Immunology

Overview of Immunology An animal must defend itself against the many potentially dangerous viruses, bacteria, and other pathogens it encounters in the air, in food, and in water. It must also contend with abnormal body cells that may develop into cancer. Two major kinds of defense have evolved that counter these threats. The first, called innate immunity, is present before any exposure to pathogens and is effective from the time of birth. Innate defenses are largely nonspecific, quickly recognizing and responding to a broad range of microbes regardless of their precise identity. Innate immunity consists of external barriers formed by the skin and mucous membranes, plus a set of internal cellular and chemical defenses that combat infectious agents that breach the external barriers. Key players in these internal defenses are macrophages and other phagocytic cells, which ingest and then destroy pathogens. The second major kind of defense is acquired immunity, also called adaptive immunity. It develops only after exposure to inducing agents such as microbes, abnormal body cells, toxins, or other foreign substances. Acquired defenses are highly specificthat is, they can distinguish one inducing agent from another, even those that differ only slightly. This recognition is achieved by white blood cells called lymphocytes, which produce two general types of immune responses. In the humoral response, cells derived from B lymphocytes secrete defensive proteins called antibodies that bind to microbes and mark them for elimination. In the cellmediated response, cytotoxic lymphocytes directly destroy infected body cells, cancer cells, or foreign tissue.

Overview of vertebrate defenses against bacteria, viruses, and other pathogens. Defenses in vertebrates can be divided into innate and acquired immunity. If an invading pathogen breaches the bodys external innate defenses, various internal innate defenses quickly come into play. The defenses provided by acquired immunity against specific pathogens develop more slowly. Some components of innate immunity also function in acquired immunity.

Review of blood cells, pages 461-463

Phagocytosis Microbes that penetrate the bodys external defenses, such as those that enter through a break in the skin, must contend with the bodys internal mechanisms of innate defense. These defenses depend mainly on phagocytosis, the ingestion of invading microorganisms by certain types of white blood cells generically referred to as phagocytes. These cells produce certain antimicrobial proteins and help initiate inflammation, which can limit the spread of microbes in the body. Phagocytes attach to their prey via surface receptors that bind to structures found on many microorganisms but not on normal body cells. Among the structures bound by these receptors are certain polysaccharides on the surface of bacteria. After attaching to one or more microbes, a phagocyte engulfs the microbes, forming a vacuole that fuses with a lysosome. Microbes are destroyed by lysosomes in two ways. First, nitric oxide and other toxic forms of oxygen contained in the lysosomes may poison the engulfed microbes. Second, lysozyme and other enzymes degrade microbial components.

Phagocytosis. This schematic depicts events following attachment of one kind of phagocyte, a macrophage, to microbes via its surface receptors (not shown). The process is similar in other types of phagocytic cells.

Four types of white blood cells (leukocytes) are phagocytic. They differ in their abundance, average life span, and phagocytic ability. By far the most abundant are neutrophils, which constitute about 6070% of all white blood cells. Neutrophils are attracted to and then enter infected tissue, engulfing and destroying the microbes there. However, neutrophils tend to selfdestruct in the process of phagocytosis, and their average life span is only a few days.

