Immunology

Pathogens

'Any organisms causing disease are termed pathogens, and the process by which they induce illness in the host is called pathogenesis.' The human pathogens can be grouped into four major categories based on shared characteristics: viruses, fungi, parasites, and bacteria. Viruses Rotavirus Poliovirus Variola virus Human immunodeficiency virus Measles virus Influenza virus Rhinovirus Ebola virus Zika Virus Poliomyelitis (polio) Smallpox AIDS Measles Influenza Common cold Hemorrhagic fever Zika fever/virus disease Bacteria Mycobacterium tuberculosis Mycobacterium tuberculosis Bordetella pertussis Vibrio cholerae Borrelia burgdorferi Neisseria gonorrhea Haemophilus influenzae Tuberculosis Whooping cough (pertussis) Cholera Lyme disease Gonorrhea Bacterial meningitis & pneumonia Fungi Candida albicans Candida albicans Tinea corporis Cryptococcus neoformans Aspergillus fumigatus Blastomyces dermatitidis Candidiasis (thrush) Ringworm Cryptococcal meningitis Aspergillosis Blastomycosis Parasites Filaria Plasmodium species Leishmania major Entamoeba histolytica Schistosoma mansoni Wuchereria bancrofti Malaria Leishmaniasis Amoebic colitis Schistosomiasis Lymphatic filariasis // The microenvironment in which the immune response begins to emerge can also influence the outcome; the same pathogen may be treated differently depending on the context in which it is encountered. Some areas of the body, such as the central nervous system or the eye, are virtually "off limits" for the immune system because the immune response could do more damage than the pathogen. . In other cases, the environment may come with inherent directional cues for immune cells. For instance, some foreign compounds that enter via the digestive tract, including the commensal microbes that help us digest food, are tolerated by the immune system. However, if these same foreigners enter the bloodstream they are typically treated much more aggressively. Each encounter with pathogen thus engages a distinct set of strategies that depends on the nature of the invader and on the microenvironment in which engagement occurs. // It is worth noting that immune pathways do not become engaged until foreign organisms first breach the physical barriers of the body. Obvious barriers include the skin and the mucous membranes. The acidity of the stomach contents, of the vagina, and of perspiration poses a further barrier to many organisms, which are unable to grow under low-pH conditions. Finally, soluble antimicrobial proteins secreted by the epithelial cells at the surfaces of the body help to hold would-be pathogens at bay. All these barriers are discussed in detail in Chapters 4 and 13. The importance of these barriers becomes obvious when they are surmounted. Animal bites can communicate rabies or tetanus, whereas insect puncture wounds can transmit the causative agents 80 of such diseases as malaria (mosquitoes), plague (fleas), and Lyme disease (ticks). A dramatic example is seen in burn victims, who lose the protective skin at the burn site and must be treated aggressively with drugs to prevent the rampant bacterial and fungal infections that often follow. //

Constant regions (C regions) - carboxy terminal

// allows the antibodies carry out its effector function

Opsonization

An immune response in which the binding of antibodies to the surface of a microbe facilitates phagocytosis of the microbe by a macrophage.

Humoral immunity

B-cell mediated immunity (adaptive): Plasma cells produce antibodies after exposure to specific antigens.

Which Biochemical rxn's stimulate Lymphocyte recruitment/count?

Histamine reaction can increase WBC count.

What factors affect host immunogenicity?

Host genetic makeup Dose and route of administration Use of agents (adjuvants) to enhance immunogenicity. "two people don't have the same MHC gene expression levels, this will obviously affect immunogenicity and immune response. "

Immune Deficiency

In most cases, when a component of innate or adaptive immunity is absent or defective, the host suffers from some form of immunodeficiency. Some of these deficiencies produce major clinical effects, including death, while others are more minor or even difficult to detect. Immune deficiency can arise due to inherited genetic factors (called primary immunodeficiencies) or as a result of disruption/damage by chemical, physical, or biological agents (termed secondary immunodeficiencies). Both of these forms of immune deficiency are discussed in greater detail in Chapter 18. The severity of the disease resulting from immune deficiency depends on the number and type of affected immune response components. A common type of primary immunodeficiency in North America is a selective immunodeficiency in which only one type of antibody, called immunoglobulin A, is lacking; the symptoms may be an increase in certain types of infections, or the deficiency may even go unnoticed. In contrast, a rarer but much more extreme deficiency, called severe combined immunodeficiency (SCID), affects both B and T cells and basically wipes out adaptive immunity. When untreated, SCID frequently results in death from infection at an early age. The most effective treatment for SCID is bone marrow transplantation, which can be long-lived and life-saving. Secondary or acquired immunodeficiency can be caused by a number of factors including severe malnutrition, chronic diseases such as diabetes, and infection. By far, the most common cause of acquired immune deficiency worldwide is severe malnutrition, namely protein-calorie 98 and micronutrient insufficiency. Estimates are that 30% to 50% of the world population suffers from some form of malnutrition, all of which can impact the potency of the immune response. Pneumonia, diarrhea, and malaria are among the most common infectious causes of death in populations suffering from malnutrition. These diseases, while caused by infectious agents, are much more likely to result in death when combined with malnutrition and the resulting immune suppression. Targeting this highly preventable condition might go further than any other global initiative to fight morbidity and mortality from infectious disease, especially in very young children. While malnutrition tops the list in terms of number of affected individuals, the most well- known cause of secondary immunodeficiency is acquired immune deficiency syndrome (AIDS) resulting from chronic human immunodeficiency virus (HIV) infection. As discussed further in Chapter 18, humans do not effectively recognize and eradicate this virus, which takes up residence in TH cells. Over the course of the infection, so many TH cells are destroyed or otherwise rendered dysfunctional that a gradual collapse of the immune system ensues, resulting in a diagnosis of AIDS. The administration of anti-HIV drugs has vastly increased the life expectancy of those infected with HIV, although access is unequal; countries most impacted by AIDS, such as those in eastern and southern Africa, have the most limited access to these life saving medications. It is important to note that many pervasive pathogens in our environment cause no problem for healthy individuals thanks to the immunity that develops following initial exposure. However, individuals with primary or secondary deficiencies in immune function become highly susceptible to disease caused by these ubiquitous microbes. For example, the fungus Candida albicans, present nearly everywhere and a nonissue for most individuals, can cause an irritating rash and a spreading infection on the mucosal surface of the mouth and vagina in patients suffering from immune deficiency. The resulting rash, called thrush, can sometimes be the first sign of immune dysfunction (Figure 1-10). If left unchecked, C. albicans can spread, causing systemic candidiasis, a life-threatening condition. Such infections by ubiquitous microorganisms that cause no harm in an immune-competent host, but that are often observed in cases of underlying immune deficiency, are termed opportunistic infections. Several rarely seen opportunistic infections identified in patients early in the AIDS epidemic were the first signs that these patients had seriously compromised immune systems, and helped scientists to identify the underlying cause.

