How the Immune System Works has helped thousands of students understand what's in their big, thick, immunology textbooks. In his book, Dr. Sompayrac cuts. LAUREN SOMPAYRAC IMMUNE HOW THE SYSTEM WORKS SIXTH EDITION How the Immune System Works I dedicate this book to my sweetheart, my best. The immune system is a network of cells, tissues, and organs that work together to defend the body against attacks by “foreign” invaders. These are primarily.
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Boehringer Ingelheim / SCANPIX. Library of Congress Cataloging-in-Publication Data. Sompayrac, Lauren. How the immune system works / Lauren Sompayrac. The immune system is a network of cells, tissues*, and organs that work together to defend the body against attacks by “foreign” invaders. These are primarily. Editorial Reviews. Review. “This edition is well justified since immunology is a constantly evolving field.” (Doody's, 12 July ). What users of the previous.
The result is a collection of B cells whose by CD40L, a protein found on the surface of activated BCRs, on average, bind more tightly to the invader than helper T cells. This sets up a positive feedback loop you to check that area in a few days. Why study the evolution of immunity? B Cell The best-studied co-stimulatory signal involves direct contact between a B cell and a Th cell. DCs and other APCs, on the other hand, remain free to live in either secondary lymphoid tissues or virtually any nonlymphoid organ of the body. Amazon Music Stream millions of songs.
I'll be keeping this book around, and will probably re-sell the Janeway's text, as I won't need to know all the nitty-gritties of the immune system later on. A few reviews have said that this little page text is "dated. The material covered is timeless.
Our understanding of T and B cells will evolve over time, but the basic function, and the ideas of receptor sites, etc. Current thinking "" is that we're entering an era of completely recasting the immune system, with as revolutionary a paradigm shift as recombinant DNA itself. One aspect of this is thinking of this system as multiple systems 6 or more in some literature. These phenomena don't subtract from antibody or cell mediated immunity as models, they ADD to them.
For complete coverage of the new models, without spending a fortune or trying to scan a whole large text, see any book or recent article by Dr. Bagasra, including: A New Perspective. That out of the way, when our ClassPros and Library Picks surveys poll med students, THIS little text has come up in the top 5 for over a decade and the top 1 or 2 in the last 3 years!
How is it possible, with texts of 1, pages, that an 8. The answer is the astonishing flow of the metaphors coupled with "aha" pictures and illustrations on every page. Each page, though PACKED with information, is told like a story, and the pictures, both descriptive and visual, "stick" in your mind in a way that allows a synthesis that no other text has ever achieved, in my opinion I'm a molecular biologist in ANY field I've reviewed!
Lauren makes the field "seem" understandable with only the most basic understanding of bio, and every reader here knows that simply isn't true--immunology is one of the most complex, rapidly changing fields in all of bio. The balance of history, metaphor, quant and color illustration is nearly perfect. You can literally get more insight into the CURRENT view of the immune system from an integrative point of view with intuitive understanding with two days immersed in this book than a semester with Janeway pages , Parham pages or Male pages.
I'm not knocking those fine texts, and you certainly need their detail, but without Sompayrac, you will sincerely miss the "whole picture" that relates SO many topics. Library Picks reviews only for the benefit of Amazon shoppers and has nothing to do with Amazon, the authors, manufacturers or publishers of the items we review. We always buy the items we review for the sake of objectivity, and although we search for gems, are not shy about trashing an item if it's a waste of time or money for Amazon shoppers.
If the reviewer identifies herself, her job or her field, it is only as a point of reference to help you gauge the background and any biases. Kindle Edition Verified Purchase. A very nice, searchable intro to the immune system. I got the kindle for PC version because I was immersed in discussions with anti-vax people who have no clue how the immune system works, preferring the magic of alternative medicine to evidence based medicine. The problem is my dated knowledge had me speaking from a similar position of ignorance.
I'm not sure my ossified brain can retain the latest discoveries, but at least I have a current reference.
If they had a book like this for every body system, med school would be soooo much easier! Forget all of those overly complicated histo and physio books, this is all you need to succeed with the immune system.
The immune system is taught in a very intuitive and straightforward manner. The author is careful to remind you of abbreviations and concepts from earlier lessons, so you don't need to waste time going back to look things up.
I can not recommend this book enough for anyone interested in immunology, be it a 1st-year med student or high school senior. Excellent breakdown of immunology for someone who is lacking a foundation. It lays things out sequentially, but you can also easily skip around if your classes are run in a different order of material presentation. It's much shorter than I expected, but I think one of the things I appreciate about this book most is its concision.
