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![4.IFN-α and IFN-β can induce an antiviral response or resistance to viral
replication by binding to the IFNα/β receptor. Once bound, IFN-α and
IFN-β activate the JAK-STAT pathway, which in turn induces the
transcription of several genes.
5.One of these genes encodes an enzyme known as 2’-5’-oligo-adenylate
synthetase [2-5(A) synthetase], which activates a ribonuclease (RNAse
L) that degrades viral RNA. Other genes activated by IFN-α/β binding to
its receptor also contribute to the inhibition of viral replication.
For example, IFN-α/β binding induces a specific protein kinase called
dsRNA-dependent protein kinase (PKR), which inactivates protein
synthesis, thus blocking viral replication in infected cells.
6.The binding of IFN-α and IFN-β to NK cells induces lytic activity,
making them very effective in killing virally infected cells. The activity
of NK cells is also greatly enhanced by IL-12, a cytokine that is
produced very early in a response to viral infection.](https://image.slidesharecdn.com/immunology-211215022932/75/Immunology-48-2048.jpg)
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Immunology
- 1. IMMUNOLOGY Presented By Soniya.S II MScBiochemistry Dkm Collage For Women Vellore
- 2. The immune systemis remarkable and versatile defense system that has evolved to protect animals from invading pathogenic microorganisms and cancer. It is able to generate an enormous variety of cells and molecules capable of specifically recognizing and eliminating an apparently limitless variety of foreign invaders. These cells and molecules act together in a dynamic network whose complexity rivals that of the nervous system. Functionally, an immune response can be divided into two related activities -recognition and response. Immune recognition is remarkable for its specificity. The immune system is able to recognize subtle chemical differences that distinguish one foreign pathogen from another. Furthermore, the system is able to discriminate between foreign molecules and the body’s own cells and proteins
- 3. Once a foreignorganism has been recognized, the immune system recruits a variety of cells and molecules to mount an appropriate response, called an effector response, to eliminate or neutralize the organism. In this way the system is able to convert the initial recognition event into a variety of effector responses, each uniquely suited for eliminating a particular type of pathogen. Later exposure to the same foreign organism induces a memory response, characterized by a more rapid and heightened immune reaction that serves to eliminate the pathogen and prevent disease. The Latin term immunis, meaning “exempt,” is the source of the English word immunity, meaning the state of protection from infectious disease.
- 4. HISTORICAL PERSPECTIVE Chines andturks – 15 century lady marry wortley montagu-1718 Edward jenner-1789 Louis pasteur Pouilly-le-Fort and pasteur in 1881
- 5. EARLY STUDIES REVEALEDHUMORALAND CELLULAR COMPONENTS OF THE IMMUNE SYSTEM Emil von Behring and Shibsaburo Kitasato 1990 Elvin Kabat in 1930 Elie Metchnikoff in 1883 Merrill Chase in 1940 Bruce Glick in 1950
- 6. THE IMMUNE SYSTEMINCLUDES INNATE AND ADAPTIVE COMPONENTS Immunity the state of protection from infectious disease has both a less specific and more specific component. The less specific component, innate immunity, provides the first line of defense against infection. Most components of innate immunity are present before the onset of infection and constitute a set of disease-resistance mechanisms that are not specific to a particular pathogen but that include cellular and molecular components that recognize classes of molecules peculiar to frequently encountered pathogens. Phagocytic cells, such as macrophages and neutrophils, barriers such as skin, and a variety of antimicrobial compounds synthesized by the host all play important roles in innate immunity. In contrast to the broad reactivity of the innate immune system, which is uniform in all members of a species, the specific component
- 7. Adaptive immunity, doesnot come into play until there is an antigenic challenge to the organism. Adaptive immunity responds to the challenge with a high degree of specificity as well as the remarkable property of “memory.” Typically, there is an adaptive immune response against an antigen within five or six days after the initial exposure to that antigen. Exposure to the same antigen some time in the future results in a memory response: the immune response to the second challenge occurs more quickly than the first, is stronger, and is often more effective in neutralizing and clearing the pathogen. The major agents of adaptive immunity are lymphocytes and the antibodies and other molecules they produce. Because adaptive immune responses require some time to marshal, innate immunity provides the first line of defense during the critical period just after the host’s exposure to a pathogen. In general, most of the microorganisms encountered by a healthy individual are readily cleared within a few days by defense mechanisms of the innate immune system before they activate the adaptive immune system.
