pediagenosis: Immunology
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Showing posts with label Immunology. Show all posts
Showing posts with label Immunology. Show all posts

Saturday, May 11, 2019

Clonal Selection

Clonal Selection


Clonal Selection
Antigen selects those lymphocytes that possess the specific receptor
Each B‐cell is programmed to make one, and only one, specificity of antibody and it places a transmembrane version of these antibodies on its cell surface to act as receptors for the specific antigen. These antibodies can be detected by using fluorescent probes and, in Figure 2.8c, one can see the molecules of antibody on the surface of a human B‐lymphocyte stained with a fluorescent rabbit antiserum raised against a preparation of human antibodies. Each B‐lymphocyte has of the order of 105 antibody molecules, all of identical antigen specificity, on its surface. The B‐cells give rise to plasma cells (Figure 2.8 d,e), which produce large amounts of soluble antibody in their rough endoplasmic reticulum (Figure 2.8 f ). The antibody is then secreted from the plasma cells into the local environment and can circulate, become attached to cells bearing Fc receptors, or be transported to mucosal surfaces.
Antibody – A Specific Antigen Recognition Molecule

Antibody – A Specific Antigen Recognition Molecule


Antibody – A Specific Antigen Recognition Molecule
Evolutionary processes came up with what can only be described as a brilliant solution to the problem of recognizing an almost infinite diversity of antigens. This solution was to design antibody molecules in such a way that not only are they able to specifically recognize the offending pathogen but they can also recruit various components of the immune response capable of subsequently destroying the pathogen.
The Innate Immune System Instigates Adaptive Immunity

The Innate Immune System Instigates Adaptive Immunity


The Innate Immune System Instigates Adaptive Immunity
As we have seen throughout this chapter, any infectious agent that manages to enter the body faces a formidable array of defensive weapons, ranging from macrophage‐and neutrophil‐mediated phagocytosis, to complement‐mediated attack, membrane perforation by defensins, and digestion by extracellular enzymes. As if all of this were not enough, the innate immune system also plays a critical role in initiating an immune response that is uniquely tailored to the ongoing infection. This is achieved by calling upon cells of the adaptive immune system and instructing these cells in the nature of the particular antigens that are giving cause for concern. This function, called antigen presentation, is carried out largely, but not exclusively, by a cell that has relatively recently come to the fore as being of critical importance as a conduit between the innate and adaptive immune systems: the dendritic cell (DC).
Natural Killer Cells Kill Virally Infected Cells

Natural Killer Cells Kill Virally Infected Cells


Natural Killer Cells Kill Virally Infected Cells
Thus far, we have dealt with situations that deal primarily with infectious agents that reside in the extracellular space. But what if an infectious agent manages to enter cells of the host, where they are protected from the attentions of the soluble PRRs (e.g., complement) and are also shielded from phagocytosis by macrophages and neutrophils? To deal with this situation, another type of immune cell has evolved – the natural killer (NK) cell, which is endowed with the ability to inspect host cells for signs of abnormal patterns of protein expression that may indicate that such cells might be harboring a virus. NK cells are also capable of killing cells that have suffered mutations and are on the way to malignant transformation into tumors. Note that although NK cells constitute a component of the innate response, under certain circumstances they exhibit immunological memory, a feature usually confined to adaptive responses.

Wednesday, October 17, 2018

Humoral Mechanisms Provide An Additional Defensive Strategy

Humoral Mechanisms Provide An Additional Defensive Strategy


Humoral Mechanisms Provide An Additional Defensive Strategy
Microbicidal factors in secretions
Turning now to those defense systems that are mediated entirely by soluble pattern recognition molecules (Figure 1.2), we recollect that many microbes activate the complement system and may be lysed by the insertion of the membrane attack complex. The spread of infection may be limited by enzymes released through tissue injury that activate the clotting system. Of the soluble bactericidal substances elaborated by the body, perhaps the most abundant and widespread is the enzyme lysozyme, a muramidase that splits the exposed peptidoglycan wall of susceptible bacteria (see Figure 11.5).
Complement Facilitates Phagocytosis And Bacterial Lysis

Complement Facilitates Phagocytosis And Bacterial Lysis


Complement Facilitates Phagocytosis And Bacterial Lysis
The complement system comprises a group of some 20 or so plasma proteins that becomes activated in a cascade‐like manner upon binding to certain microbial polysaccharides that are not normally present in vertebrates, but are commonly found on bacterial membranes. Many of the complement factors are proteases that are initially produced as inactive precursors and become activated through the detection of PAMPs, with each protease activating the next in the chain. Complement activation can result in binding of complement to bacterial cell surfaces (called opsonization in immunological parlance), which can greatly enhance their uptake by phagocytes. Deposition of complement factors onto its surface can also result in direct lysis of a bacterium that has had the misfortune to trigger this cascade. Just as importantly, certain complement fragments that are produced as byproducts of complement activation can act as chemotactic factors to guide phagocytic cells (such as neutrophils and macrophages) to the hapless bacterium, resulting in its capture through phagocytosis. The latter complement factors can also activate local mast cells (as we mentioned earlier) to release molecules that help to recruit neutrophils and other cells of the immune system to the site of infection, through increasing the permeability of local blood vessels. Either way, complement activation spells trouble for our little bacterial foe. The many proteins involved can make the complement system appear daunting initially, but do keep in mind the overall objectives of enhancing phagocytosis, recruitment of other immune cells, and direct lysis of microorganisms, as we proceed through the details.
Phagocytes Employ An Array Of Killing Mechanisms