Immune Imbalance

The immune response is so often described in "warfare" terms that it is hard to appreciate the gentler side to this system. The healthy immune system involves a constant balancing act between immune pathways leading to aggression and those requiring inhibition. While we rarely fail to consider erroneous attacks (such as autoimmunity) or failures to engage (such as immune deficiency) as dysfunctional, we sometimes forget to consider the significance of the inhibitory side of the immune response. Imperfections in the inhibitory arm of the immune response, present as a check to balance all the immune attacks we regularly initiate, can be equally profound. Healthy immune responses must therefore be viewed as a delicate balance, spending much of the time with one foot on the brake and one on the gas. Many, maybe most, noncommunicable (noncontagious) diseases have now been linked to uncontrolled inflammation, like a stuck gas pedal (Figure 1-11). These include the usual suspects, such as the more common allergic and autoimmune disorders. More surprising is that some of the major life-threatening chronic medical conditions, including cardiovascular disease, insulin resistance, and obesity, have also been linked to inflammation. Recent additions to this list include neurologic and behavioral disturbances such as autism, depression, and bipolar disorder. If these observations hold true, what is tipping the balance toward uncontrolled inflammation over immune regulation or homeostasis? Likely candidates include the microbiome, diet, and stress, all of which have been shown to impact the immune, digestive, endocrine, and nervous systems. There is now clear evidence, both in mice and in humans, of a multidirectional interaction between diet, the microbiome, and immune function. In particular, it appears that the absence of certain gut commensal organisms, those microbes that live in and on us that cause no harm, and modern dietary changes may be linked to a paucity of "brakes" in the immune balance equation, leaving the inflammatory gas pedal stuck on! Key Concepts: -Dysfunctions of the immune system can include underperformance (immune deficiency) as well as overactivity or uncontrolled inflammation (allergy and autoimmune disease). -Mounting evidence suggests that recent environmental and behavioral changes have tipped the immune balance toward uncontrolled inflammation and are contributing to many modern-day chronic conditions (e.g., diabetes, heart disease, autism). //FIGURE 1-11 The proposed role of the microbiome in regulating immune, metabolic, and neurologic function. Diet, exercise, genotype, and environmental factors such as stress and the body microflora have a significant influence on the composition of the gut microbiome. In turn, this community of microbes helps to maintain gut integrity and "tune" the extensive gut immune system to create systemic homeostasis. Changes in diet and other lifestyle factors can lead to disruption of this community, or dysbiosis, resulting in immune imbalances that feed forward into a state of immune overstimulation (chronic inflammation, autoimmunity, and allergic disease). This state results in increased gut permeability and proposed disruptions to other body systems (metabolic and 102 neurologic) and is believed to contribute to conditions such as type 2 diabetes, inflammatory bowel disease, and mood disorders, as well as others.

The Immune Response Quickly Becomes Tailored to Suit the Assault

With the above in mind, an effective defense is one that is specifically designed to address the nature of the invading pathogen offense. The cells and molecules that become activated in a given immune response have evolved to meet the specific challenges posed by each pathogen, which include the structure of the pathogen and its location within or external to host cells. This means that different chemical structures and microenvironmental cues need to be detected and appropriately evaluated, initiating the most effective response strategy. The process of pathogen recognition involves an interaction between the foreign organism and a recognition molecule (or molecules) expressed by host cells. Although these recognition molecules are frequently membrane-bound receptors, soluble receptors or secreted recognition molecules can also be engaged. Ligands for these recognition molecules can include whole pathogens, antigenic fragments of pathogens, or products secreted by these foreign organisms. The outcome of this ligand binding is an intracellular or extracellular cascade of events that ultimately leads to the labeling and destruction of the pathogen—simply referred to as the immune response. The culmination of this response is engagement of a complex system of cells that can recognize and kill or engulf a pathogen (cellular immunity), as well as soluble proteins that help to orchestrate labeling and destruction of foreign invaders (humoral immunity). The nature of the immune response will vary depending on the number and type of recognition molecules engaged. For instance, all viruses are tiny, obligate, intracellular pathogens that spend the majority of their life cycle residing inside host cells. An effective defense strategy must therefore involve identification of infected host cells along with recognition of the surface of the pathogen. This means that some immune cells must be capable of detecting changes that occur in a host cell after it becomes infected. This is achieved by a range of cytotoxic cells but especially by cytotoxic T lymphocytes (also known as CTLs, or Tc cells), a part of the cellular arm of immunity. In this case, recognition molecules positioned inside cells are key to the initial response. These intracellular receptors bind to viral proteins present in the cytosol and initiate an early warning system, alerting the cell to the presence of an invader. Sacrifice of virally infected cells often becomes the only way to truly eradicate this type of 81 pathogen. In general, this sacrifice is for the good of the whole organism, although in some instances it can cause disruptions to normal function. For example, HIV infects a type of T cell called a T helper cell (T cell). These cells are called helpers because they guide the behavior of other immune cells, including B cells, and are therefore pivotal for selecting the pathway taken by the immune response. Once too many of these cells are destroyed or otherwise rendered nonfunctional, many of the directional cues needed for a healthy immune response are missing and fighting all types of infections becomes problematic. As we discuss later in this chapter, the resulting immunodeficiency allows opportunistic infections to take hold and potentially kill the patient. Similar but distinct immune mechanisms are deployed to mediate the discovery of extracellular pathogens, such as fungi, most bacteria, and some parasites. These rely primarily on cell surface or soluble recognition molecules that probe the extracellular spaces of the body. In this case, B cells and the antibodies they produce as a part of humoral immunity play major roles. For instance, antibodies can squeeze into spaces in the body where B cells themselves may not be able to reach, helping to identify pathogens hiding in these out-of-reach places. Large parasites present yet another problem; they are too big for phagocytic cells to envelop. In cases such as these, cells that can deposit toxic substances or that can secrete products that induce expulsion (e.g., sneezing, coughing, vomiting) become a better strategy. As we study the complexities of the mammalian immune response, it is worth remembering that a single solution does not exist for all pathogens. At the same time, these various immune pathways carry out their jobs with considerable overlap in structure and in function. // Key Concepts -During the initial stages of infection, the receptors that first recognize the foreign agent help the immune response categorize the offender and tailor the subsequent immune response. -Unique pathways begin to emerge that are specific for different types of pathogens, such as cytotoxic T cells that kill virally infected host cells, T helper cells that assist other immune cells, and antibodies secreted by B cells to fight extracellular infection.

light chain editing

editing the variablility of the light chain of an antibody to prevent recognition of self antigen.

Bone marrow stromal cells

important bone marrow cells that constantly select, feed, and silence pro-apoptotic genes of maturing B-cells.

RSS

recombination signal sequences are the "launching pad" for RAG-1 and RAG-2 during somatic recombination

Immunity

the ability of an organism to resist a particular infection or toxin by the action of specific antibodies or sensitized white blood cells.

Antigenicity

the ability of the antigen to induce antibody production and response in the host memory and effector cells.