- 8. INNATE IMMUNITY Innate immunitycan be seen to comprise four types of defensive barriers: anatomic, physiologic, phagocytic, and inflammatory (Table 1-2). Type Mechanism Anatomic barriers Skin Mechanical barrier retards entry of microbes. Acidic environment (pH 3–5) retards growth of microbes Mucous membranes Normal flora compete with microbes for attachment sites and nutrients. Mucus entraps foreign microorganisms. Cilia propel microorganisms out of body Physiologic barriers Temperature Normal body temperature inhibits growth of some pathogens. Fever response inhibits growth of some pathogens. Low Ph Acidity of stomach contents kills most ingested microorganisms
- 9. Chemical mediators Lysozymecleaves bacterial cell wall. Interferon induces antiviral state in uninfected cells. Complement lyses microorganisms or facilitates phagocytosis. Toll-like receptors recognize microbial molecules, signal cell to secrete immunostimulatory cytokines. Collectins disrupt cell wall of pathogen. Phagocytic/endocytic barriers Various cells internalize (endocytose) and break down foreign macromolecules. Specialized cells (blood monocytes, neutrophils, tissue macrophages) internalize (phagocytose), kill, and digest whole microorganisms. nflammatory barriers Tissue damage and infection induce leakage of vascular fluid, containing serum proteins with antibacterial activity, and influx of phagocytic cells into the affected area
- 10. A variety ofsoluble factors contribute to innate immunity, among them the soluble proteins lysozyme, interferon, and complement. -Lysozyme, a hydrolytic enzyme found in mucous secretions and in tears, is able to cleave the peptidoglycan layer of the bacterial cell wall. -Interferon comprises a group of proteins produced by virus-infected cells. Among the many functions of the interferons is the ability to bind to nearby cells and induce a generalized antiviral state. -Complement, is a group of serum proteins that circulate in an inactive state
- 12. CELLS THAT INGESTANDDESTROY PATHOGENS MAKE UPA PHAGOCYTIC BARRIER TO INFECTION Another important innate defense mechanism is the ingestion of extracellular particulate material by phagocytosis. Phagocytosis is one type of endocytosis, the general term for the uptake by a cell of material from its environment. In phagocytosis, a cell’s plasma membrane expands around the particulate material, which may include whole pathogenic microorganisms, to form large vesicles called phagosomes . Most phagocytosis is conducted by specialized cells, such as blood monocytes, neutrophils, and tissue macrophages . Most cell types are capable of other forms of endocytosis, such as receptor- mediated endocytosis, in which extracellular molecules are internalized after binding by specific cellular receptors, and pinocytosis, the process by which cells take up fluid from the surrounding medium along with any molecules contained in it.
- 14. INFLAMMATION REPRESENTS ACOMPLEX SEQUENCE OF EVENTS THAT STIMULATES IMMUNE RESPONSES Tissue damage caused by a wound or by an invading pathogenic microorganism induces a complex sequence of events collectively known as the inflammatory response. As described above, a molecular component of a microbe, such as LPS, may trigger an inflammatory response via interaction with cell surface receptors. The end result of inflammation may be the marshalling of a specific immune response to the invasion or clearance of the invader by components of the innate immune system. Many of the classic features of the inflammatory response were described as early as 1600 BC, in Egyptian papyrus writings. In the first century AD, the Roman physician Celsus described the “four cardinal signs of inflammation” as rubor (redness), tumor (swelling), calor (heat), and dolor (pain). In the second century AD, another physician, Galen, added a fifth sign: functio laesa (loss of function).
- 15. The cardinal signsof inflammation reflect the three major events of an inflammatory response 1. Vasodilation—an increase in the diameter of blood vessels—of nearby capillaries occurs as the vessels that carry blood away from the affected area constrict, resulting in engorgement of the capillary network. The engorged capillaries are responsible for tissue redness (erythema) and an increase in tissue temperature. 2. An increase in capillary permeability facilitates an influx of fluid and cells from the engorged capillaries into the tissue. The fluid that accumulates (exudate) has a much higher protein content than fluid normally released from the vasculature. Accumulation of exudate contributes to tissue swelling (edema)
- 16. 3. Influx ofphagocytes from the capillaries into the tissues is facilitated by the increased permeability of the capillaries. The emigration of phagocytes is a multistep process that includes adherence of the cells to the endothelial wall of the blood vessels (margination), followed by their emigration between the capillaryendothelial cells into the tissue (diapedesis or extravasation), and, finally, their migration through the tissue to the site of the invasion (chemotaxis). As phagocytic cells accumulate at the site and begin to phagocytose bacteria, they release lytic enzymes, which can damage nearby healthy cells. The accumulation of dead cells, digested material, and fluid forms a substance called pus.
- 17. ADAPTIVE IMMUNITY Adaptive immunityis capable of recognizing and selectively eliminating specific foreign microorganisms and molecules (i.e., foreign antigens). Unlike innate immune responses, adaptive immune responses are not the same in all members of a species but are reactions to specific antigenic challenges. Adaptive immunity displays four characteristic attributes: Antigenic specificity Diversity Immunologic memory Self/nonself recognition -The antigenic specificity of the immune system permits it to distinguish subtle differences among antigens. Antibodies can distinguish between two protein molecules that differ in only a single amino acid. -The immune system is capable of generating tremendous diversity in its recognition molecules, allowing it to recognize billions of unique structures on foreign antigens.