Phagocytes Employ An Array Of Killing Mechanisms


Phagocytes Employ An Array Of Killing Mechanisms
Killing by reactive oxygen intermediates
Trouble starts for the invader from the moment phagocytosis is initiated. There is a dramatic increase in activity of the hexose monophosphate shunt, generating reduced nicotinamide adenine dinucleotide phosphate (NADPH). Electrons pass from the NADPH to a flavine adenine dinucleotide (FAD) containing membrane flavoprotein and thence to a unique plasma membrane cytochrome (cyt b558). This has the very low midpoint redox potential of −245 mV that allows it to reduce molecular oxygen directly to superoxide anion (Figure 1.29a). Thus the key reaction catalyzed by this NADPH oxidase, which initiates the formation of reactive oxygen intermediates (ROI), is:
Phagocytic Cells Engulf And Kill Microorganisms

Phagocytic Cells Engulf And Kill Microorganisms


Phagocytic Cells Engulf And Kill Microorganisms
Macrophages and neutrophils are dedicated “professional” phagocytes
The engulfment and digestion of microorganisms are assigned to two major cell types recognized by Elie Metchnikoff at the turn of the last century as microphages (now known as neutrophils) and macrophages.
There Are Several Classes Of Pattern Recognition Receptors

There Are Several Classes Of Pattern Recognition Receptors


There Are Several Classes Of Pattern Recognition Receptors
PRRs on phagocytic cells recognize and are activated by PAMPs
Because the ability to discriminate friend from foe is of paramount importance for any self‐respecting phagocyte, macrophages are fairly bristling with receptors capable of recognizing diverse PAMPs. Many of the PRRs are also expressed on DCs, NK cells, neutrophils and mast cells, as well as cells of the adaptive immune system. Several of these PRRs are lectin‐like and bind multivalently with considerable specificity to exposed microbial surface sugars with their characteristic rigid three‐dimensional geometric configurations. They do not bind appreciably to the array of galactose or sialic acid groups that are commonly the penultimate and ultimate sugars that decorate mammalian surface polysaccharides, so providing the molecular basis for discriminating between self and nonself microbial cells. Other PRRs detect nucleic acids derived from bacterial and viral genomes by virtue of modifications not commonly found within vertebrate nucleic acids or conformations not normally found in the cytoplasm (e.g., double‐stranded RNA).

Wednesday, October 10, 2018

The Beginnings Of An Immune Response

The Beginnings Of An Immune Response


The Beginnings Of An Immune Response
Macrophages play an important role in instigating innate immune responses
As noted above, a major player in the initiation of immune responses is the macrophage. These cells are relatively abundant in most tissues (approaching 10–15% of the total cell number in some areas of the body) and act as sentinels for infectious agent through an array of pathogen recognition receptors (PRRs) borne on their plasma membranes as well as other cellular compartments such as endosomes. Tissue macrophages are relatively quiescent cells, biding their time sampling the environment around them through continuous phagocytosis. However, upon entry of a microorganism that engages one or more of their PRRs (such as a Toll‐like receptor or a NOD‐like receptor), a startling transition occurs. Engagement of the PRR on the macrophage switches on a battery of genes that equip it to carry out a number of new functions (Figure 1.12).
Cells Of The Immune System

Cells Of The Immune System


Cells Of The Immune System
The cells of the immune system can be divided broadly into two main classes – myeloid and lymphoid cells
Immune cells, which are collectively called leukocytes (white blood cells), can be divided broadly into myeloid and lymphoid subsets (Figure 1.7).

Tuesday, September 18, 2018

External Barriers Against Infection

External Barriers Against Infection


External Barriers Against Infection
As mentioned above, the simplest way to avoid infection is to prevent the microorganisms from gaining access to the body (Figure 1.6). When intact, the skin is impermeable to most infectious agents; when there is skin loss, as for example in burns, infection becomes a major problem. Additionally, most bacteria fail to survive for long on the skin because of the direct inhibitory effects of lactic acid and fatty acids in sweat and sebaceous secretions and the low pH that they generate. An exception is Staphylococcus aureus, which often infects the relatively vulnerable hair follicles and glands.
Innate Versus Adaptive Immunity