Hybridoma: Fusion of activated, antibody-producing B cell with a myeloma cell (a cancerous plasma cell - immortal).

this allows us to make antibodies

Pathogen Recognition Molecules Can Be Encoded as Genes are Generated by DNA Rearrangement

As one might imagine, most pathogens express at least a few chemical structures that are not typically found in mammals. Pathogen-associated molecular patterns (or PAMPs) are common foreign structures that characterize whole groups of pathogens. It is these unique antigenic structures that the immune system frequently recognizes first. Animals, both invertebrates and vertebrates, have evolved to express several types of cell surface and soluble proteins that quickly recognize many of these PAMPs: a form of pathogen profiling. For example, encapsulated bacteria possess a polysaccharide coat with a unique chemical structure that is not found on other bacterial or human cells. White blood cells naturally express a variety of receptors, collectively referred to 82 as pattern recognition receptors (PRRs), that specifically recognize these sugar residues, as well as other common foreign structures. When PRRs detect these chemical structures, a cascade of events labels the target pathogen for destruction. PRRs are proteins encoded in the genomic DNA and are always expressed by many different immune cells. These conserved proteins are found in one form or another in many different types of organism, from plants to fruit flies to humans, and represent a first line of defense for the quick detection of many of the typical chemical identifiers carried by the most common invaders. Collectively, these receptors and the cellular processes they help to enact constitute a primitive and highly conserved response system known as innate immunity (discussed in more detail below). A significant and powerful corollary to this is that it allows early categorizing or profiling of the sort of pathogen of concern. This is key to the subsequent immune response routes that will be followed, and therefore the fine tailoring of the immune response as it develops. For example, viruses frequently expose unique chemical structures only during their replication inside host cells. Many of these can be detected via intracellular receptors that bind exposed chemical moieties while still inside the host cell. This can trigger an immediate antiviral response in the infected cell that blocks further virus replication. At the same time, this initiates the secretion of chemical warning signals sent to nearby cells to help them guard against infection (a neighborhood watch system!). This early categorizing happens via a subtle tracking system that allows the immune response to make note of which recognition molecules were involved in the initial detection event and relay that information to subsequent responding immune cells, allowing the follow-up response to begin to focus attention on the likely type of assault underway. Host-pathogen interactions are an ongoing arms race; pathogens evolve to express unique structures that avoid host detection, and the host recognition system co-evolves to match these new challenges. However, because pathogens generally have much shorter life cycles than their vertebrate hosts, and some use error-prone DNA polymerases to replicate their genomes, pathogens can evolve rapidly to evade host-encoded recognition systems. If this were our only defense, the host immune response would quickly become obsolete thanks to these real-time pathogen avoidance strategies. How can the immune system prepare for this? How can our DNA encode a recognition system for things that change in random ways over time? Better yet, how do we build a system to recognize new chemical structures that may arise in the future? Thankfully, the vertebrate immune system has evolved a clever, albeit resource-intensive, response to this dilemma: to favor randomness in the design of some recognition molecules. This strategy, called generation of diversity, is employed only by developing B and T lymphocytes. The result is a group of B and T cells in which each cell expresses many copies of one unique recognition molecule—collectively, a cell population with the theoretical potential to respond to any antigen that may come along (Figure 1-6). This feat is accomplished by rearranging and editing the genomic DNA that encodes the antigen receptors expressed by each B or T lymphocyte. Not unlike the error-prone DNA replication method employed by pathogens, this system allows chance to play a role in generating a menu of responding recognition molecules. Thus, B and T cells make surface receptors unique to each individual, which are then not passed on to offspring. This is in direct contrast to the DNA that encodes PRRs, which are inherited and passed on to the next generation. As one might imagine, however, this cutting and splicing of chromosomes is not without risk. Many B and T cells do not survive this DNA surgery or the quality control processes that follow, all of which take place in primary lymphoid organs: the thymus for T cells and bone marrow for B cells. Surviving cells move into the circulation of the body, where they are available if their specific, or cognate, antigen is encountered. When antigens bind to the surface receptors on these cells, they trigger clonal selection (see Figure 1-6). The ensuing proliferation of the selected clone of cells creates an army of cells, all with the same receptor and responsible for binding more of the same antigen, with the ultimate goal of destroying the pathogen in question. In B lymphocytes, these recognition molecules are B-cell receptors when they are surface structures and antibodies in their secreted form. In T lymphocytes, where no soluble form exists, they are T-cell receptors. In 1976 Susumu Tonegawa, then at the Basel Institute for Immunology in Switzerland, discovered the molecular mechanism behind the DNA recombination events that generate B-cell receptors and antibodies (Chapter 6 covers this in detail). This was a true turning point in immunologic understanding; for this discovery he received widespread recognition, including the 1987 Nobel Prize in Physiology or Medicine //Key Concepts: -Initial immune responses rely on recognition molecules that are conserved and recognize common pathogenic structures. These are inherited. -As the immune response progresses, antigen-specific recognition molecules that were generated randomly in each individual T and B cell via DNA rearrangement drive the bulk of the response. These are not inherited.

Immune Cells and Molecules Can Be Found in Many Places

For an immune response to be effective, the required cells and molecules need to be wherever the pathogen is. This means that unlike many of the body's other systems, which can be concentrated in one or a few specialized organs (e.g., the digestive and reproductive systems), the immune system is highly dispersed. Specialized depots of immune activity are positioned at strategic locations in the body, and immune cells can be found to reside as sentinels in most other tissues. White blood cells or their products are constantly circulating through the body visiting these depots in search of pathogen. White blood cells, which mediate both innate and adaptive immune responses, come in many different types, and one or more of their members can be found in most of the spaces in the body. Some spaces get more than others, like the gut versus the nervous system, and this is frequently commensurate with the potential threat in terms of the sheer number of intimate daily exposures to potential invaders. Tissue-resident immune cells, sometimes referred to as sentinel cells, typically remain inconspicuous and relatively inactive unless a threat arises. Their job is to serve as a local alarm system and as first responders, kicking off the cascade of innate immune events to get the ball rolling. That cascade may begin at the site of infection, but in order for adaptive immunity to be initiated the rare lymphocytes with receptors specific for a particular pathogen need to be found. This means that the perfect lymphocytes for the job need to somehow end up in the right place at the right time. To solve this issue of place and time, the immune system has evolved specialized organs such as lymph nodes (Chapter 2), where the transition from innate to adaptive immunity occurs. Through one route, the fluid bathing our tissues is funneled to and filtered through these sieve-like structures before it is returned to the blood. Through another route, antigen-specific lymphocytes enter these lymphoid organs, scanning for foreign antigens. This fluid and cell recirculation pattern allows relatively quick convergence of antigen and antigen-specific lymphocytes at the same location and in a microenvironment designed for the task. The result of this encounter is clonal selection and the start of an adaptive response. Having a system that is spread throughout the body creates challenges regarding coordination and communication. In order for the cells involved in innate and adaptive immunity to work together, these two systems must be able to communicate with one another and coordinate a plan of attack. This communication is achieved both by direct cell-to-cell communication and by messenger proteins that are typically secreted and known by the general name cytokines (Chapter 3). Whether soluble or membrane-bound, these messengers bind to receptors on responding cells, inducing intracellular signaling cascades that can result in activation, proliferation, and differentiation of target cells. This is usually, but not always, mediated by changes in gene transcription that induce new functions in the target cell population. The target cells may now have the ability to make new factors or ligands of their own, or to migrate to new locations based on a fresh set of adhesion molecules. A subset of these soluble signals are called chemokines because they have chemotactic activity, meaning they can recruit specific cells to the site—like a trail of molecular breadcrumbs. In this way, cytokines, chemokines, and other soluble factors produced by immune cells recruit cells and draw fluid to the site of infection, providing help for pathogen eradication. We've probably all felt this convergence in the form of swelling, heat, and tenderness at a site of infection. These events 89 are part of a larger process collectively referred to as an inflammatory response, which is covered throughout this text in the context of a normal immune response, and in detail in Chapters 4 and 15. Frequently, more than one type of cytokine or chemokine is involved in these communication sessions between cells, and the unique set of receptors activated by this combination of signals helps to fine-tune the message and the resulting cellular response. Overview Figure 1-7 highlights the major events of an immune response. In this example, bacteria are shown breaching a mucosal or skin barrier, where they are recognized and engulfed by a local phagocytic cell (step 1). As part of the innate immune response, the local phagocytic cell releases cytokines and chemokines that attract other white blood cells to the site of infection, initiating inflammation (step 2). A phagocytic cell that has engulfed pathogen or the infectious agent itself then migrates to a local lymph node or other secondary lymphoid structure through lymphatic vessels (step 3). Lymphocytes (B and T cells) that have developed in primary lymphoid organs like the bone marrow and thymus make their way to these secondary lymphoid structures (step 4), where they can now meet up with the pathogen. Those lymphocytes with receptors that are specific for the pathogen are selected, proliferate, and begin the adaptive phase of the immune response, as shown in an example lymph node (step 5). This results in many antigen-specific T and B cells (called effector cells), the latter releasing antibodies that are specific for the pathogen. Many of these cells will exit the secondary lymphoid structure and join with the blood circulating through the body (step 6). At sites in the body experiencing the effects of innate responses, or inflammation, these effector cells and molecules will exit blood vessels and enter the inflamed tissue (step 7), migrating towards the pathogen and first responder phagocytic cells. Antibodies and T cells can now attach to and or attack the intruder, directing its destruction (step 8). At the conclusion, the adaptive response leaves behind memory T and B cells that recall the strategy used to eradicate the pathogen and can employ this strategy again during subsequent encounters. It is worth noting that memory is a unique capacity that arises from adaptive responses; there is no memory component of innate immunity (see below). // Key Concepts: -Components of the immune system can be found throughout the body, as sentinel cells in most tissues, in the form of specialized lymphoid organs, and through the specific recruitment of immune cells and fluid to sites of infection. -Overview Figure 1-7 outlines the basic scheme of an immune response and serves as a preview of concepts essential to the stages of the immune response, discussed in detail in later chapters.