- 18. -Once the immunesystem has recognized and responded to an antigen, it exhibits immunologic memory; that is, a second encounter with the same antigen induces a heightened state of immune reactivity. Because of this attribute, the immune system can confer life-long immunity to many infectious agents after an initial encounter. -Finally, the immune system normally responds only to foreign antigens, indicating that it is capable of self/nonself recognition. The ability of the immune system to distinguish self from nonself and respond only to nonself molecules is essential, for, as described below, the outcome of an inappropriate response to self molecules can be fatal.
- 19. Adaptive immunity isnot independent of innate immunity. The phagocytic cells crucial to nonspecific immune responses are intimately involved in activating the specific immune response. Conversely, various soluble factors produced by a specific immune response have been shown to augment the activity of these phagocytic cells. As an inflammatory response develops, for example, soluble mediators are produced that attract cells of the immune system. The immune response will, in turn, serve to regulate the intensity of the inflammatory response. Through the carefully regulated interplay of adaptive and innate immunity, the two systems work together to eliminate a foreign invader.
- 20. THE ADAPTIVE IMMUNESYSTEM REQUIRES COOPERATION BETWEEN LYMPHOCYTES AND ANTIGEN-PRESENTING CELLS An effective immune response involves two major groups of cells: T lymphocytes and antigen-presenting cells. Lymphocytes are one of many types of white blood cells produced in the bone marrow by the process of hematopoiesis . Lymphocytes leave the bone marrow, circulate in the blood and lymphatic systems, and reside in various lymphoid organs. Because they produce and display antigenbinding cell-surface receptors, lymphocytes mediate the defining immunologic attributes of specificity, diversity, memory, and self/nonself recognition. The two major populations of lymphocytes-B lymphocytes (B cells) and T lymphocytes (T cells)
- 21. B LYMPHOCYTES B cell- Antibodies Receptor B cell-Small navie B lymphocytes (without antigen) Induces cell cycle entry(antigen activation) lymphoblasts (DNA synthesis) Cell division Effector cell Memory cell Effector B cells called plasma cells. . Plasma cells produce the antibody in a form that can be secreted and have little or no membrane-bound antibody. Although plasma cells live for only a few days, they secrete enormous amounts of antibody during this time. It has been estimated that a single plasma cell can secrete more than 2000 molecules of antibody per second. Secreted antibodies are the major effector molecules of humoral immunity Memory B cells have a longer life span than naive cells, and they express the same membrane-bound antibody as their parent B cell.
- 24. T LYMPHOCYTES T –cell arise in bone marrow and mature in thymus (migration) T-cell have receptor – CD4 & CD8 receptor(express a unique antigen-binding molecule, called the T-cell receptor, on its membrane.) T-cell receptors can recognize only antigen that is bound to cell-membrane proteins called major histocompatibility complex (MHC) molecules. T lymphocytes Class I MHG or CD8 &Tc (nucleoted cell) Class II MHGor CD4&TH(APC) Class I MHC molecules, which are expressed by nearly all nucleated cells of vertebrate species, consist of a heavy chain linked to a small invariant protein called β2-microglobulin Class II MHC molecules, which consist of an alpha and a beta glycoprotein chain, are expressed only by antigen-presenting cells. When a naive T cell encounters antigen combined with a MHC molecule on a cell, the T cell proliferates and differentiates into memory T cells and various effector T cells
- 26. ANTIGEN-PRESENTING CELLS Activation ofboth the humoral and cell-mediated branches of the immune system requires cytokines produced by TH cells. It is essential that activation of TH cells themselves be carefully regulated, because an inappropriate T-cell response to self- components can have fatal autoimmune consequences. To ensure carefully regulated activation of TH cells, they can recognize only antigen that is displayed together with class MHC II molecules on the surface of antigen-presenting cells (APCs). These specialized cells, which include macrophages, B lymphocytes, and dendritic cells, are distinguished by two properties: (1) they express class II MHC molecules on their membranes, and (2) they are able to deliver a co-stimulatory signal that is necessary for TH-cell activation. Antigen-presenting cells first internalize antigen, either by phagocytosis or by endocytosis, and then display a part of that antigen on their membrane bound to a class II MHC molecule. The TH cell recognizes and interacts with the antigen–class II MHC molecule complex on the membrane of the antigen-presenting cell . An additional costimulatory signal is then produced by the antigen-presenting cell, leading to activation of the TH cell
- 27. HUMORAL IMMUNITY BUTNOT CELLULAR IMMUNITY IS TRANSFERRED WITH ANTIBODY EFECTOR B-CELL Humoral branch of the immune system is –B cell Prolifercationand differentiation into antibody-secreting plasma cell Antibody functionas the effector of the humoral response by binding to antigen and neutralizing 1.Cross link several antigen to form clusters-ingested by phagocytic cell 2.Activation of complement system-lysis 3.Neutralize toxic or viral-coating them-prevents binding to host cell EFFECTOR T- CELL Effector t cell generated in the response to antigen are responsible for the cell- mediated Both activated TH cell+cytotoxic T Lymphocytes (CTLs) serves as effector cell in cell- imediated immune reaction. Cytokines secreted by TH cells can activate various phagocytic cell-phagocutose&kill microorganism more effectively CTLs participate –play important role in the killing of virus infected cell ,tumor cell & altered self cell