A more effective phagocytic defense comes from macrophages. These large, long-lived cells develop from monocytes, which constitute about 5% of circulating white blood cells. New monocytes circulate in the blood for only a few hours and then migrate into tissues where they are transformed into macrophages. Some macrophages migrate throughout the body, while others reside permanently in various organs and tissues. Macrophages that are permanent residents in the spleen, lymph nodes, and other tissues of the lymphatic system are particularly well positioned to combat infectious agents. The other two types of phagocytes are less abundant and play a more limited role in innate defense than neutrophils and macrophages. Eosinophils have low phagocytic activity but are critical to defense against multicellular parasitic invaders. Rather than engulfing such a parasite, eosinophils position themselves against the parasites body and then discharge destructive enzymes that damage the invader. The fourth type of phagocyte, dendritic cells, can ingest microbes like macrophages do. However, their primary role is to stimulate the development of acquired immunity. Numerous proteins function in innate defense by attacking microbes directly or by impeding their reproduction. Other antimicrobial proteins include about 30 serum proteins that make up the complement system. In the absence of infection, these proteins are inactive. Substances on the surface of many microbes, however, can trigger a cascade of steps that activate the complement system, leading to lysis (bursting) of invading cells. Certain complement proteins also help trigger inflammation or play a role in acquired defense. Damage to tissue by physical injury or the entry of pathogens leads to release of numerous chemical signals that trigger a localized inflammatory response. One of the most active chemicals is histamine, which is stored in mast cells found in connective tissues. When injured, mast cells release their histamine, triggering dilation and increased permeability of nearby capillaries. Activated macrophages and other cells discharge additional signals, such as prostaglandins, that further promote blood flow to the injured site. The resulting increased local blood supply causes the redness and heat typical of inflammation. The blood-engorged capillaries leak fluid into neighboring tissues, causing swelling, another sign of local inflammation.

Immune response The immune response is based upon the recognition of a foreign or non-self chemical substance produced by an invading organisms followed by the production of chemicals and cells that effectively repel the invasion. In short, this is the production of antibodies in response to antigens. The invading substance is called an antigen. The chemical substance produced by the threatened organism in response to the invader is called an antibody. Lymphocytes are special types of white blood cells with the ability to recognize foreign cells and reject them. A lymphocyte actually recognizes and binds to just a small, accessible portion of an antigen, called an epitope or antigenic determinant. A single antigen usually has several different epitopes, each capable of inducing a response from lymphocytes that recognize that epitope. Antibodies, which are secreted by certain lymphocytes in response to antigens, likewise bind to specific epitopes. Lymphocyte development Lymphocytes originate from pluripotent stem cells (cells capable of developing into any type of cell under certain conditions) in the bone marrow. Newly formed lymphocytes are all alike, but they later develop into either T cells or B cells, depending on where they continue their maturation. Lymphocytes that migrate from the bone marrow to the thymus, a gland in the thoracic cavity above the heart, develop into T cells (T for thymus). Lymphocytes that remain in the bone marrow and complete their maturation there become B cells. As B cells and T cells are maturing in the bone marrow and thymus, respectively, their antigen receptors are tested for potential self-reactivity. Lymphocytes bearing receptors specific for molecules already present in the body are either destroyed by apoptosis or rendered nonfunctional, leaving only lymphocytes that react to foreign (nonself) molecules. This capacity to distinguish self from nonself continues to develop even as the cells migrate to lymphoid organs. Thus, the body normally has no mature lymphocytes that react against self components: The immune system exhibits the critical feature of self-tolerance. Failure of self-tolerance can lead to autoimmune diseases such as multiple sclerosis. Antigen Recognition by Lymphocytes The two main types of lymphocytes: B lymphocytes (B cells) and T lymphocytes (T cells) circulate through the blood and lymph and are concentrated in the spleen, lymph nodes, and other lymphoid tissues (thymus, liver, bone marrow etc). B cells and T cells recognize antigens by means of antigen-specific receptors embedded in their plasma membranes. A single B or T cell bears about 100,000 of these antigen receptors, and all the receptors on a single cell are identical. In other words, each lymphocyte displays specificity for a particular receptor on an antigen and defends against that antigen or a small set of closely related antigens. B-cell receptor Each B cell receptor for an antigen is a Y-shaped molecule consisting of four polypeptide chains: two identical heavy chains (H-chains) and two identical light chains (L-chains) linked by disulfide bridges (Fig. 14.38 textbook, page 486). A region in the tail portion of the molecule, the transmembrane region, anchors the receptor in the cells plasma membrane, and a short region at the end of the tail extends into the cytoplasm. At the tips of the Y are the light- and heavy-chain variable (V) regions, so named because their amino acid sequences vary extensively from one B cell to another. The remainder of the molecule is made up of the constant (C) regions, whose amino acid sequences vary little from cell to cell.