If you're thinking about getting a supplement for immuno, this should be your first stop. It doesn't go as in detail as needed in some cases, but it will give you a solid foundation. One person found this helpful. How the Immune System Works is a great book. The author provides a clear and concise overview of the immune system without drowning the reader with endless details. The analogies and plain language make immunology easy to understand and remember.
I read Kuby's Immunology as an undergrad and is no doubt an excellent reference. As a medical student, however, How the Immune System Works was all I needed to organize the facts and develop a solid understanding of the subject. See all 74 reviews. Endogenous molecules released by stressed or dying cells participate in acute kidney injury, transplant rejection, or autoimmunity by triggering the same innate immune receptors that sense microbes leading to stimulation of the adaptive immune response.
Optimal and timely activation of the adaptive immune response, however, cannot possibly rely on chance encounters between T lymphocytes and the mature DCs that carry the antigenic peptides they recognize. Nor can random wanderings guarantee that B lymphocytes will find their target antigens or the help they need from T lymphocytes to differentiate into antibody-producing plasma cells.
After all, your descendants are destined to have large bodies with extensive mucosal surfaces and complex three-dimensional organs, making the surveillance of every tissue fold by lymphocytes an impossible task. So how could one guarantee that rare immune cells find antigen and each other quickly and efficiently? The solution that evolution makes available to you turns out to be a simple one.
Your descendants will harbor anatomic structures, known as secondary lymphoid organs or tissues, and will synthesize molecular messages, known as chemokines and adhesion molecules, that bring immune cells together at the right place and time DCs and other APCs, on the other hand, remain free to live in either secondary lymphoid tissues or virtually any nonlymphoid organ of the body.
The kidney, in fact, has an extensive network of such cells. Upon sensing a nonself intruder and capturing its antigens e. This organized rendezvous between innate and adaptive immune cells generates ample effector and memory lymphocytes that then exit the lymph node and migrate through the bloodstream to the site of antigen entry e.
Effector and memory cell migration to the target tissue is once again guided by chemokines and adhesion molecules and, importantly, by antigen-presenting DCs within the tissue. Some memory T lymphocytes remain in the nonlymphoid tissues as resident memory cells that guard against reinfection with the same pathogen. In addition to secondary lymphoid tissues, evolution has set aside primary lymphoid organs dedicated to the production and education of nascent immune cells.
These are the bone marrow and the thymus. The bone marrow is where both innate and adaptive immune cells are born and is the site where B lymphocytes are educated. Newborn T lymphocytes, on the other hand, receive their education in the thymus. So what is lymphocyte education all about and why is it essential? The primary goal of education is to weed out those lymphocytes that recognize self antigens and therefore could cause harm to the organism itself by either killing them off or inducing in them a permanent state of unresponsiveness called anergy.
This education process, referred to as negative selection 17 , is necessary because the specificity of antigen receptors on B and T lymphocytes arose in the first place through random, somatic gene arrangement and not through a predetermined, germline embedded route selected over evolutionary time such as the case is with innate receptors.
Before negative selection, T lymphocytes also undergo a positive selection step in the thymus, which ensures that only those that recognize self-MHC molecules survive In any given individual, T lymphocytes that recognize self-MHC with a reasonable affinity are positively selected and those that engage self-MHC with either too low or too high of an affinity die—the former by neglect and the latter in the negative selection step that ensues.
What emerges at the end is a mature lymphocyte repertoire that detects millions of nonself antigens but has a limited ability to mount an immune response against self antigens. Your heirs will be beneficiaries of this well orchestrated educational system but, as we shall see later, will also pay the price for its inherent imperfections. You have thus far conducted your work carefully, dividing the immune system into innate and adaptive and separating antigens along simple, clean lines into harmless self antigens on one side and harmful nonself microbes on the other.
But is all self harmless, and is all nonself harmful? Are all harmful nonselves microbes? And do all immune cells fit neatly into separate innate and adaptive bins? The immune system that you have assembled is in fact a model of versatility rather than rigid divisions. Not only do innate cells detect traditional harmful intruders bacteria, viruses, fungi, and other pathogens , but they also respond to a subset of self-molecules some protein and nucleic acid, others simple chemicals such as uric acid that alarm the immune system to the presence of tissue damage 20 , Damage-associated molecules or alarmins are released by dying or stressed cells in infected, ischemic, or injured tissues and serve two purposes: We now know that both lymphoid e.
In other words, components of both the innate and adaptive systems are ready to react to self when it signals harm or becomes harmful itself. Your immune system also quickly grasps the reality that not all microbial nonself is harmful. The billions of commensal bacteria and other microbes that will accompany your descendants throughout their life journeys will in fact be essential for their well-being.