- 28. ANTIGEN IS RECOGNIZEDDIFFERENTLY BY B AND T LYMPHOCYTES Antigens, which are generally very large and complex, are not recognized in their entirety by lymphocytes. Instead, both B and T lymphocytes recognize discrete sites on the antigen called antigenic determinants, or epitopes. Epitopes are the immunologically active regions on a complex antigen, the regions that actually bind to B-cell or T-cell receptors. Although B cells can recognize an epitope alone, T cells can recognize an epitope only when it is associated with an MHC molecule on the surface of a self-cell (either an antigen-presenting cell or an altered self- cell). Each branch of the immune system is therefore uniquely suited to recognize antigen in a different milieu. The humoral branch (B cells) recognizes an enormous variety of epitopes: those displayed on the surfaces of bacteria or viral particles, as well as those displayed on soluble proteins, glycoproteins, polysaccharrides, or lipopolysaccharides that have been released from invading pathogens. The cell-mediated branch (T cells) recognizes protein epitopes displayed together with MHC molecules on self-cells, including altered self-cells such as virus-infected self-cells and cancerous cells. Thus, four related but distinct cell-membrane molecules are responsible for antigen recognition by the immune system: ■ Membrane-bound antibodies on B cells ■ T-cell receptors ■ Class I MHC molecules ■ Class II MHC molecules Each of these molecules plays a unique role in antigen recognition, ensuring that the immune system can recognize and respond to the different types of antigen that it encounters.
- 30. COMPLEXANTIGENS ARE DEGRADED(PROCESSED) AND DISPLAYED (PRESENTED) WITH MHC MOLECULES ON THE CELL SURFACE In order for a foreign protein antigen to be recognized by a T cell, it must be degraded into small antigenic peptides that form complexes with class I or class II MHC molecules. This conversion of proteins into MHC-associated peptide fragments is called antigen processing and presentation. Whether a particular antigen will be processed and presented together with class I MHC or class II MHC molecules appears to be determined by the route that the antigen takes to enter a cell Exogenous pathway Endogenous pathway
- 31. EXOGENOUS PATHWAY Exogenous antigenis produced outside of the host cell and enters the cell by endocytosis or phagocytosis. Antigen presenting cells (macrophages, dendritic cells, and B cells) degrade ingested exogenous antigen into peptide fragments within the endocytic processing pathway. Experiments suggest that class II MHC molecules are expressed within the endocytic processing pathway and that peptides produced by degradation of antigen in this pathway bind to the cleft within the class II MHC molecules. The MHC molecules bearing the peptide are then exported to the cell surface. Since expression of class II MHC molecules is limited to antigen-presenting cells, presentation of exogenous peptide– class II MHC complexes is limited to these cells. T cells displaying CD4 recognize antigen combined with class II MHC molecules and thus are said to be class II MHC restricted. These cells generally function as T helper cells
- 33. ENDOGENOUS PATHWAY Endogenous antigenis produced within the host cell itself. Two common examples are viral proteins synthesized within virus-infected host cells and unique proteins synthesized by cancerous cells. Endogenous antigens are degraded into peptide fragments that bind to class I MHC molecules within the endoplasmic reticulum. The peptide–class I MHC complex is then transported to the cell membrane. Since all nucleated cells express class I MHC molecules, all cells producing endogenous antigen use this route to process the antigen. T cells displaying CD8 recognize antigen associated with class I MHC molecules and thus are said to be class I MHC restricted. These cytotoxic T cells attack and kill cells displaying the antigen–MHC class I complexes for which their receptors are specific
- 35. ANTIGEN SELECTION OFLYMPHOCYTES CAUSES CLONAL EXPANSION A mature immunocompetent animal contains a large number of antigen- reactive clones of T and B lymphocytes; the antigenic specificity of each of these clones is determined by the specificity of the antigen-binding receptor on the membrane of the clone’s lymphocytes. As noted above, the specificity of each T and B lymphocyte is determined before its contact with antigen by random gene rearrangements during maturation in the thymus or bone marrow. The role of antigen becomes critical when it interacts with and activates mature, antigenically committed T and B lymphocytes, bringing about expansion of the population of cells with a given antigenic specificity. In this process of clonal selection, an antigen binds to a particular T or B cell and stimulates it to divide repeatedly into a clone of cells with the same antigenic specificity as the original parent cell . Clonal selection provides a framework for understanding the specificity and self/nonself recognition that is characteistic of adaptive immunity. Specificity is shown because only lymphocytes whose receptors are specific for a given epitope on an antigen will be clonally expanded and thus mobilized for an immune response. Self/nonself discrimination is accomplished by the elimination, during development, of lymphocytes bearing self-reactive receptors or by the functional suppression of these cells in adults.