Each B cell receptor has two identical antigen-binding sites. The unique contour of each binding site is formed from part of a heavy-chain V region and part of a light-chain V region. The interaction between an antigen-binding site and its corresponding antigen is stabilized by multiple non-covalent bonds between chemical groups on the respective molecules. The antigens bound by B cell receptors in this way include molecules that are on the surface of, or are released from, all types of infectious agents. In other words, a B cell recognizes an intact antigen in its native state. T-cell receptor Each T cell receptor for an antigen consists of two different polypeptide chains, an chain and a chain, linked by a disulfide bridge. Near the base of the molecule is a transmembrane region that anchors the molecule in the cells plasma membrane. At the outer tip of the molecule, the and chain variable (V) regions form a single antigen-binding site. The remainder of the molecule is made up of the constant (C) regions. T cell receptors recognize and bind with antigens just as specifically as B cell receptors. However, while the receptors on B cells recognize intact antigens, the receptors on T cells recognize small fragments of antigens that are bound to normal cell-surface proteins called MHC molecules. MHC molecules are so named because they are encoded by a family of genes called the major histocompatibility complex (MHC). As a newly synthesized MHC molecule is transported toward the plasma membrane, it binds with a fragment of protein (peptide) antigen within the cell and brings it to the cell surface, a process called antigen presentation (The process by which an MHC molecule binds to a fragment of an
intracellular protein antigen and carries it to the cell surface, where it is displayed and can be recognized by a T cell). A nearby T cell can detect the antigen fragment thus displayed on the cells surface.

Antigen receptors on lymphocytes. All the antigen receptors on a particular B cell or T cell bind the same antigen. The variable (V) regions vary extensively from cell to cell, accounting for the different binding specificities of individual lymphocytes; the constant (C) regions vary little or not at all.

Class I MHC molecules, found on almost all nucleated cells of the body, bind peptides derived from foreign antigens that have been synthesized within the cell. Any body cell that becomes infected or cancerous can display such peptide antigens by virtue of its class

I MHC molecules. Class I MHC molecules displaying bound peptide antigens are recognized by a subgroup of T cells called cytotoxic T cells.

Class II MHC molecules are made by just a few cell types, mainly dendritic cells, macrophages, and B cells. In these cells, class II MHC molecules bind peptides derived from foreign materials that have been internalized and fragmented through phagocytosis or endocytosis. Dendritic cells, macrophages, and B cells are known as antigenpresenting cells because of their key role in displaying such internalized antigens to another subgroup of T cells called helper T cells.

Clonal selection of lymphocytes A soluble antigen or an antigen present on the surface of a microbe, infected body cell, or cancer cell encounters a large repertoire of B cells and T cells in the body. However, a given antigen interacts only with the relatively few lymphocytes bearing receptors specific for epitopes on that antigen. The selection of a B cell or T cell by an antigen activates the lymphocyte, stimulating it to divide many times and to differentiate, forming two clones of daughter cells. One clone consists of a large number of short-lived effector cells that combat the same antigen. The nature and function of the effector cells depend on whether the lymphocyte selected is a helper T cell, a cytotoxic T cell, or a B cell. The other clone consists of memory cells, long-lived cells bearing receptors specific for the same inducing antigen. This antigen-driven cloning of lymphocytes is called clonal selection. Each antigen, by binding to specific receptors, selectively activates a tiny fraction of cells from the bodys diverse pool of lymphocytes; this relatively small number of selected cells gives rise to clones of thousands of cells, all specific for and dedicated to eliminating that antigen.

Clonal selection of B cells. A B cell is selected by an antigen to proliferate and differentiate into memory B cells and antibody-secreting plasma cells. All the B cells whose receptors have a different specificity (indicated by different shapes and colors) do not respond to this antigen. T lymphocytes undergo a similar process, generating memory T cells and effector T cells.

