by one specific virus, natural killer cells can attack a wider range.

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Eosinophils attack organisms that are too big to be eaten by a single phagocyte (see below), like worms. 2

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The phagocytes are cells that attack and destroy foreign cells by engulfing them. There are two main different types of phagocytes: macrophages and neutrophils.

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Macrophages roam the blood and the body tissues, killing organisms that can cause AIDS-related diseases and cells infected by viruses.

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Neutrophils leave the blood to go to tissues where infection or inflammation is developing. They attack mainly bacteria and fungi.

What is the immune system? The immune system is a complex part of the body and its main function is to eradicate invading infectious agents, viruses, bacteria, protozoa and parasites, called micro-organisms. In adults the cells making up the immune system are produced in the bone marrow and circulate in the blood and lymphatic vessels. The smallest lymphatic vessels collect lymph fluid from the tissues. These join together as lymphatic ducts, passing through lymph nodes (glands) where foreign material is trapped leading to an immune response. Eventually one major lymphatic duct joins the large veins returning blood back to the heart so that lymph rejoins the bloodstream. Both blood and lymph pass through organs such as the spleen and liver where foreign material to which the immune system has reacted is destroyed. A distinctive feature of the system is the ability of immune cells to leave the blood and travel into the tissues of the body. About half of one of the most important types of cells, called lymphocytes, are associated with the skin or lining of the lungs and bowel where it is most likely that microorganisms might invade the body. The skin and linings of the lungs and bowel are in themselves good barriers against micro-organisms. Grease (sebum) from skin, tears, saliva and mucous on other linings have a good but non-specific protective effect. In the bowel, helpful (symbiotic) bacteria are present which prevent the growth of disease-causing microorganisms, probably by competing more successfully for nutrients. This balance can be disturbed by some antibiotics. Apart from cells the immune system uses molecules – usually proteins – which function to help destroy micro-organisms and to co-ordinate the cells by passing messages between them. Co-ordination can occur for cells in close proximity or over long distances. Our immune system has components which react to any micro-organism (non-specific or innate immunity) but these reactions do not change with experience. Other components have the ability to react to particular

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micro-organisms more powerfully and more quickly if they invade the body more than once (specific or acquired immunity). Acquired immunity involves the immune system developing a memory, and during our lifetime a vast number of highly specific memories accumulate to help the immune system become more efficient. This ability is exploited in vaccination where a non-harmful vaccine induces specific immunity to subsequent infection with a particular micro-organism. However, because these reactions are specific, a polio vaccine, for example, will not give protection against chickenpox.

Immune cells The immune cells are collectively called leukocytes or white cells. Immune cells are generally divided into two main types depending on their function: specific cells and non-specific cells. The specific cells, or lymphocytes, interact with specific micro-organisms that they are programmed to recognise. The non-specific cells depend on molecules produced by the specific cells (such as antibodies) for their activity. Nonspecific cells include the three sub-groups: phagocytes, dendritic cells and granulocytes. All immune cells are continuously produced in the bone marrow from the same precursor cells, called stem cells. These stem cells mature into many types which are classified by their appearance and function.

Phagocytic cells Phagocytic cells are able to ingest and destroy foreign material. The main population of cells in this family are the monocytes (in the blood) and macrophages (in the tissue). In addition, there are also the neutrophils, basophils and eosinophils which belong to a group of cells called granulocytes, which contain granules of toxic substances used to kill bacteria, fungi and large parasites. Neutrophils circulate in the bloodstream and can migrate into the tissues if necessary. These cells do not live for long and can be produced in enormous quantities in the bone marrow, especially for bacterial infections. They are attracted to where they are needed in the body. Sometimes the production of neutrophils is inhibited by drugs. A low neutrophil count is called neutropenia. Eosinophils are similar to neutrophils and are important for killing larger micro-organisms such as parasites. Basophils (when in blood) and mast cells (when in tissues) are another population of cells in the granulocyte group. However, basophils are not phagocytic - that is, they cannot ingest and destroy foreign material,

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indicating that there is cross over between the activities of different immune cell groups. Basophils are important in responding to inhaled material and gut parasites. They attract other immune cells to sites of foreign material and are involved in allergies, such as hay fever. The other main division of phagocytes is called monocytes (when in the blood) or macrophages (when in the tissues). Macrophages are also a type of 'antigen presenting cell'. (Antigen is a foreign substance, usually a protein, that stimulates an immune response). Macrophages present antigen in a particular way to the lymphocytes, thereby helping to induce an immune response. While they can act as antigen-presenting cells, their main role is to envelop and destroy foreign material. Monocytes and macrophages filter foreign material and are concentrated in the liver, spleen, kidney and lymph nodes where blood and lymph fluid pass. These cells live for a long time and carry the CD4 molecule on their surface, and thus can be infected by HIV.