- 36. Immunologic memory alsois a consequence of clonal selection. During clonal selection, the number of lymphocytes specific for a given antigen is greatly amplified. Moreover, many of these lymphocytes, referred to as memory cells, appear to have a longer life span than the naive lymphocytes from which they arise. The initial encounter of a naive immunocompetent lymphocyte with an antigen induces a primary response; a later contact of the host with antigen will induce a more rapid and heightened secondary response. The amplified population of memory cells accounts for the rapidity and intensity that distinguishes a secondary response from the primary response.
- 37. a) When ananimal is injected with an antigen, it produces a primary serum antibody response of low magnitude and short duration, peaking at about 10–17 days. A second immunization with the same antigen results in a secondary response that is greater in magnitude, peaks in less time (2–7 days), and lasts longer (months to years) than the primary response. Compare the secondary response to antigen A with the primary response to antigen B administered to the same mice. DIFFERENCES IN THE PRIMARYAND SECONDARY RESPONSE TO INJECTEDANTIGEN (HUMORALRESPONSE)AND TOASKIN GRAFT (CELL-MEDIATED RESPONSE) REFLECT THE PHENOMENON OF IMMUNOLOGIC MEMORY
- 38. (b) Results froma hypothetical experiment in which skin grafts from strain C mice are transplanted to 20 mice of strain A; the grafts are rejected in about 10–14 days. The 20 mice are rested for 2 months and then 10 are given strain C grafts and the other 10 are given skin from strain B. Mice previously exposed to strain C skin reject C grafts much more vigorously and rapidly than the grafts from strain B. Note that the rejection of the B graft follows a time course similar to that of the first strain C graft
- 39. COMPARISON OF ADAPTIVEANDINNATE IMMUNITY INNATE ADAPTIVE Response time Hours Days Specificity Limited and fixed Highly diverse, improves during the course of immune response Response response infection to Identical to primary response Much more rapid than repeat primary response
- 40. IMMUNE DYSFUNCTIONAND ITS CONSEQUENCES Sometimesthe immune system fails to protect the host adequately or misdirects its activities to cause discomfort, debilitating disease, or even death. There are several common manifestations of immune dysfunction: ■ Allergy and asthma ■ Graft rejection and graft-versus-host disease ■ Autoimmune disease ■ Immunodeficiency Allergy and asthma are results of inappropriate immune responses, often to common antigens such as plant pollen, food, or animal dander. The possibility that certain substances increased sensitivity rather than protection was recognized in about 1902 by Charles Richet, who attempted to immunize dogs against the toxins of a type of jellyfish, Physalia. He and his colleague Paul Portier observed that dogs exposed to sublethal doses of the toxin reacted almost instantly, and fatally, to subsequent challenge with minute amounts of the toxin. Richet concluded that a successful immunization or vaccination results in phylaxis, or protection, and that an opposite result may occur—anaphylaxis—in which exposure to antigen can result in a potentially lethal sensitivity to the antigen if the exposure is repeated. Richet received the Nobel Prize in 1913 for his discovery of the anaphylactic response.
- 41. When the immunesystem encounters foreign cells or tissue, it responds strongly to rid the host of the invaders. However, in some cases, the transplantation of cells or an organ from another individual, although viewed by the immune system as a foreign invasion, may be the only possible treatment for disease. For example, it is estimated that more than 60,000 persons in the United States alone could benefit from a kidney transplant. Because the immune system will attack and reject any transplanted organ that it does not recognize as self, it is a serious barrier to this potentially life-saving treatment. An additional danger in transplantation is that any transplanted cells with immune function may view the new host as nonself and react against it. This reaction, which is termed graft-versus-host disease, can be fatal. The rejection reaction and graft-versus-host disease can be suppressed by drugs, but this type of treatment suppresses all immune function, so that the host is no longer protected by its immune system and becomes susceptible to infectious diseases.
- 42. In certain individuals,the immune system malfunctions by losing its sense of self and nonself, which permits an immune attack upon the host. This condition, autoimmunity, can cause a number of chronic debilitating diseases. The symptoms of autoimmunity differ depending on which tissues and organs are under attack. For example, multiple sclerosis is due to an autoimmune attack on the brain and central nervous system, Crohn’s disease is an attack on the tissues in the gut, and rheumatoid arthritis is an attack on joints of the arms and legs. The genetic and environmental factors that trigger and sustain autoimmune disease are very active areas of immunologic research, as is the search for improved treatments. If any of the many components of innate or specific immunity is defective because of genetic abnormality, or if any immune function is lost because of damage by chemical, physical, or biological agents, the host suffers from immunodeficiency. The severity of the immunodeficiency disease depends on the number of affected components.