Tolerance Ensures That the Immune System Avoids Destroying the Host

One consequence of generating random recognition receptors is that some could recognize and target the host. In order for the immune system's diversity strategy to work effectively, it must somehow avoid accidentally recognizing and destroying host tissues. This principle, which relies on self/nonself discrimination, is called tolerance, another hallmark of the immune response. Sir Frank Macfarlane Burnet was the first to propose that exposure to nonself antigens during certain stages of life could result in an immune system that ignored these antigens later. Sir Peter Medawar later proved the validity of this theory by exposing mouse embryos to foreign antigens and showing that these mice developed the ability to tolerate these antigens later in life. Together, Burnet and Medawar were awarded the Nobel Prize in Physiology or Medicine in 1960 for their foundational work characterizing immune tolerance (see Table 1-2). To establish tolerance, the antigen receptors present on developing B and T cells must first pass a test of nonresponsiveness against host structures. This process, which begins shortly after these randomly generated receptors are produced, is achieved by the destruction or inhibition of any cells that have inadvertently generated receptors with the ability to harm the host. Successful maintenance of tolerance ensures that the host always knows the difference between self and nonself (usually referred to as "foreign"). Key Concepts: Initial immune responses rely on recognition molecules that are conserved and recognize common pathogenic structures. These are inherited. As the immune response progresses, antigen-specific recognition molecules that were generated randomly in each individual T and B cell via DNA rearrangement drive the bulk of the response. These are not inherited. 85 One recent re-envisioning of how tolerance is operationally maintained is the danger or damage model. This theory, proposed by Polly Matzinger at the National Institutes of Health, suggests that the immune system constantly evaluates each new encounter more for its potential to be dangerous versus safe to the host than for whether it is self versus nonself. For instance, cell death can have many causes, including natural homeostatic processes, mechanical damage, or infection. The former is a normal part of the everyday biological events in the body ("good death") and only requires a cleanup response to remove debris. This should not and normally does not activate an immune response. The latter two ("bad death"), however, come with warning signs that include the release of intracellular-only contents, expression of cellular stress proteins, and sometimes also pathogen-specific products. The host damage or danger-associated compounds released in these situations, collectively referred to as alarmins, can engage specific host recognition molecules (e.g., the same PRRs that recognize PAMPs) that deliver a signal to immune cells to get involved during these unnatural causes of cellular death. In other words, seeing "other" in some instances (without danger signals) may not lead to an immune response, while seeing "self" in the wrong context (with danger signals) can lead to a break in tolerance. In fact, there is significant support for this theory, including the coincidence between exposure to some infectious agents and the development of autoimmunity (immune reactivity against host structures). As one might imagine, failures in the establishment or maintenance of tolerance can have devastating clinical outcomes. One unintended consequence of robust self-tolerance is that the immune system frequently ignores cancerous cells that arise in the body, as long as these cells continue to express self structures that the immune system has been trained to ignore. Dysfunctional tolerance is at the root of most autoimmune diseases, discussed further at the end of this chapter and in greater detail in Chapter 16. //Key Concepts: -The phenomenon of self-tolerance, which prohibits immune responses to host tissue, is maintained through the elimination or inhibition of cells or receptors that could respond to self-structures. -The danger or damage model of self-tolerance postulates that the immune response is not activated when host cell death occurs safely, but only when this death is accompanied by damage- or danger-associated signals produced by host cells.

Recombinant Signal Sequence (RSS)

Recombination signal sequences are conserved sequences of noncoding DNA that are recognized by the RAG1/RAG2 enzyme complex during V(D)J recombination in immature B cells and T cells.

The Immune Response Is Composed of Two Interconnected Arms: Innate Immunity and Adaptive Immunity