The selective proliferation and differentiation of lymphocytes that occurs the first time the body is exposed to a particular antigen represents the primary immune response. In the primary response, the maximum effector response does not occur until about 10 to 17 days after the initial exposure to the antigen. During this time, selected B cells generate antibody-secreting effector B cells, called plasma cells, and selected T cells are activated to their effector forms, which have distinct functions. While these effector cells are developing, a stricken individual may become ill. Eventually, symptoms of illness diminish and disappear as antibodies and effector T cells clear the antigen from the body. If an individual is exposed again to the same antigen, the response is faster (typically only 2 to 7 days), of greater magnitude, and more prolonged. This is the secondary immune response. Measures of antibody concentrations in the blood serum over time show clearly the difference between primary and secondary immune responses. In addition to being more numerous, antibodies produced in the secondary response tend to have greater affinity for the antigen than those secreted in the primary response.

The specificity of immunological memory. Long-lived memory cells generated in the primary response to antigen A give rise to a heightened secondary response to the same antigen, but do not affect the primary response to a different antigen (B).

The immune systems capacity to generate secondary immune responses, called immunological memory, depends on the clones of long-lived T and B memory cells generated following initial exposure to an antigen. These memory cells are poised to proliferate and differentiate rapidly when they later contact the same antigen.

Humoral and cell mediated response Acquired immunity includes two branches: the humoral immune response which involves the activation and clonal selection of B cells, resulting in production of secreted antibodies that circulate in the blood and lymph and the cell-mediated immune response involves the activation and clonal selection of cytotoxic T cells, which directly destroy certain target cells. The diagram below outlines the roles of the major participants in acquired immune responses. Central to this network of cellular interactions is the helper T cell, which responds to peptide antigens displayed on antigen-presenting cells and in turn stimulates the activation of nearby B cells and cytotoxic T cells.

An overview of the acquired immune response. Stimulation of helper T cells by an antigen generally requires direct contact between a dendritic cell and helper T cell in a primary response (shown here) or between a macrophage and memory T cell in a secondary response (not shown). Once activated, a helper T cell stimulates the humoral response directly by contacting B cells and indirectly by secreting cytokines. An activated helper T cell stimulates the cell-mediated response indirectly via cytokines.

Helper T Cells
When a helper T cell encounters and recognizes a class II MHC moleculeantigen complex on an antigen-presenting cell, the helper T cell proliferates and differentiates into a clone of activated helper T cells and memory helper T cells. A surface protein called CD4, present on most helper T cells, binds the class II MHC molecule. This interaction helps keep the helper T cell and the antigen-presenting cell joined while activation of the helper T cell proceeds. Activated helper T cells secrete several different cytokines that stimulate other lymphocytes, thereby promoting cell-mediated and humoral responses. The helper T cell itself is also subject to regulation by cytokines. For instance, as a dendritic cell presents an antigen to a helper T cell, the dendritic cell is stimulated to secrete cytokines that, along with an antigen, stimulate the helper T cell to produce its own set of cytokines. The class II MHC molecules recognized by helper T cells are found mainly on dendritic cells, macrophages, and B cells. Dendritic cells are particularly effective in presenting antigens to naive helper T cells, so called because they have not previously detected an antigen. In other words, dendritic cells are important in triggering a primary immune response. Dendritic cells are located in the epidermis and in many other tissues, where they efficiently capture antigens. They then migrate from the site of infection to various lymphoid tissues, where they present antigens, via class II MHC molecules, to helper T cells. Macrophages play the key role in initiating a secondary immune response by presenting antigens to memory helper T cells, while B cells primarily present antigens to helper T cells in the course of the humoral response.