The immune system therefore promptly takes advantage of the regulatory mechanisms it has to ensure that DCs and lymphocytes at barrier surfaces such as the gut, skin, and lungs are carefully controlled to avoid needless attacks on helpful commensals It also recognizes that nonself that is neither microbial nor pathogenic can also be harmful and must be rejected at times. Take for example a stem cell or fetus in the wrong place or potentially transmissible tumor cells 24 , This form of nonself, known as allogeneic nonself, triggers powerful adaptive immune responses that are most apparent in the setting of transplant rejection.
How lymphocytes recognize allogeneic nonself will be discussed later. How commensals interact with and shape the innate and adaptive immune systems and how the innate immune system distinguishes between self and allogeneic nonself are not entirely clear and will surely intrigue the inquisitive minds of your descendants Finally, you come to realize that building an immune system based on inflexible distinctions between innate and adaptive immune cells is not possible Evolution is not a predetermined design process; rather, it is one that advances in fits of trial and error as well as chance and necessity.
Your successors will carry in them not only the final product of these efforts, a one-and-only perfect immune system, but also the marks and remnants of many immune systems. This is best exemplified, we believe, in the recent discovery of several families of innate lymphoid cells that defy traditional classification On one hand, they lack antigen receptors and therefore do not display antigen specificity.
On the other, they secrete classic lymphocyte cytokines and in some cases exhibit classic memory. Among innate lymphoid cells, natural killer cells pose the biggest classification challenge because they are capable of interacting with MHC molecules and generating antigen-specific immunologic memory that mirrors that of adaptive T lymphocytes The precise role that innate lymphoid cells have in immunity in general and in kidney disease in particular remains to be determined.
Pondering the relationship between the kidney and the immune system brings three medical inflictions immediately to mind: The first two can be thought of as mishaps or unintended consequences of the immunologic design you have put in place, whereas the third is a result of the well intentioned but sometimes overzealous response of the immune system to tissue damage.
A fourth connection between the kidney and the immune system is the influence of chronic renal insufficiency on immunity. Uremia weakens crucial defenses required for protection against infection and, paradoxically, also causes generalized inflammation that is linked to excessive cardiovascular disease The relationship between the immune system and kidney disease. The principal renal afflictions in which the immune system plays a major or important role are shown. Conversely, renal insufficiency affects the immune system by weakening immune defenses and by causing systemic inflammation that contributes to cardiovascular disease.
The kidney can be either the direct target of autoimmunity, whereby a T lymphocyte or antibody that binds a renal antigen elicits renal pathology, or the kidney can be a victim of collateral damage caused by a systemic immune response to self or nonself antigens.
In the latter setting, the culprits are usually antibody-antigen complexes immune complexes trapped in the glomerular filtration barrier that then instigate local inflammation Autoimmunity is the consequence of the activation of those few self-reactive lymphocytes that the immune system failed to purge in the bone marrow or thymus during ontogeny.
Immunologists refer to the purge as central tolerance because it takes place in central or primary lymphoid organs. Fortunately, the activation of self-reactive lymphocytes is a relatively rare event because of additional regulatory mechanisms present outside primary lymphoid organs.
Immunologists refer to these as peripheral tolerance because they exert their regulatory functions in secondary lymphoid and nonlymphoid organs—that is, in the periphery. A key component of peripheral tolerance is regulatory T lymphocytes, which ensure that self-reactive lymphocytes are prevented from reacting to self or are quickly silenced if they do. Several events or circumstances, however, can lead to the breakdown of peripheral tolerance and the emergence of autoimmune disease These include genetic mutations that disrupt regulatory T lymphocyte development, maintenance, or function; inflammatory events such as infection that interfere with the function of regulatory T lymphocytes; cross-reactivity between self and nonself antigens whereby T lymphocytes or antibodies specific to microbial antigens, which are readily incited during infection, also happen to bind self antigens; and finally, local tissue accidents that uncover hidden self antigens that had thus far been ignored by the immune system, neither deleted in the process of central tolerance nor regulated in the periphery.
Finally, because of its key function in blood filtration, the kidney is often the resting place for antigen-antibody complexes that form elsewhere or sometimes locally after antigen is trapped in the glomerulus Immune complexes can either be the result of a systemic autoimmune process e.
In both cases, complement activation by antibody molecules appears to play a major role in triggering renal pathology, but the full armamentarium of the immune system, including innate and adaptive cells as well as the cytokines they produce, participates. Through no fault of its own, the kidney obviously can be the target of the wrath of immunity.