Innate Versus Adaptive Immunity


Innate Versus Adaptive Immunity
Three levels of immune defense
Before we get into the details, we will first summarize how the immune system works in broad brushstrokes. The vertebrate immune system comprises three levels of defense (Figure 1.5). First, there is a physical barrier to infection that is provided by the skin on the outer surfaces of the body, along with the mucous secretions covering the epidermal layers of the inner surfaces of the respiratory, digestive, and reproductive tracts. Any infectious agent attempting to gain entry to the body must first breach these surfaces that are largely impermeable to microorganisms; this is why cuts and scrapes that breach these physical barriers are often followed by infection. The second level of defense is provided by the innate immune system, a relatively broad‐acting but highly effective defense layer that is largely preoccupied with trying to kill infectious agents from the moment they enter the body. The actions of the innate immune system are also responsible for alerting the cells that operate the third level of defense, the adaptive (or acquired) immune system. The latter cells represent the elite troops of the immune system and can launch an attack that has been specifically adapted to the nature of the infectious agent using sophisticated weapons such as antibodies. As we shall see, the innate and adaptive immune systems each have their own particular advantages and disadvantages and therefore act cooperatively to achieve much more effective immune protection than either could achieve in isolation.
Immune Responses Are Tailored Towards Particular Types Of Infection

Immune Responses Are Tailored Towards Particular Types Of Infection


Immune Responses Are Tailored Towards Particular Types Of Infection
Not all pathogens are equal
We will shortly get into the specifics of the immune system, but before doing so it is useful to consider the diversity of infectious agents that our immune systems may encounter (Figure 1.1), and to contemplate whether a “one size fits all” immune response is likely to suffice in all of these situations. One of the frustrations expressed by many students of immunology is that the immune system appears to be almost byzantine in its complexity. Although this is indeed partly true, the reasons for this are two‐fold. First, because there are different types of infection, immune responses need to be tailored towards the particular class of infection (whether viral, extra-cellular bacterial, intracellular bacterial, worm, fungal, etc.) in order to mount the most effective immune response towards a particular infectious agent. Second, although there is indeed complexity in the immune system, there is also a great deal of order and repeated use of the same basic approach when recognizing pathogens and initiating an immune response. Therefore, although many of molecules used in the pursuit of pathogen recognition belong to different classes, many of these plug into the same effector mechanisms as soon as the pathogen is successfully identified. So, dear reader, please bear with us while we try to make sense of the apparent chaos. But mean-while, let us get back to pathogens to consider why our immune systems need to be fairly elaborate and multi‐layered.
Pattern Recognition Receptors Detect Nonself

Pattern Recognition Receptors Detect Nonself


Pattern Recognition Receptors Detect Nonself
Pattern recognition receptors (PRRs) raisethe alarm
To identify potentially dangerous microbial agents, our immune systems need to be able to discriminate between “non-infectious self and infectious nonself” as Janeway elegantly put it. Recognition of nonself entities is achieved by means of an array of pattern recognition receptors and proteins (collectively called pattern recognition molecules) that have evolved to detect conserved (i.e., not prone to mutation) components of microbes that are not normally present in the body (i.e., PAMPs).

Tuesday, August 7, 2018

Lymphoid Organs

Lymphoid Organs


Lymphoid Organs
The central and peripheral lymphoid organs are responsible for the production, maturation, and storage of large numbers of immune system cells including the B and T lymphocytes. These organs and tissues are widely distributed throughout the body and provide different, but often overlapping, functions (Fig. 13.12). The central lymphoid organs are comprised of the bone marrow and the thymus and are responsible for immune cell production and maturation. The tissues and cells of the peripheral lymphoid system store the cells of the immune system where they function to concentrate and process antigen as well as support cellular processes necessary for development of fully functioning, adaptive immune responses. The peripheral lymphoid tissues are comprised of the lymph nodes, spleen, tonsils, appendix, Peyer patches in the intestine, and mucosa-associated lymphoid tissues in the respiratory, gastrointestinal, and reproductive systems. Networks of lymph channels, blood vessels, and capillaries connect the lymphoid organs and transport immune cells, antigens, and cellular debris throughout the body.
T Lymphocytes and Cellular Immunity

T Lymphocytes and Cellular Immunity


T Lymphocytes and Cellular Immunity
T lymphocytes serve many functions in the immune system including the activation of other T cells and B cells, control of intracellular viral infections, rejection of foreign tissue grafts, activation of autoimmune processes, and activation of delayed hypersensitivity reactions. These processes make up the body’s cell-mediated or cellular immunity. The effector phase of cell-mediated immunity is carried out by T lymphocytes and macrophages.
B Lymphocytes and Humoral Immunity

B Lymphocytes and Humoral Immunity


B Lymphocytes and Humoral Immunity
The humoral immune response is mediated by antibodies, which are produced by the B lymphocytes. The primary functions of the B lymphocytes are the elimination of extracellular microbes and toxins and subsequent “memory” for a heightened response during future encounters. Humoral immunity is more important than cellular immunity in defending against microbes with capsules rich in polysaccharides and lipid tox-insbecause only the B lymphocytes are capable of responding to and producing antibodies specific for many types of these molecules. The T cells, which are the mediators of cellular immunity, respond primarily to surface protein antigens.

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