The central role of helper T cells in humoral and cell-mediated immune responses. The SEM of a dendritic cell reveals its long branching extensions, reminiscent of the dendrites of a nerve cell. Dendritic cells are the primary antigen-presenting cells during the primary response to an antigen. TCR = T cell receptor. A indicates stimulation/

Cytotoxic T Cells: A Response to Infected Cells and Cancer Cells

Cytotoxic T cells, the effectors of cell-mediated immunity, eliminate body cells infected by viruses or other intracellular pathogens as well as cancer cells and transplanted cells. Fragments of nonself proteins synthesized in such target cells associate with class I MHC molecules and are displayed on the cell surface, where they can be recognized by cytotoxic T cells. A surface protein called CD8, present on most cytotoxic T cells, greatly enhances the interaction between a target cell and a cytotoxic T cell. Binding of CD8 to the side of a class I MHC molecule helps keep the two cells in contact during activation of the cytotoxic T cell. Thus, the role of class I MHC molecules and CD8 is similar to that of class II MHC molecules and CD4, except that different cell types are involved. When a cytotoxic T cell is selected by binding to class I MHC moleculeantigen complexes on an infected body cell, the cytotoxic T cell is activated and differentiates into an active killer. Cytokines secreted from nearby helper T cells promote this activation. The activated cytotoxic T cell then secretes proteins that act on the bound infected cell, leading to its destruction. The death of the infected cell not only deprives the pathogen of a place to reproduce but also exposes it to circulating antibodies, which mark it for disposal. After destroying an infected cell, the cytotoxic T cell may move on and kill other cells infected with the same pathogen.

The killing action of cytotoxic T cells. After interacting with a target cell, such as an infected body cell or cancer cell, an activated cytotoxic T cell releases perforins and proteolytic enzymes (granzymes) that promote death of the target cell. The colorized SEM shows a cancer cell with a perforin-induced pore in the early stages of apoptosis. TCR = T cell receptor.

In the same way, cytotoxic T cells defend against malignant tumors. Because tumor cells carry distinctive molecules (tumor antigens) not found on normal body cells, they are identified as foreign by the immune system. Class I MHC molecules on a tumor cell display fragments of tumor antigens to cytotoxic T cells. Interestingly, certain cancers and viruses (such as the Epstein-Barr virus) actively reduce the number of class I MHC molecules on affected cells, helping them escape detection by cytotoxic T cells. But the body has a backup defense: the natural killer (NK) cells, which are a part of the bodys nonspecific innate defenses, can induce apoptosis in virus-infected and cancer cells. NK cells patrol the body and attack virus-infected body cells and cancer cells. Surface receptors on an NK cell recognize general features on the surface of its targets. Once it is attached to a virus-infected cell or cancer cell, the NK cell releases chemicals that lead to the death of the stricken cell by apoptosis, or programmed cell death. Although the defense provided by NK cells is not 100% effective, viral infections and cancer would occur much more often without these innate sentinels of the body.

B Cells
Antigens that elicit a humoral immune response are typically proteins and polysaccharides present on the surface of bacteria or incompatible transplanted tissue or transfused blood cells. In addition, for some people, proteins of foreign substances such as pollen or bee venom act as antigens that induce an allergic, or hypersensitive, humoral response. The diagram below depicts the events in the humoral response to a typical protein antigen. The activation of B cells is aided by cytokines secreted from helper T cells activated by the same antigen. Stimulated by both an antigen and cytokines, the B cell proliferates and differentiates into a clone of antibody-secreting plasma cells and a clone of memory B cells. When an antigen first binds to receptors on the surface of a B cell, the cell takes in a few of the foreign molecules by receptor-mediated endocytosis. In a process similar to antigen presentation by macrophages and dendritic cells, the B cell then presents antigen fragments to a helper T cell. This achieves the direct cell-cell contact critical to B cell activation (step 2 in diagram below). Note, however, that a macrophage or dendritic cell can present peptide fragments from a wide variety of antigens, whereas a B cell internalizes and presents only the antigen to which it specifically binds.

Humoral immune response. Most protein antigens require activated helper T cells to trigger a humoral response. Either a macrophage (shown here) or a dendritic cell can activate helper T cells. The TEM of a plasma cell reveals abundant endoplasmic reticulum, a common feature of cells dedicated to making proteins for secretion. TCR = T cell receptor. A indicates stimulation.