- 43. A common typeof immunodeficiency in North America is a selective immunodeficiency in which only one type of immunoglobulin, IgA, is lacking; the symptoms may be minor or even go unnoticed. In contrast, a rarer immunodeficiency called severe combined immunodeficiency (SCID), which affects both B and T cells, if untreated, results in death from infection at an early age. Since the 1980s, the most common form of immunodeficiency has been acquired immune deficiency syndrome, or AIDS, which results from infection with the retrovirus human immunodeficiency virus, or HIV. In AIDS, T helper cells are infected and destroyed by HIV, causing a collapse of the immune system
- 44. IMMUNE RESPONSE TOINFECTIOUS DISEASES One of the first and most important features of host innate immunity is the barrier provided by the epithelial surfaces of the skin and the lining of the gut. The difficulty of penetrating these epithelial barriers ensures that most pathogens never gain productive entry into the host. In addition to providing a physical barrier to infection, the epithelia also produce chemicals that are useful in preventing infection. The secretion of gastric enzymes by specialized epithelial cells lowers the pH of the stomach and upper gastrointestinal tract, and other specialized cells in the gut produce antibacterial peptides. A major feature of innate immunity is the presence of the normal gut flora, which can competitively inhibit the binding of pathogens to gut epithelial cells. Innate responses can also block the establishment of infection. For example, the cell walls of some gram-positive bacteria contain a peptidoglycan that activates the alternative complement pathway, resulting in the generation of C3b, which opsonizes bacteria and enhances phagocytosis
- 45. Some bacteria produceendotoxins such as LPS, which stimulate the production of cytokines such as TNF-, IL-1, and IL-6 by macrophages or endothelial cells. These cytokines can activate macrophages. Phagocytosis of bacteria by macrophages and other phagocytic cells is another highly effective line of innate defense. However, some types of bacteria that commonly grow intracellularly have developed mechanisms that allow them to resist degradation within the phagocyte. Viruses are well known for the stimulation of innate responses. In particular, many viruses induce the production of interferons, which can inhibit viral replication by inducing an antiviral response. Viruses are also controlled by NK cells. As described in Chapter 14, NK cells frequently form the first line of defense against viral infections.
- 46. VIRAL INFECTIONS A numberof specific immune effector mechanisms, together with nonspecific defense mechanisms, are called into play to eliminate an infecting virus . At the same time, the virus acts to subvert one or more of these mechanisms to prolong its own survival. The outcome of the infection depends on how effectively the host’s defensive mechanisms resist the offensive tactics of the virus. 1. The innate immune response to viral infection is primarily through the induction of type I interferons (IFN-α and IFN-β) and the activation of NK cells. 2. Double stranded RNA (dsRNA) produced during the viral life cycle can induce the expression of IFN-α and IFN-β by the infected cell. 3. Macrphages, monocytes, and fibroblasts also are capable of synthesizing these cytokines, but the mechanisms that induce the production of type I interferons in these cells are not completely understood.
- 48. 4.IFN-α and IFN-βcan induce an antiviral response or resistance to viral replication by binding to the IFNα/β receptor. Once bound, IFN-α and IFN-β activate the JAK-STAT pathway, which in turn induces the transcription of several genes. 5.One of these genes encodes an enzyme known as 2’-5’-oligo-adenylate synthetase [2-5(A) synthetase], which activates a ribonuclease (RNAse L) that degrades viral RNA. Other genes activated by IFN-α/β binding to its receptor also contribute to the inhibition of viral replication. For example, IFN-α/β binding induces a specific protein kinase called dsRNA-dependent protein kinase (PKR), which inactivates protein synthesis, thus blocking viral replication in infected cells. 6.The binding of IFN-α and IFN-β to NK cells induces lytic activity, making them very effective in killing virally infected cells. The activity of NK cells is also greatly enhanced by IL-12, a cytokine that is produced very early in a response to viral infection.
- 50. MANY VIRUSES ARENEUTRALIZED BY ANTIBODIES Antibodies specific for viral surface antigens . Antibodies are particularly effective in protecting against infection if they are localized at the site of viral entry into the body. Most viruses express surface receptor molecules that enable them to initiate infection by binding to specific host-cell membrane molecules. For example, influenza virus binds to sialic acid residues in cellmembrane glycoproteins and glycolipids; rhinovirus binds to intercellular adhesion molecules (ICAMs); and Epstein-Barr virus binds to type 2 complement receptors on B cells. If antibody to the viral receptor is produced, it can block infection altogether by preventing the binding of viral particles to host cells. Secretory IgA in mucous secretions plays an important role in host defense against viruses by blocking viral attachment to mucosal epithelial cells. The advantage of the attenuated oral polio vaccine, is that it induces production of secretory IgA, which effectively blocks attachment of poliovirus along the gastrointestinal tract. Viral neutralization by antibody sometimes involves mechanisms that operate after viral attachment to host cells. In some cases, antibodies may block viral penetration by binding to epitopes that are necessary to mediate fusion of the viral envelope with the plasma membrane. If the induced antibody is of a complement-activating isotype, lysis of enveloped virions can ensue. Antibody or complement can also agglutinate viral particles and function as an opsonizing agent to facilitate Fc- or C3b-receptor–mediated phagocytosis of the viral particles.