Dendritic cells Dendritic cells are the main antigen-presenting cells and they are much more effective at presenting antigen than macrophages. Therefore, dendritic cells are crucial in stimulating an immune response. They are concentrated in the lymph nodes and spleen where they are able to trap foreign material. Dendritic cells also trap material elsewhere and take it to the lymph nodes where they present it to lymphocytes.

Lymphocytes The third group of immune cells is the lymphocytes. There are three main sub-groups of lymphocytes: the B, T and Natural Killer (NK) cells. B and T cells are the most important immune cells for specific or acquired immunity.

B-lymphocytes B-cells (B-lymphocytes) settle in the lymph nodes and spleen. They mature in the bone marrow where they are primed to react with only one tiny part of a particular foreign material (called antigen recognition). When presented with that particular antigen, B-cells become activated to release molecules called specific antibody (or immunoglobulin – a disease-fighting protein molecule). Each antibody attaches itself to a single specific chemical sequence on a foreign body. When a B-cell is activated after recognising antigen, it divides many times making two types of clones. One type is the plasma cell which makes and releases large amounts of the same antibody into the bloodstream. It then dies within a few weeks. The other type is a memory B- cell which can live for years. If antigen is recognised again, these cells are activated and divide into plasma cells more quickly than in the original response. In this way, the release of specific antibodies becomes more efficient.

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There are several classes of antibody called immunoglobulins G, M, A, D and E. Immunoglobulin G (IgG) is particularly useful against bacteria and their toxins. IgM is the earliest antibody to appear to a newly recognised antigen. IgA is present on surfaces and secretions, such as saliva. IgD is present on the surface of B-cells, and B-cells and IgD express the same antigen receptor. IgE is useful against parasites and plays an important role in allergic reactions. Circulating specific antibody which attaches to specific antigens helps other immune cells destroy the micro-organism. This is called humoral immunity.

T-lymphocytes T-cells, also known as T-lymphocytes, mature in the thymus gland situated under the breastbone and possibly in some other lymphoid tissue. They are specifically primed, like B-cells, to react with only one specific antigen and also have receptors on their surface to recognise specific antigen. When a T-cell recognises an antigen, the T-cell is activated - it produces clones of itself. However, instead of releasing antibodies into the bloodstream, the T-cell releases cytokines - another type of protein molecule. Cytokines can attract immune cells towards specific antigens on micro-organisms so that the immune cell can destroy the infective agent. The response of T-cells is called therefore called cell-mediated immunity.

CD4 and CD8 T lymphocytes T-cells have on their surfaces either CD4 or CD8 receptors. These are molecules which help the T-cells attach to the antigen. CD4 cells are also known as helper cells (Th cells). Experiments have shown that in other animals CD4 cells can be separated into Th1 and Th2 cells with different functions. In humans there are also a fair number of Th0 cells which cannot easily be classified. Th2 cells are particularly important. They assist B-cells in producing specific antibody by making cytokines which promote activation and growth of B-cells, and so enhance humoral immunity. Th1 cells are involved in immune responses to viruses and bacteria inside human cells (cytotoxicity) and so enhance cell-mediated immunity. CD8 cells are mainly responsible for killing cells that are infected with viruses. Hence, CD8 cells are important in HIV infection. They are also known as cytotoxic (cell-killing) lymphocytes (CTL).

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Memory, naive and activated T-cells CD4 and CD8 T-cells include a range of subsets identified by the expression of various cell surface molecules called 'markers'. All T-cells start their lives as 'naive cells' and activate when they meet a particular antigen that they are programmed to recognise. The cells fight the infection and then most die. However, a proportion become long-lived memory cells, awaiting the possible reappearance of the same antigen. T cells which express the marker CD45RO are 'memory' cells and make up most of the initial rise in CD4 and CD8 cells after the commencement of antiretroviral therapy. T-cells which express CD45RA are 'naive' cells and make up the second, slower phase of the CD4 increase during antiretroviral treatment. CD38 and HLA-DR are markers which are expressed when a T-cell is activated. Markers such as these are measured because it is important to have some idea of the proportions of T-cells which are activated, as many of these cells will subsequently die. When T-cells activate they express the marker CD95 also known as Fas. When T-cells subsequently die (through the process known as apoptosis or cell suicide), they express CD95L in addition. A plus sign (+) indicates that an immune cell is activated; a subtraction sign (-) indicates that a cell is resting. In HIV infection there appears to be too much T-cell activation alongside high levels of apoptosis or T-cell death. Both these factors may contribute to loss of CD4 cells and eventually also CD8 cells.