Antigens that induce antibody production only with assistance from helper T cells, as shown in Figure 43.17, are known as T-dependent antigens. Some antigens, however, can evoke a B cell response without involvement of helper T cells. Such T-independent antigens include the polysaccharides of many bacterial capsules and the proteins that make up bacterial flagella. Apparently, the repeated subunits of these molecules bind simultaneously to several antigen receptors on a single B cell, providing enough stimulus to activate the cell without the help of cytokines. The response to T-independent antigens is very important in defending against many bacteria. However, this response is generally weaker than the response to T-dependent antigens and generates no memory B cells. Most antigens recognized by B cells contain multiple epitopes. For this reason, exposure to a single antigen normally stimulates a variety of different B cells, each giving rise to a clone of thousands of plasma cells. All the plasma cells in one clone secrete antibodies specific for the epitope that provoked their production. Each plasma cell secretes an estimated 2,000 antibody molecules per second over the cells 4- to 5-day life span. Next we look more closely at antibodies and how they mediate the disposal of antigens.

Active and Passive Immunization

Immunity conferred by natural exposure to an infectious agent is called active immunity because it depends on the action of a persons own lymphocytes and the resulting memory cells specific for the invading pathogen. Active immunity also can develop following immunization, often called vaccination. The first vaccine consisted of the virus causing cowpox, a mild disease usually seen in cows but also occasionally in humans. Modern vaccines include inactivated bacterial toxins, killed microbes, parts of microbes, viable but weakened microbes that generally do not cause illness, and even genes encoding microbial proteins. All these agents induce an immediate immune response and long-lasting immunological memory (thanks to memory cells). A vaccinated person who encounters the actual pathogen from which the vaccine was derived will have the same quick secondary response as a person previously infected with the pathogen. Immunity can also be conferred by transferring antibodies from an individual who is immune to a particular infectious agent to someone who is not. This is called passive immunity because it does not result from the action of the recipients own B and T cells. Instead, the transferred antibodies are poised to immediately help destroy any microbes for which they are specific. Passive immunity provides immediate protection, but it persists only as long as the transferred antibodies last (a few weeks to a few months). Passive immunization occurs naturally when IgG antibodies of a pregnant woman cross the placenta to her fetus. In addition, IgA antibodies are passed from a mother to her nursing infant in breast milk. These help protect the infant from infection while the babys own immune system is maturing. In artificial passive immunization, antibodies from an immune animal are injected into a nonimmune animal. For example, a person bitten by a rabid animal may be given antibodies isolated from other people who have been vaccinated against rabies. This measure is important because rabies may progress rapidly, and the response to active immunization may be too slow to save the victim. Most people who have been exposed to the rabies virus are both passively and actively immunized. The injected antibodies help keep the virus in check until the victims own immune response, induced by active immunization and by the infection itself, takes over.

Antibodies
A secreted antibody has the same general Y-shaped structure as a B cell receptor but lacks a transmembrane region that would anchor it to the plasma membrane. Although the antigenbinding sites on an antibody are responsible for its ability to identify a specific antigen, the tail of the Y-shaped molecule, formed by the constant (C) regions of the heavy chains, is responsible for the antibodys distribution in the body and for the mechanisms by which it mediates antigen disposal.

The power of antibody specificity and antigen-antibody binding has been harnessed in laboratory research, clinical diagnosis, and the treatment of diseases. Some of these antibody tools are polyclonal: They are the products of many different clones of B cells, each specific for a different epitope. Antibodies produced in the body following exposure to a microbial antigen are polyclonal. In contrast, other antibody tools are monoclonal: They are prepared from a single clone of B cells grown in culture. All the monoclonal antibodies (Any of a preparation of
antibodies that have been produced by a single clone of cultured cells and thus are all specific for the same epitope) produced by such a culture are identical and specific for the same epitope on an antigen.