Another price that your descendants will pay for the highly sophisticated but imperfect immune system you have bestowed upon them is the rejection of life-saving organ transplants.
In the absence of any immunosuppressive drugs, a kidney transplanted from one human to a genetically disparate human i. The rejection process is dependent on T lymphocytes, although all other immune defenses participate in one way or another in the rejection process, and the T lymphocyte response to the transplanted organ the allograft is characterized by sheer immensity that far exceeds any antimicrobial response So why are T lymphocytes strongly alloreactive if natural selection has indeed been busy perfecting the repulsion of harmful pathogens, not harmless organ transplants?
The answer lies first in the fact that any given individual harbors a large number of T lymphocyte clones that recognize and react to MHC antigens, which are the principal histocompatibility antigens responsible for transplant rejection; second, many of these T lymphocyte clones have already acquired memory properties The large number of T lymphocytes that react to MHC antigens is a byproduct of an immune system that selects its T lymphocytes based on their ability to recognize peptides bound to MHC molecules The memory nature of many of the alloreactive T lymphocytes is because TCRs specific for a microbial peptide presented in the context of self-MHC are also capable of recognizing allogeneic, nonself MHC—that is, they are cross-reactive For example, memory T lymphocytes generated after exposure to a ubiquitous virus such as the Epstein—Barr virus cross-react with allogeneic MHC molecules and cause vigorous transplant rejection.
Therefore, in its obsession to create an immune system that is able to respond to practically any pathogen, evolution put in place a highly diverse polymorphic MHC system that can bind virtually any microbial peptide and present it to T lymphocytes, whose TCRs to begin with are biased to bind to and sample all sorts of MHC molecules.
Neither you nor evolution, it appears, predicted that some of your descendants will become talented transplant surgeons and nephrologists and that the polymorphic MHC proteins that are essential for antimicrobial immunity will also act as a powerful histocompatibility barrier to organ transplantation.
A less anticipated and, until recently, overlooked function of the immune system is its role in tissue injury unrelated to infection—so-called sterile tissue injury. AKI, which is the end result of a variety of noninfectious insults such as ischemia, drugs, and toxins, is often accompanied by subtle infiltration of the kidney with leukocytes from the blood and not-so-subtle activation of intrarenal immune cells.
The infiltrate is not restricted to innate, myeloid cells neutrophils and monocytes, for example but also includes lymphoid cells, both adaptive and innate Similarly, activation of renal cells involves resident macrophages and DCs as well as renal epithelial cells. The latter are increasingly recognized as accomplices of the immune system because they express innate receptors such as the TLR, respond to TLR ligands, and produce a host of inflammatory and immune cytokines The net sum of immune activation after AKI, however, is still puzzling.
On one hand, it can lead to more harm by causing excessive inflammation; on the other, it can be beneficial by repairing damaged tissues and cleaning up the mess 31 , If nephrologists could uncover the secret to striking the right balance, immune therapy of AKI will one day become a reality It is not often that one biologic system touches so many aspects of human biology in both sickness and health.
Although it is seemingly esoteric and beyond comprehension at first blush, the immune system, once viewed through the prism of evolution, is the epitome of versatility and simplicity of purpose. By peeling its layers one at a time, immunologists have succeeded not only in elucidating the inner workings of immunity but have also enabled the translation of their discoveries into real life benefits, such as vaccines that eradicate scourges, immunosuppressive drugs that conquer allograft rejection, cytokine-based therapies that subdue autoimmune disease, and antibodies that unbridle T lymphocytes to attack cancer cells.
However, there is still much left for us nephrologists to do and discover. Which immunologic pathways should we target to interrupt or reverse GN? Of the many T lymphocyte, B lymphocyte, cytokine, and complement-based treatments that are now available in the clinic, which ones should we test in our patients?
How can we improve long-term renal allograft outcomes without further compromising the immune system and therefore the health of the transplant recipient? What have we missed at a fundamental scientific level that still prevents us from achieving immunologic tolerance to autoantigens or organ transplants in a safe and effective manner, sparing patients the unwanted consequences of global immunosuppression?
What immunologic trick can we pull to combat AKI? The list goes on and on as far as the imagination can see. The real journey has only begun. Adaptive immunity comprises defense mechanisms mediated by immune cells known as lymphocytes T, B, and natural killer cells and the specialized molecules required for their function. The term adaptive is applied because lymphocytes rapidly adapt to the situation at hand e. Antigen is a nonself molecule, usually a protein, that incites an adaptive immune response.
Cytokines are protein molecules produced by cells of the immune system that mediate diverse defensive functions. These include inflammation, lymphocyte activation and differentiation, and killing of cells harboring foreign antigens.