Natural killer cells Apart from B- and T-cells, the other type of lymphocyte is the natural killer (NK) cell which is also important in killing virus-infected cells.

Antigens and antibodies An antigen is any material causing an immune reaction. Antigens are usually foreign materials from invading micro-organisms but can include foods and inorganic chemicals. Individual or specific antigens are tiny and usually of molecular size – even parts of molecules can cause immune reactions. Sometimes the body will react to its own molecules (autoimmunity) in a harmful way, but the immune system has a way of eliminating most cells reacting in this way. There are literally millions upon millions of potential antigens the body might have to deal with in a lifetime. Antibodies are a class of protein made by B-cells. They are specific for each antigen. The best way of imagining how an antibody is specific for an 7

antigen is to think of the three dimensional fit between a lock and key. On the surface of a B-cell there are the receptors for a specific antigen. Most importantly, B-cells usually cannot perform this function without help from T-cells (the CD4 Th2 helper cells). Once activated by recognising a specific antigen, more specific antibody is made by a clone of B-cells and released into the bloodstream. T-cells also have molecular receptors on their surface to recognise a specific antigen, but this receptor is not an antibody – although it is structurally related to an antibody. Again, the best analogy for the way Tcell receptors recognise specific antigen is to think of a lock and key. CD4 and CD8 molecules on the surface of T-cells help the T-cell receptor attach to an antigen when it is presented to them.

Recognising antigens Most antigens are materials foreign to the body (‘non-self') but occasionally molecules of ‘self’ material cause immune reactions. The Tand B-lymphocytes are both primed during maturation to be able to recognise specific antigens even before they are present in the body. Considering that there are literally millions upon millions of potential antigens, it used to be a mystery how the immune system could prepare so many lymphocytes. It is now known that in the thymus gland and the bone marrow the genetic code of lymphocytes is randomly rearranged billions of times to create all the variations in antibody and T-cell receptors needed during life. So for each specific antigen encountered during life, there will be at least several T- and B-cells existing to recognise the antigen and set off a specific immune response. These activated lymphocytes will then increase in number establishing immune memory and contributing to acquired immunity. T- and B-cells are also primed to recognise ‘self’ molecules called MHC (major histocompatibility complex) molecules. This priming occurs during their maturation. Lymphocytes that over-react to MHC molecules are eliminated because triggering an immune response to MHC molecules can do damage to the body. T-and B-cells only recognise specific antigens when ‘presented’ to them next to an MHC molecule. So the recognition of antigen (usually foreign material) is done in conjunction with recognising a ‘self' molecule. The main presenting cells are dendritic cells, and less often, macrophages. One type of MHC molecule (class 1) contains a protein called beta-2 microglobulin which is released from activated or killed cells including lymphocytes. It can be measured in blood as a marker of immune activation.

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MHC molecules are genetically determined and it is incredibly unlikely that two unrelated people will have the same collection of MHC molecules on the surface of their cells. It seems likely that the efficiency of the immune system in dealing with antigens varies by the type of MHC molecules we carry. Lymphocytes react strongly to other people's MHC molecules as being foreign which is why matching for tissue type is so important to stop rejection of transplanted organs.

Human leukocyte antigens (HLAs) The human MHC 'self' molecules are also known as human leukocyte antigens (HLAs). That is, they are inherited antigens which occur on human cell surfaces. There are two main classes of HLA. Class I is divided into HLA A, B and C which are expressed by most human cells. Class I HLAs are involved in presenting antigen to CD8 cells, thus activating the CD8s. When CD8 cells recognise antigen presented by HLA class I, they kill the cell presenting it. In this way the CD8 cells destroy cells infected with viruses, including HIV. Genetic make-up of a person's HLA affects the rate of HIV disease progression. Class II is divided into HLA DP, DQ and DR which are expressed by cells such as macrophages and dendritic cells. See How the immune system works: Immune cells for more details. Class II is involved in presenting antigen to CD4 cells, thus activating CD4 cells. When CD4 cells recognise antigen presented by HLA class II, they secrete chemical messengers called cytokines (e.g. IL-2, IL-4) which in turn stimulate further immune response.