- 51. CELL-MEDIATED IMMUNITY ISIMPORTANT FOR VIRAL CONTROLAND CLEARANCE Although antibodies have an important role in containing the spread of a virus in the acute phases of infection, they are not usually able to eliminate the virus once infection has occurred—particularly if the virus is capable of entering a latent state in which its DNA is integrated into host chromosomal DNA. Once an infection is established, cell-mediated immune mechanisms are most important in host defense. In general, CD8+ TC cells and CD4+ TH1 cells are the main components of cell-mediated antiviral defense, although in some cases CD4+ TC cells have also been implicated. Activated TH1 cells produce a number of cytokines, including IL-2, IFN-γ, and TNF, that defend against viruses either directly or indirectly. IFN-γ acts directly by inducing an antiviral state in cells. IL-2 acts indirectly by assisting in the recruitment of CTL precursors into an effector population. Both IL-2 and IFN-γ activate NK cells, which play an important role in host defense during the first days of many viral infections until a specific CTL response develops. In most viral infections, specific CTL activity arises within 3–4 days after infection, peaks by 7–10 days, and then declines.
- 52. Within 7–10 daysof primary infection, most virions have been eliminated, paralleling the development of CTLs. CTLs specific for the virus eliminate virus-infected self-cells and thus eliminate potential sources of new virus. The role of CTLs in defense against viruses is demonstrated by the ability of virus-specific CTLs to confer protection for the specific virus on nonimmune recipients by adoptive transfer. The viral specificity of the CTL as well can be demonstrated with adoptive transfer: adoptive transfer of a CTL clone specific for influenza virus strain X protects mice against influenza virus X but not against influenza virus strain Y.
- 53. BACTERIAL INFECTIONS Immunity tobacterial infections is achieved by means of antibody unless the bacterium is capable of intracellular growth, in which case delayed- type hypersensitivity has an important role. Bacteria enter the body either through a number of natural routes (e.g., the respiratory tract, the gastrointestinal tract, and the genitourinary tract) or through normally inaccessible routes opened up by breaks in mucous membranes or skin. Depending on the number of organismsentering and their virulence, different levels of host defense are enlisted. If the inoculum size and the virulence are both low, then localized tissue phagocytes may be able to eliminate the bacteria with an innate, nonspecific defense. Larger inoculums or organisms with greater virulence tend to induce an adaptive, specific immune response.
- 54. IMMUNE RESPONSES TOEXTRACELLULAR AND INTRACELLULAR BACTERIA CAN DIFFER Infection by extracellular bacteria induces production of humoral antibodies, which are ordinarily secreted by plasma cells in regional lymph nodes and the submucosa of the respiratory and gastrointestinal tracts. The humoral immune response is the main protective response against extracellular bacteria. The antibodies act in several ways to protect the host from the invading organisms, including removal of the bacteria and inactivation of bacterial toxins . Extracellular bacteria can be pathogenic because they induce a localized inflammatory response or because they produce toxins. The toxins, endotoxin or exotoxin, can be cytotoxic but also may cause pathogenesis in other ways. An excellent example of this is the toxin produced by diphtheria, which exerts a toxic effect on the cell by blocking protein synthesis. Endotoxins, such as lipopolysaccharides (LPS), are generally components of bacterial cell walls, while exotoxins, such as diphtheria toxin, are secreted by the bacteria. Antibody that binds to accessible antigens on the surface of a bacterium can, together with the C3b component of complement, act as an opsonin that increases phagocytosis and thus clearance of the bacterium .