Although reference is made to "the immune system," it is important to appreciate that there are really two interconnected systems of response: innate and adaptive. These two systems collaborate to protect the body against foreign invaders. Innate immunity includes built-in molecular and cellular mechanisms that are evolutionarily primitive and aimed at preventing infection or quickly eliminating common invaders. This includes physical and chemical barriers to infection, as well as the DNA-encoded receptors recognizing common chemical structures of many pathogens (see Key Concepts: The phenomenon of self-tolerance, which prohibits immune responses to host tissue, is maintained through the elimination or inhibition of cells or receptors that could respond to self-structures. The danger or damage model of self-tolerance postulates that the immune response is not activated when host cell death occurs safely, but only when this death is accompanied by damage- or danger-associated signals produced by host cells. 86 PRRs, above; and Chapter 4). These are inherited from our parents and constitute a quick-and-dirty response; rapid recognition and subsequent phagocytosis or destruction of the pathogen is the outcome. Innate immunity also includes a series of preexisting serum proteins, collectively referred to as complement, that bind common pathogen-associated structures and initiate a cascade of labeling and destruction events (Chapter 5). This highly effective first line of defense prevents most pathogens from taking hold, or eliminates infectious agents within hours of encounter. The recognition elements of the innate immune system are fast, some occurring within seconds of a barrier breach, but they are not very specific and are therefore unable to distinguish between small differences in foreign antigens. A second form of immunity, known as adaptive immunity, is much more attuned to subtle molecular differences. This part of the system, which relies on B and T lymphocytes, takes longer to come on board but is much more antigen specific. Typically, there is an adaptive immune response against a pathogen within 5 or 6 days after the barrier breach and initial exposure, followed by a gradual resolution of the infection. Adaptive immunity is slower partly because fewer cells possess the perfect receptor for the job: the antigen-specific receptors on T and B cells that are generated via DNA rearrangement, mentioned earlier. It is also slower because parts of the adaptive response rely on prior encounter and "categorizing" of antigens undertaken by innate processes. After antigen encounter, T and B lymphocytes undergo selection and proliferation, according to the clonal selection theory of antigen specificity described earlier (see Figure 1-5). Although slow to act, once these B and T cells have been selected, replicated, and have honed their attack strategy, they become formidable opponents that can typically resolve the infection. The adaptive arm of the immune response evolves in real time in response to infection and adapts (thus the name) to better recognize, eliminate, and remember the invading pathogen. Adaptive responses involve a complex and interconnected system of cells and chemical signals that come together to finish the job initiated during the innate immune response. The goal of all vaccines against infectious disease is to elicit the development of specific and long-lived adaptive responses, so that the vaccinated individual will be protected in the future when the real pathogen comes along. This arm of immunity is orchestrated mainly via B and T lymphocytes following engagement of their randomly generated antigen recognition receptors. How these receptors are generated is a fascinating story, covered in detail in Chapter 6 of this text. An explanation of how these cells develop to maturity (Chapters 8 and 9), become activated during an immune response (Chapters 10 and 11), and then work in the body to protect us from infection (Chapters 12-14) or sometimes fail us (Chapters 15-19) takes up the vast majority of this text. The number of pages dedicated to discussing adaptive responses should not give the impression that this arm of the immune response is more important, or can work independently from innate immunity. In fact, the full development of the adaptive response is dependent on earlier innate pathways. The intricacies of their interconnections remain an area of intense study. The 2011 Nobel Prize in Physiology or Medicine was awarded to three scientists who helped clarify these two arms of the response: Bruce Beutler and Jules Hoffmann for discoveries related to the activation events important for innate immunity, and Ralph Steinman for his discovery of the role 87 of dendritic cells in activating adaptive immune responses (see Table 1-2). Because innate pathways make first contact with pathogens, the cells and molecules involved in this arm of the response use information gathered from their early encounter with pathogen to help direct the process of adaptive immune development. Adaptive immunity thus provides a second and more comprehensive line of defense, informed by the struggles undertaken by the innate system. It is worth noting that some infections are, in fact, eliminated by innate immune mechanisms alone, especially those that remain localized and involve very low numbers of fairly benign foreign invaders. (Think of all those insect bites or splinters in life that introduce bacteria under the skin!) Table 1-4 compares the major characteristics that distinguish innate and adaptive immunity. Although for ease of discussion the immune system is typically divided into these two arms of the response, there is considerable overlap of the cells and mechanisms involved in each of these arms of immunity. //Key Concepts: -The vertebrate immune response can be divided into two interconnected arms of immunity: innate and adaptive. Innate responses are rapid but less pathogen-specific, using inherited recognition molecules and phagocytic cells. Adaptive responses are slower (taking days to develop) but highly specialized to the pathogen, and rely on randomly generated recognition receptors made by B and T cells. -Innate and adaptive immunity operate cooperatively; activation of the innate immune response produces signals that are required to stimulate and direct the behavior of subsequent adaptive immune pathways.

Active vs Passive immunity

Active = individual has memory cells - can make their own antibodies & provides long term immunity. Passive = person given antibodies, these work then die, no long term immunity, no memory cells.

Genetic Regulation of Lineage Commitment during Hematopoiesis

Each step a hematopoietic stem cell takes toward commitment to a particular blood cell lineage is accompanied by genetic changes. HSCs maintain a relatively large number of genes in a "primed" state, meaning that they are accessible to transcriptional machinery. Environmental signals that induce HSC differentiation upregulate distinct sets of transcription factors that drive the cell down one of a number of possible developmental pathways. As cells progress down a lineage pathway, primed chromatin regions containing genes that are not needed for the selected developmental pathway are shut down. Many transcription factors that regulate hematopoiesis and lineage choices have been identified. Some have distinct functions, but many are involved at several developmental stages and engage in complex regulatory networks. Some transcription factors associated with hematopoiesis are illustrated in Figure 2-2. However, our understanding of their roles continues to evolve. A suite of factors appear to regulate HSC quiescence, proliferation, and differentiation (see Figure 2-2). Recent sequencing techniques have identified a "top ten" that include GATA-2, RUNX1, Scl/Tal-1, Lyl1, Lmo2, Meis1, PU.1, ERG, Fli-1, and Gfi1b, although others are bound to play a role. Other transcriptional regulators regulate myeloid versus lymphoid cell lineage choices. For instance, Ikaros is required for lymphoid but not myeloid development; animals survive in its absence but cannot mount a full immune response (i.e., they are severely immunocompromised). Low levels of PU.1 also favor lymphoid differentiation, whereas high levels of PU.1 direct cells to a myeloid fate. Activity of Notch1, one of four Notch family members, induces lymphoid progenitors to develop into T rather than B lymphocytes (see Chapter 8). GATA-1 directs myeloid progenitors toward red blood cell (erythroid) development rather than granulocyte/monocyte lineages. PU.1 also regulates the choice between erythroid and other myeloid cell lineages.

Hematopoietic Stem Cells Differentiate into All Red and White Blood Cells

HSCs originate in fetal tissues and reside primarily in the bone marrow of adult vertebrates. A small number can be found in the adult spleen and liver. Regardless of where they reside, HSCs are a rare subset—less than one HSC is present per 5 ×10 cells in the bone marrow. Their numbers are strictly controlled by a balance of cell division, death, and differentiation. Their development is tightly regulated by signals they receive in the microenvironments of primary lymphoid organs. Under conditions when the immune system is not being challenged by a pathogen (steady state or homeostatic conditions), most HSCs are quiescent; only a small number divide, generating daughter cells. Some daughter cells retain the stem-cell characteristics of the mother cell—that is, they remain self-renewing and are able to give rise to all blood cell types. Other daughter cells differentiate into progenitor cells that have limited self-renewal capacity and become progressively more committed to a particular blood cell lineage. As an organism ages, the number of HSCs decreases, demonstrating that there are limits to an HSC's self-renewal potential. When there is an increased demand for hematopoiesis, for example, during an infection or after chemotherapy, HSCs display an enormous proliferative capacity. This can be demonstrated in mice whose hematopoietic systems have been completely destroyed by a lethal dose of x-rays (950 rads). Such irradiated mice die within 10 days unless they are infused with normal bone marrow cells from a genetically identical mouse. Although a normal mouse has 3 ×10 bone marrow cells, infusion of fewer than 10 bone marrow cells from a donor is sufficient to completely restore the hematopoietic system. Our ability to identify and purify this tiny subpopulation has improved considerably, and in theory we can rescue the immune systems of irradiated animals with just a few purified stem cells, which give rise to progenitors that proliferate rapidly and repopulate the blood system. Because of their rarity, investigators initially found it very difficult to identify and isolate HSCs. Classic Experiment Box 2-1 describes experimental approaches that led to the first successful isolation of HSCs. Briefly, these efforts featured clever process-of-elimination strategies. Investigators reasoned that undifferentiated HSCs would not express surface markers specific for mature cells from the multiple blood lineages ("Lin" markers). They used several approaches to eliminate cells in the bone marrow that did express these markers (Lin cells) and then examined the remaining (Lin ) population for its potential to continually give rise to all blood cells over the long term. Other investigators took advantage of two technological developments that revolutionized immunological research—monoclonal antibodies and flow cytometry (see Chapter 20)—and identified surface proteins, including CD34, Sca-1, and c-Kit, that were expressed by the rare HSC population and allowed them to be isolated directly. We now recognize several different types of Lin Sca-1 c-Kit (LSK) HSCs, which vary in their capacity for self-renewal and their ability to give rise to all blood cell populations (pluripotency). Long-term HSCs (LT-HSCs) are the most quiescent and retain pluripotency throughout the life of an organism. These give rise to short-term HSCs (ST-HSCs), which are also predominantly quiescent but divide more frequently and have limited self-renewal capacity. In addition to being a useful marker for identifying HSCs, c-Kit is a receptor for the cytokine SCF, which promotes the development of multipotent progenitors (MPPs); these cells have a much more limited ability to self-renew, but proliferate rapidly and can give rise to both lymphoid and myeloid cell lineages. Key Concepts: -All red and white blood cells develop from pluripotent HSCs during a highly regulated process called hematopoiesis. In the adult vertebrate, hematopoiesis occurs primarily in the bone marrow, a primary lymphoid organ that supports both the selfrenewal of stem cells and their differentiation into multiple blood cell types. -The HSC is a rare cell type that is self-renewing and multipotent. HSCs have the capacity to differentiate and replace blood cells rapidly. First isolated by negative selection techniques that enriched for undifferentiated stem cells, they are now isolated by high-powered sorting techniques. -HSCs include multiple subpopulations that vary in their quiescence and capacity to self-renew. Long-term HSCs are the most quiescent and long-lived. They give rise to short-term HSCs, which can develop into more proliferative MPPs, which give rise to lymphoid and myeloid cell types.