In both basic research and medical applications, monoclonal antibodies are particularly useful for tagging specific molecules. For example, certain types of cancer are treated with tumor-specific

monoclonal antibodies bound to toxin molecules. The toxin-linked antibodies carry out a precise search-and-destroy mission, selectively attaching to and killing tumor cells. Monoclonal antibodies: anticancer drug, MabThera; use of monoclonal antibodies in pregnancy testing. (Read textbook, chapter 12) ***** The highly regulated interplay of lymphocytes with foreign substances, with each other, and with other body cells provides extraordinary protection against many pathogens. However, if this delicate balance is disrupted by an immune system malfunction, the effects on the individual can range from the minor inconvenience of some allergies to the serious and often fatal consequences of certain autoimmune and immunodeficiency diseases. Autoimmune Diseases In some individuals, the immune system loses tolerance for self and turns against certain molecules of the body, causing one of the many autoimmune diseases. In systemic lupus erythematosus (lupus), the immune system generates antibodies (known as autoantibodies) against a wide range of self molecules, including histones and DNA released by the normal breakdown of body cells. Lupus is characterized by skin rashes, fever, arthritis, and kidney dysfunction. Another antibody-mediated autoimmune disease, rheumatoid arthritis, leads to damage and painful inflammation of the cartilage and bone of joints. In insulin-dependent diabetes mellitus, the insulin-producing beta cells of the pancreas are the targets of autoimmune cytotoxic T cells. Yet another example is multiple sclerosis, the most common chronic neurological disease in developed countries. In this disease, T cells infiltrate the central nervous system and destroy the myelin sheath that surrounds some neurons. This results in a number of serious neurological abnormalities.

X-ray of a hand deformed by rheumatoid arthritis

Immunodeficiency Diseases The inability of the immune system to protect the body from pathogens or cancer cells that it should normally be able to defeat reflects some sort of deficiency in the system. An immunodeficiency disease caused by a genetic or developmental defect in the immune system is classified as an inborn or primary immunodeficiency. An immunodeficiency disease that develops later in life following exposure to various chemical and biological agents is classified as an acquired or secondary immunodeficiency. Whatever the cause and nature of the

immunodeficiency, a person with this kind of disease is subject to frequent and recurrent infections and also is more susceptible to cancer. Acquired (Secondary) Immunodeficiencies Immune dysfunction that develops later in life can be caused by exposure to a number of agents. Drugs used to fight autoimmune diseases or to prevent the rejection of a transplant suppress the immune system, leading to an immunodeficient state. In addition, the immune system is suppressed by certain cancers, especially Hodgkins disease, which damages the lymphatic system. Acquired immunodeficiencies range from temporary states that may arise from physiological stress to the devastating acquired immunodeficiency syndrome, or AIDS, which is caused by a virus. Acquired Immunodeficiency Syndrome (AIDS) Because AIDS arises from the loss of helper T cells, both humoral and cell-mediated immune responses are impaired. This loss of helper T cells results from infection by the human immunodeficiency virus (HIV), a retrovirus. HIV gains entry into cells by making use of three proteins that participate in normal immune responses. The main receptor for HIV on helper T cells is the cells CD4 molecule. The virus also infects other cell types, such as macrophages and brain cells that have low levels of CD4. In addition to CD4, HIV entry requires a second cellsurface protein, a co-receptor. One co-receptor, called fusin, is present on all the cell types infected by HIV, while a different co-receptor is present only on macrophages and helper T cells. Both of these HIV co-receptors function as chemokine receptors in uninfected cells. In fact, these proteins were first recognized as HIV co-receptors after it was discovered that chemokines can block HIV entry into cells.

A T cell infected with HIV

Once inside a cell, the HIV RNA genome is reverse-transcribed, and the product DNA is integrated into the host cells genome. In this form, the viral genome can direct the production of new virus particles (see Figure 18.10). The infected cells machinery for transcription and translation thus are hijacked for the benefit of the virus. The death of helper T cells in HIV infection is thought to occur in two ways: Infected cells may succumb to the damaging effects of virus reproduction, and both infected and uninfected cells may undergo inappropriately timed apoptosis triggered by the virus.