- 55. In the caseof some bacteria—notably, the gram-negative organisms— complement activation can lead directly to lysis of the organism. Antibody- mediated activation of the complement system can also induce localized production of immune effector molecules that help to develop an amplified and more effective inflammatory response. For example, the complement split products C3a, C4a, and C5a act as anaphylatoxins, inducing local mast-cell degranulation and thus vasodilation and the extravasation of lymphocytes and neutrophils from the blood into tissue space . Other complement split products serve as chemotactic factors for neutrophils and macrophages, thereby contributing to the buildup of phagocytic cells at the site of infection. Antibody to a bacteria toxin may bind to the toxin and neutralize it; the antibody-toxin complexes are then cleared by phagocytic cells in the same manner as any other antigen antibody complex. While innate immunity is not very effective against intracellular bacterial pathogens, intracellular bacteria can activate NK cells, which, in turn, provide an early defense against these bacteria. Intracellular bacterial infections tend to induce a cell-mediated immune response, specifically, delayed type hypersensitivity. In this response, cytokines secreted by CD4+ T cells are important—notably IFN-, which activates macrophages to kill ingested pathogens more effectively
- 56. BACTERIACAN EFFECTIVELY EVADEHOST DEFENSE MECHANISMS There are four primary steps in bacterial infection: ■ Attachment to host cells ■ Proliferation ■ Invasion of host tissue ■ Toxin-induced damage to host cells Host-defense mechanisms act at each of these steps, and many bacteria have evolved ways to circumvent some of these host defenses Some bacteria have surface structures or molecules that enhance their ability to attach to host cells. A number of gram-negative bacteria, for instance, have pili (long hairlike projections), which enable them to attach to the membrane of the intestinal or genitourinary tract . Other bacteria, such as Bordetella pertussis, secrete adhesion molecules that attach to both the bacterium and the ciliated epithelial cells of the upper respiratory tract
- 57. Secretory IgA antibodiesspecific for such bacterial structures can block bacterial attachment to mucosal epithelial cells and are the main host defense against bacterial attachment. However, some bacteria (e.g., Neisseria gonorrhoeae, Haemophilus influenzae, and Neisseria meningitidis) evade the IgA response by secreting proteases that cleave secretory IgA at the hinge region; the resulting Fab and Fc fragments have a shortened half-life in mucous secretions and are not able to agglutinate microorganisms. Some bacteria evade the IgA response of the host by changing these surface antigens. In N. gonorrhoeae, for example, pilin, the protein component of the pili, has a highly variable structure. Variation in the pilin amino acid sequence is generated by gene rearrangements of its coding sequence. The pilin locus consists of one or two expressed genes and 10–20 silent genes. Each gene is arranged into six regions called minicassettes. Pilin variation is generated by a process of gene conversion, in which one or more minicassettes from the silent genes replace a minicassette of the expression gene. This process generates enormous antigenic variation, which may contribute to the pathogenicity of N. gonorrhoeae by increasing the likelihood that expressed pili will bind firmly to epithelial cells. In addition, the continual changes in the pilin sequence allow the organism to evade neutralization by IgA.
- 58. Some bacteria possesssurface structures that serve to inhibit phagocytosis. A classic example is Streptococcus pneumoniae, whose polysaccharide capsule prevents phagocytosis very effectively. There are 84 serotypes of S. pneumoniae that differ from one another by distinct capsular polysaccharidesDuring infection, the host produces antibody against the infecting serotype. This antibody protects against reinfection with the same serotype but will not protect against infection by a different serotype. In this way, S. pneumoniae can cause disease many times in the same individual. On other bacteria, such as Streptococcus pyogenes, a surface protein projection called the M protein inhibits phagocytosis. Some pathogenic staphylococci are able to assemble a protective coat from host proteins. These bacteria secrete a coagulase enzyme that precipitates a fibrin coat around them, shielding them from phagocytic cells. Mechanisms for interfering with the complement system help other bacteria survive. In some gram-negative bacteria, for example, long side chains on the lipid A moiety of the cell-wall core polysaccharide help to resist complementmediated lysis. Pseudomonas secretes an enzyme, elastase, that inactivates both the C3a and C5a anaphylatoxins, thereby diminishing the localized inflammatory reaction. A number of bacteria escape host defense mechanisms by their ability to survive within phagocytic cells. Some, such as Listeria monocytogenes, do this by escaping from the phagolysosome to the cytoplasm, which is a more favorable environment for their growth. Other bacteria, such as Mycobacterium avium, block lysosomal fusion with the phagolysosome; and some mycobacteria are resistant to the oxidative attack that takes place within the phagolysosome.
- 60. IMMUNE RESPONSES CANCONTRIBUTE TO BACTERIAL PATHOGENESIS In some cases, disease is caused not by the bacterial pathogen itself but by the immune response to the pathogen. Pathogen-stimulated overproduction of cytokines leads to the symptoms of bacterial septic shock, food poisoning, and toxic-shock syndrome. For instance, cell-wall endotoxins of some gram-negative bacteria activate macrophages, resulting in release of high levels of IL-1 and TNF-α, which can cause septic shock. In staphylococcal food poisoning and toxic-shock syndrome, exotoxins produced by the pathogens function as superantigens, which can activate all T cells that express T-cell receptors with a particular Vβ domain. The resulting overproduction of cytokines by activated TH cells causes many of the symptoms of these diseases. The ability of some bacteria to survive intracellularly within infected cells can result in chronic antigenic activation of CD4+ T cells, leading to tissue destruction by a cell- mediated response with the characteristics of a delayed-type hypersensitivity reaction . Cytokines secreted by these activated CD4+ T cells can lead to extensive accumulation and activation of macrophages, resulting in formation of a granuloma. The localized concentrations of lysosomal enzymes in these granulomas can cause extensive tissue necrosis. Much of the tissue damage seen with M. tuberculosis is due to a cell-mediated immune response.