Key Concepts:

Long before we understood much about the immune system, key principles of this system were already being studied and applied to solve public health issues associated with infectious disease. The principle behind vaccination is that exposure to safe forms of an infectious agent can result in future acquired protection, or immunity, to the real and more dangerous infectious agent. Worldwide vaccination programs have effectively eradicated or protected us from many previously deadly infectious diseases, especially in young children. If many individuals in a group are protected from an infectious agent, either naturally or through vaccination, it is less likely to spread and unvaccinated individuals in the group are inadvertently protected as well. // Despite the many successes of vaccine programs, such as the eradication of smallpox, many vaccine challenges still remain. Perhaps the greatest current challenge is the design of effective vaccines for major killers such as malaria and human immunodeficiency virus (HIV). As the tools of molecular and cellular biology, genomics, and proteomics improve, so will our understanding of the immune system, leaving us better positioned to make progress toward preventing these and other emerging infectious diseases. A further issue is the fact that millions of children in developing countries die from diseases that are fully preventable by available, safe vaccines. High manufacturing costs, instability of the products, and cumbersome delivery problems keep these vaccines from reaching those who might benefit the most. This problem could be alleviated in many cases by development of future-generation vaccines that are inexpensive, heat stable, and administered without a needle. Finally, misinformation and myth surrounding vaccine efficacy and side effects continue to hamper many potentially life saving vaccination programs (see Clinical Focus Box 1-1). //Passive immunization based on the transfer of antibodies is widely used in the treatment of immunodeficiency and some autoimmune diseases. It is also used to protect individuals against anticipated exposure to infectious and toxic agents against which they have no immunity. Finally, passive immunization can be lifesaving during episodes of certain types of acute infection, such as following exposure to rabies virus. //Immunoglobulin for passive immunization is prepared from the pooled plasma of thousands of donors. In effect, recipients of these antibody preparations are receiving a sample of the antibodies produced by many people to a broad diversity of pathogens—a gram of intravenous immune globulin (IVIG) contains about 10 molecules of antibody that recognize more than 10 different antigens. However, a product derived from the blood of such a large number of donors carries a risk of harboring pathogenic agents, particularly viruses. This risk is minimized by modern-day production techniques. The manufacture of IVIG involves treatment with solvents, such as ethanol, and the use of detergents that are highly effective in inactivating viruses such as HIV and hepatitis. In addition to treatment against infectious disease, or in acute situations, IVIG is also used today to treat some chronic diseases, including several forms of immune deficiency. In all cases, the transfer of passive immunity supplies only temporary protection. //Today, more than ever, we are beginning to understand at the molecular and cellular levels how a vaccine or infection leads to the development of immunity. As highlighted by the historical studies described above, this involves a complex system of cells and soluble compounds that have evolved to protect us against an enormous range of invaders of all shapes, sizes, and chemical structures

the granulocytes have a higher expression of IgE this is what causes allergic response. Mast cells Eosinophils Basophils

Meaning IgE is the antibody responsible for allergic response.

Morbidity

Refers to ill health in an individual and the levels of ill health in a population or group.

Autoimmune Disease

Sometimes the immune system malfunctions and a breakdown in self-tolerance occurs. This could be caused by a sudden inability to distinguish between self and nonself or by a misinterpretation of a self-component as dangerous, causing an immune attack on host tissues. This condition, called autoimmunity, can result in a number of chronic debilitating diseases. The symptoms of autoimmunity differ, depending on which tissues or organs are under attack. For example, multiple sclerosis is due to an autoimmune attack on a protein in nerve sheaths in the brain and central nervous system that results in neuromuscular dysfunction. Crohn's disease is an attack on intestinal tissues that leads to destruction of gut epithelia and poor absorption of food. One of the most common autoimmune disorders, rheumatoid arthritis, results from an immune attack on joints of the hands, feet, arms, and legs. Both genetic and environmental factors are likely involved in the development of most autoimmune diseases. However, the exact combination of genes and environmental exposures that favors the development of each particular autoimmune disease is difficult to pin down; immunologic research in this area is very active. Recent discoveries and the search for improved treatments are all covered in greater detail in Chapter 16.

Hematopoiesis and Cells of the Immune System

Stem cells are defined by two capacities: (1) the ability to regenerate or "self-renew" and (2) the ability to differentiate into diverse cell types. Embryonic stem cells have the capacity to generate almost every specialized cell type in an organism (in other words, they are pluripotent). Adult stem cells, in contrast, have the capacity to give rise to the diverse cell types that specify a particular tissue (they are multipotent). Multiple adult organs harbor stem cells that can give rise to cells specific for that tissue (tissue-specific stem cells). The HSC was the first tissue-specific stem cell identified and is the source of all of our red blood cells (erythroid cells) and white blood cells (leukocytes).

Affinity

The strength of the bond between the antigen and its receptor. //Higher for the monomer antibodies. -IgG -IgD -IgE

Outline for the Humoral and Cell-Mediated (Cellular) Branches of the Immune system. (figure 1-5)

We now know that B cells produce antibodies, a soluble version of their receptor protein, that bind to foreign proteins, flagging them for destruction. T cells, which come in several different forms, also use their surface-bound T-cell receptors to sense antigen. These cells can perform a range of different functions once selected by antigen encounter, including the secretion of soluble compounds to aid other white blood cells (such as B lymphocytes) and the destruction of infected host cells

Anaphylaxis

a severe response to an allergen in which the symptoms develop quickly, and without help, the patient can die within a few minutes. // However, most allergic or anaphylactic responses involve a type of antibody called immunoglobulin E (IgE). Binding of IgE to its specific antigen (allergen) induces the release of substances that cause irritation and inflammation, or the accumulation of cells and fluid at the site.