Immune responses The reactions of the immune system to the wide variety of microorganisms are varied. Antibodies released by B-cells can be abundant in bodily secretions where they can react to specific antigens in tears, saliva and fluids in the lung and gut. Sometimes specific antibody will eliminate a micro-organism at the skin, lung or gut barrier before it invades the body tissues or enters the bloodstream. A vaccine that can produce this kind of response is valuable.

Bacteria When dealing with bacteria the responses depend on whether the bacteria are growing inside or outside human cells. Bacteria can produce and release poisonous molecules called toxins which the immune system will also try to eliminate. Bacteria outside cells and bacterial toxins are dealt with by antibody released by B-cells. Bacteria coated with antibody are killed by cytotoxic cells and phagocytes.

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Intracellular bacteria Paradoxically, macrophages ingesting bacteria may then become the host cell (and the breeding ground) for bacteria that can live inside cells. Organisms such as M.TB (the agent that causes tuberculosis) and MAI (closely related to TB) are good examples. Antibodies are useless in attacking organisms inside cells. The mechanism to kill these bacteria is ’cell mediated’ by the action of cytokines from CD4 cells on the macrophages. Cytotoxic CD8 cells may also kill macrophages if specific antigens from the bacteria are recognised on the surface of the macrophage. HIV infection can severely inhibit the immune response to intracellular bacteria by damaging the response of CD4 and CD8 cells. Not surprisingly, TB and MAI are more common diseases during HIV infection.

Viruses Viruses can exist outside cells (when they are encased in a coat) but they can only replicate themselves inside a host cell. Specific antibodies can attack specific viral antigens when the virus is outside cells but not inside cells. However, virus-infected cells usually show some viral material (antigens) on their surface. MHC or 'self' molecules are already on the cell surface. CD4 and CD8 cells (T-cells) recognise the `self’ molecules of MHC in association with viral antigen which triggers a cell-mediated response. Cytokines released by these cells attract macrophages to ingest the infected cell and can make nearby cells resistant to infection by the virus. One feature of some viruses (and other micro-organisms) is their ability to alter their antigens. One effect of this can be to avoid the efficient immune response to previous antigens stored in the immune memory. The immune system has to start an immune response to a new antigen – like a game of cat and mouse. Antigen shift is an important feature of HIV.

Fungi Fungi are not usually susceptible to antibodies and the immune response is carried out by lymphocytes secreting cytokines to attract neutrophils and macrophages. Some fungi live and reproduce inside human cells. These organisms may also be more likely to cause disease in HIV infection.

Cytokines and chemokines Cytokines are the chemical messengers of the immune system. Secreted by white blood cells and tissue cells, cytokines affect immune cell interaction, communication and behaviour. Cytokines act locally, stimulating nearby cells into action. Cytokines include small proteins and biological factors such as interleukins, chemokines, lymphokines, interferons and other signaling 10

molecules such as tumor necrosis factor. The Online Medical Dictionary of the CancerWeb website refers to cytokine as rather an imprecise term. One example of a cytokine is IL-2 (interleukin-2). Activated CD4 Th1 cells produce IL-2 which stimulates the growth of other T cells and attract macrophages towards antigen. Chemokines are one class of cytokines that have the ability to attract or activate white blood cells. This directional movement of an immune cell is known as chemotaxis. There are three types of chemokines: c, cc and cxc. The three types of chemokines have variations in an amino acid known as cysteine. The c chemokines are chemoattractants for lymphocytes. The cc chemokines are chemoattractants for lymphocytes, monocytes, eosinophils, and basophils. The cxc chemokines are chemoattractants for neutrophils. The beta-chemokines are RANTES and the macrophage inflammatory proteins (MIP) 1 alpha and 1 beta. In HIV infection, the normal levels and activities of some cytokines are disrupted. Consequently, some cytokines have been tested as experimental treatments for people with HIV. Other cytokines may play a part in facilitating or blocking HIV’s entry into cells. Research is continuing into the role of cytokines in the immune system and, in particular, how cytokines affect HIV disease progression.

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