Clonal selection

"Through the insights of F. Macfarlane Burnet, Niels Jerne, and David Talmadge, this hypothesis was restructured into a model that came to be known as the clonal selection theory. This model has been further refined over the years and is now accepted as an underlying paradigm of modern immunology. According to this theory, an individual B or T lymphocyte expresses many copies of a membrane receptor that is specific for a single, distinct antigen." Clonal selection is the process by which individual T and B lymphocytes are engaged by antigen and cloned to create a population of antigen-reactive cells with identical antigen specificity //This unique receptor specificity is determined in the lymphocyte before it is exposed to the antigen. Binding of antigen to its specific receptor activates the cell, causing it to proliferate into a clone of daughter cells that have the same receptor specificity as the parent cell.

CDR3

*Complementarity determining region* -Part of the variable chains of immunoglobulins >Where molecules bind to their specific antigen -Most diverse compared to other regions -CDR1 and CDR2 ONLY found in V region -CDR 3 found in some of V, ALL of D region, and ALL of J region. *CDR3 seen in most of variable domain*

Inappropriate or Dysfunctional Immune Responses Can Result in a Range of Disorders

-Hypersensitivity (allergy): Overly zealous attacks on common benign but foreign antigens. -Autoimmune disease: Erroneous targeting of self-proteins or tissues by immune cells -Immune deficiency: Insufficiency of the immune response to protect against infectious agents -Immune imbalance: Dysregulation in the immune system that leads to aberrant activity of immune cells, especially enhanced inflammation and/or and reduced immune inhibition A brief overview of these situations and some examples of each are presented below. At its most basic level, immune dysfunction occurs as a result of improper regulation that allows the immune system either to attack something it shouldn't or fail to attack something it should. Hypersensitivities, including allergy, and autoimmune disease are cases of the former, where the immune system attacks an improper target. As a result, the symptoms can manifest as pathological inflammation—an influx of immune cells and molecules that results in detrimental symptoms, including chronic inflammation and rampant tissue destruction. In contrast, immune deficiencies, caused by a failure to properly deploy the immune response, usually result in weakened or dysregulated immune responses that can allow pathogens to get the upper hand. Immune imbalance, a less well-characterized phenomenon, can result from changes in the environment that disrupt immune homeostasis. Manifestations of this typically present as either allergic or autoimmune conditions, both examples of overly active immune response states.

Hypersensitivity Reactions

Allergies and asthma are examples of hypersensitivity reactions. These result from inappropriate and overly active immune responses to common innocuous environmental antigens, such as pollen, food, or animal dander. The possibility that certain substances induce increased sensitivity 94 (hypersensitivity) rather than protection was recognized in about 1902 by Charles Richet, who attempted to immunize dogs against the toxins of a type of jellyfish. He and his colleague Paul Portier observed that dogs exposed to sublethal doses of the toxin reacted almost instantly, and fatally, to a later challenge with even minute amounts of the same toxin. Richet concluded that a successful vaccination typically results in phylaxis (protection), whereas anaphylaxis (antiprotection)—an extreme, rapid, and often lethal overreaction of the immune response to something it has encountered before—can result in certain cases in which exposure to antigen is repeated. Richet received the Nobel Prize in 1913 for his discovery of the anaphylactic response (see Table 1-2). The term is used today to describe a severe, life-threatening, allergic response. Fortunately, most hypersensitivity or allergic reactions in humans are not fatal. There are several different types of hypersensitivity reactions; some are caused by antibodies and others are the result of T-cell activity (see Chapter 15). However, most allergic or anaphylactic responses involve a type of antibody called immunoglobulin E (IgE). Binding of IgE to its specific antigen (allergen) induces the release of substances that cause irritation and inflammation, or the accumulation of cells and fluid at the site. When an allergic individual is exposed to an allergen symptoms may include sneezing (Figure 1-9), wheezing and difficulty breathing (asthma); dermatitis or skin eruptions (hives); and, in more severe cases, strangulation due to constricted airways following extreme inflammation. A significant fraction of our health resources is expended to care for those suffering from allergies and asthma. One particularly interesting rationale to explain the unexpected rise in allergic disease, called the hygiene hypothesis and linked to immune imbalance, is discussed in Clinical Focus Box 1-3.

HSCs Differentiate into Myeloid and Lymphoid Blood Cell Lineages

An HSC that is induced to differentiate ultimately loses its ability to self-renew as it progresses from being an LT-HSC to an ST-HSC and then an MPP (Figure 2-2). At this stage, a cell makes one of two lineage commitment choices. It can become a myeloid progenitor cell (sometimes referred to as a common myeloid progenitor or CMP), which gives rise to red blood cells, platelets, and myeloid cells (granulocytes, monocytes, macrophages, and some dendritic cell populations). Myeloid cells are members of the innate immune system, and are the first cells to respond to infection or other insults. Alternatively, it can become a lymphoid progenitor cell (sometimes referred to as a common lymphoid progenitor or CLP), which gives rise to B lymphocytes, T lymphocytes, innate lymphoid cells (ILCs), as well as specific dendritic cell populations. B and T lymphocytes are members of the adaptive immune response and generate a refined antigenspecific immune response that also gives rise to immune memory. ILCs have features of both innate and adaptive cells. Recent data suggest that precursors of red blood cells and platelets can arise directly from the earliest LT- and ST-HSC subpopulations (see Figure 2-2). Indeed, the details behind lineage choices are still being worked out by investigators, who continue to identify intermediate cell populations within these broad progenitor categories. As HSC descendants progress along their chosen lineages, they also progressively lose the capacity to contribute to other cellular lineages. For example, MPPs that are induced to express the receptor Flt-3 lose the ability to become erythrocytes and platelets and are termed lymphoidprimed, multipotent progenitors (LMPPs) (Figure 2-3). As LMPPs become further committed to the lymphoid lineage, levels of the stem-cell antigens c-Kit and Sca-1 fall, and the cells begin to express RAG1/2 and TdT, enzymes involved in the generation of lymphocyte receptors. Expression of RAG1/2 defines the cell as an early lymphoid progenitor (ELP). Some ELPs migrate out of the bone marrow to seed the thymus as T-cell progenitors. The rest of the ELPs remain in the bone marrow as B-cell progenitors. Their levels of the interleukin-7 receptor (IL-7R) increase, and the ELP now develops into a CLP, a progenitor that is now c-Kit Sca-1 IL-7R and has lost myeloid potential. However, it still has the potential to mature into any of the lymphocyte lineages: T cell, B cell, or ILC

Cancer Presents a Unique Challenge to the Immune Response

Just as graft rejection is the expected response of a healthy immune system to the addition of foreign (if benign) tissues, a tendency to ignore cancer cells might also be viewed as a normal response to what belongs and is accepted as self. Cancer, or malignancy, occurs in host cells when they begin to divide out of control. Since these cells are self in origin, self-tolerance mechanisms can inhibit the development of an immune response, making the detection and eradication of cancerous cells a continual challenge. That said, it is clear that many tumor cells do express unique or developmentally inappropriate proteins, making them potential targets for immune cell recognition and elimination, as well as targets for therapeutic intervention. However, as with many microbial pathogens, the increased genetic instability of these rapidly dividing cells gives them an advantage in terms of evading immune detection and elimination machinery. We now know that the immune system actively participates in the detection and control of cancer in the body (see Chapter 19). The number of malignant disorders that arise in individuals with compromised immunity, such as those taking immune-suppressing medications, highlights the degree to which the immune system normally controls the development of cancer. Both innate and adaptive elements have been shown to be involved in this process, although adaptive immunity likely plays a more significant role. However, associations between inflammation and the development of cancer, as well as the degree to which cancerous cells evolve to become more aggressive and evasive under pressure from the immune system, have demonstrated that the immune response to cancer can have both healing and disease-inducing characteristics. As the mechanics of these elements are resolved in greater detail, there is hope that therapies can be designed to boost or maximize the antitumor effects of immune cells while dampening their tumor-enhancing activities. Our understanding of the immune system has clearly come a very long way in a fairly short time. Yet much still remains to be learned about the mammalian immune response and the ways in which this system interacts with other body systems. With this enhanced knowledge, the hope is that we will be better poised to design ways to modulate these immune pathways through intervention. This would allow us to develop more effective prevention and treatment strategies for cancer and other diseases that plague society today, not to mention preparing us to respond quickly to the new diseases or infectious agents that will undoubtedly arise in the future. Key Concept: -The healthy immune system tolerates or ignores cells it identifies as self, which alas often includes those that become cancerous.

Chapter 1: Key Terms

Key Terms Immunity Immunoglobulin Antibodies Humoral immunity Passive immunity Active immunity Cell-mediated immunity T lymphocytes (T cells) B lymphocytes (B cells) Antigen Clonal selection Pathogens B-cell receptors T-cell receptors Tolerance Innate immunity Adaptive immunity Inflammatory response Primary response Secondary response

Chapter 1: Overview of the immune system

Learning Objectives After reading this chapter, you should be able to: 1. Trace the study of immunology from a desire to vaccinate against infectious disease to far reaching applications in basic research, medicine, and other fields of study. 2. Examine and question prior assumptions related to immunology and categorize features unique to the immune system. 3. Practice and apply some immunology-specific vocabulary, while distinguishing cells, structures, and concepts important to the field of immunology. 4. Recognize the need for balance and regulation of immune processes and evaluate the consequences of dysregulation. 5. Begin to integrate concepts from immunity into real-world issues and medical applications.

The Immune Response Renders Tissue Transplantation Challenging

Normally, when the immune system encounters foreign cells, it responds strongly to rid the host of the presumed invader. However, in the case of transplantation, these cells or tissues from a donor may be the only possible treatment for life-threatening disease. For example, it is estimated that more than 70,000 persons in the United States alone would benefit from a kidney transplant. The fact that the immune system will attack and reject any transplanted organ that is nonself, or not a genetic match, raises a formidable barrier to this potentially lifesaving treatment, presenting a unique challenge to clinicians who treat these patients. While the rejection of a transplant by a recipient's immune system may be seen as a "failure," in fact it is just a consequence of the immune system functioning properly. Normal tolerance processes governing self/nonself discrimination and immune engagement caused by danger signals (partially the result of the trauma caused by surgical transplantation) lead to the rapid influx of immune cells and coordinated attacks on the new resident cells. Some of these transplant rejection responses can be suppressed using immune-inhibitory drugs, but treatment with these drugs also suppresses general immune function, leaving the host susceptible to opportunistic infections. Research related to transplantation studies has played a major role in the development of the field of immunology. A Nobel Prize was awarded in 1930 to Karl Landsteiner (mentioned earlier for his contributions to the concept of immune specificity) for the discovery of the human ABO blood groups, a finding that allowed blood transfusions to be carried out safely. In 1980, George Snell, Jean Dausset, and Baruj Benacerraf were recognized for discovery of the major histocompatibility complex (MHC). These are the tissue antigens that differ most between nongenetically identical individuals, and are thus one of the primary targets of immune rejection of transplanted tissues. Finally, in 1990 E. Donnall Thomas and Joseph Murray were awarded the Nobel Prize for treatment advances that paved the way for more clinically successful tissue transplants (see Table 1-2). The development of procedures that would allow a foreign organ or cells to be accepted without suppressing immunity to all antigens still remains a major goal, and a challenge, for immunologists today (see Chapter 16) Key Concept: -The rejection of a tissue transplant is an example of the immune system functioning properly, by identifying the graft as foreign.

Adaptive Immune Responses Typically Generate Memory

One particularly significant and unique attribute of the adaptive arm of the immune response is immunologic memory. This is the ability of the immune system to respond much more swiftly and with greater efficiency during a second exposure to the same pathogen. Unlike almost any other biological system, the vertebrate immune response has evolved not only the ability to learn from (adapt to) its encounters with foreign antigen in real time but also the ability to store this information for future use. During a first encounter with foreign antigen, adaptive immunity undergoes what is termed a primary response, during which the key lymphocytes that will be used to eradicate the pathogen are clonally selected, honed, and enlisted to resolve the infection. As mentioned above, these cells incorporate messages received from the innate players into their tailored response to the specific pathogen. All subsequent encounters with the same antigen or pathogen are typically referred to as the secondary response (Figure 1-8). During a secondary response, memory cells, kin of the final and most efficient B and T lymphocytes trained during the primary response, are re-enlisted to fight again. These cells begin almost immediately and pick up right where they left off, continuing to learn and improve their eradication strategy during each subsequent encounter with the same antigen. Depending on the antigen in question, memory cells can remain for decades after the conclusion of the primary response. Memory lymphocytes provide the means for subsequent responses that are so rapid, antigen-specific, and effective that when the same pathogen infects the body a second or subsequent time, dispatch of the offending organism often occurs without symptoms. It is the remarkable property of memory that prevents us from catching many diseases a second time. Immunologic memory harbored by residual B and T lymphocytes is the foundation for vaccination, which uses crippled or killed pathogens as a safe way to "educate" the immune system to prepare it for later attacks by life-threatening pathogens. Memory cells then save the strategy used, not the pathogen (or vaccine), for later reference during repeat encounters with the same infectious agent. Sometimes, as is the case for some vaccines, one round of antigen encounter and adaptation is not enough to impart protective immunity from the pathogen in question. In many of these cases, immunity can develop after a second or even a third round of exposure to an antigen. It is these sorts of pathogens that necessitate the use of vaccine booster shots. Booster shots are nothing more than a second or third episode of exposure to the antigen, each driving a new round of adaptive events (secondary response) and refinements in the responding lymphocyte population. The aim is to hone these responses to a sufficient level to afford protection against the real pathogen at some future date. //Key Concept: -The first exposure to a pathogen results in a primary immune response, which culminates in the creation of memory cells, or B and T cells that remain after pathogen eradication and that can be activated during a subsequent exposure to that same pathogen (a secondary response).

Attenuate

To decrease the virulence of a pathogen and render it incapable of causing disease. Many vaccines are composed of attenuated bacteria or viruses that induce protective immunity without causing harmful infection.

Avidity (more than one binding site)

What is the term for the strength of association between multiple binding sites and multiple antigenic determinants? higher for the pentamer antibodies or polymer

poly-Ig receptor

binding to dimeric IgA, and pentamer IgM and facilitation of its transcytosis.

Complement Activation

causes inflammation and cell lysis. -Classic pathway—IgG or IgM mediated. -Alternative pathway—microbe surface molecules. -Lectin pathway—mannose or other sugars on microbe surface. //binding on the surface of NK FC receptor will activate similar to binding to macrophage FC receptors

B220

marker of committed B cells

Every Antibody that exits the bone marrow exits with either IgM, and IgD FC regions (Constant) ...

meaning they need to be recombinatned by switch recombinases that bind on switch regions of FC regions. // happens in periphery

BCR receptors are normally found on the protein surface.

more easily accessed than the TCR is with its ligands.