Cytokines play an important role in the pathogenesis of autoimmunity and immune-mediated renal disease. Dendritic cells DCs are a specialized myeloid cell that is induced by infection to take up antigens, process them into small peptides, package them inside major histocompatibility complex MHC molecules, and present them to T lymphocytes after migrating to secondary lymphoid organs. DCs are prototypical antigen-presenting cells APCs.
They link innate to adaptive immunity. Innate immunity comprises defense mechanisms mediated by the evolutionary more primitive components of our immune system.
These include myeloid cells such as macrophages, DCs, and neutrophils and protein molecules such as the complement and coagulation systems. The term innate is used because these defenses are hardwired in the genome, responding in a rather unvarying manner to injury or infection.
The innate immune system activates the adaptive immune system, principally via antigen-presenting DCs. The affinity of duce IgG3 antibodies that are very effective against bac- the antibody molecule for its cognate antigen may remain teria and viruses. So, to insure that the antibody response will be T cells. Those B cells whose BCRs have mutated to higher appropriate for a given invader, all that is required is affinity compete more successfully for limited T cell help.
But how could this be accomplished? One way they B cells whose BCRs bind tightly to their cognate antigen. In response to cytokines made by Th cells, affinity for their cognate antigen. This whole process is B cells can switch from making IgM antibodies to pro- called affinity maturation.
What could be better than that?! The assistance of helper T cells usually is required for B cells to make either of these upgrades. How- The final step in the maturation of a B cell is the choice of ever, in very restricted regions of the chromosomes of profession. Plasma B cells are antibody place. It is the memory B cell that recalls your first antibody molecule.
Some plasma B cells can synthesize exposure to a pathogen and helps defend you against 2, of these antibodies each second. However, as a subsequent exposures. The ability of plasma B cells to make so or a plasma cell. However, they do know that the interac- many antibody molecules helps the immune system keep tion between the co-stimulatory molecule CD40L on the up with invaders such as bacteria and viruses which mul- surface of a helper T cell and CD40 on the B cell surface is tiply very quickly.
The result is a collec- requisite for T cell-independent activation of a naive B cell, tion of B cells with receptors so diverse that they probably it is not enough.
A second, co-stimulatory signal also is can recognize any organic molecule in the universe. For needed. By multiple BCRs be clustered crosslinked. And when guards against inappropriate B cell activation. However, as a B cell matures, it can B cells also have co-receptor molecules on their surface choose to produce a different class of antibody: Conse- antigen, the number of BCRs which must be crosslinked quently, the antibody recognizes the same antigen before to signal activation is dramatically reduced.
Consequently, and after its class has been switched. This is the part of the mole- tem as dangerous and which have been opsonized. This key class is determined by the cytokines present in the usually is provided by a helper T cell, and involves cell—cell local environment of the B cell when class switching contact, during which CD40L molecules on the surface of takes place.
So by arranging to have the appropriate a helper T cell bind to CD40 proteins on the surface of a B cytokines produced at the appropriate places, the right cell. B cells can also be activated without T cell help. The class of antibody to defend against a particular invader first requirement for this T cell-independent activation can be made. In contrast to class switching, the outcomes in these two cases usually are very different.
In contrast, T cell-dependent antibody. One reason for this difference is that both class the B cells which proliferate most will be those for which switching and somatic hypermutation require ligation of somatic hypermutation has increased the binding affinity CD40 proteins on B cells.
This signal is usually provided of their BCRs. The result is a collection of B cells whose by CD40L, a protein found on the surface of activated BCRs, on average, bind more tightly to the invader than helper T cells.
These upgraded B As B cells mature, they must decide whether to become cells are especially useful as memory cells. Because their short-lived plasma cells, which produce vast quantities of affinity-matured BCRs are sensitive to small amounts of antibodies, or to stick around as longer lived, memory B antigen, these B cells can be reactivated early in a second cells.
These memory B cells are responsible for making the infection while the number of invaders is still relatively antibodies which can protect us from a subsequent attack small. B cells are produced according to the principle of clonal 4.
Describe fail-safe systems that are involved in B cell selection. Exactly what does this mean? Describe what happens during T cell-dependent activa- 5. How can B cells be activated without T cell help, and why 6. Why do class switching and somatic hypermutation is T cell-independent activation of B cells important in produce B cells that are better able to defend against defending us against certain pathogens? Presentation of anti- tide bulge out a bit in the center.
Within the Mom and one from Dad , we all have a total of six class I human population, there are genes for many slightly MHC genes. In the human population, there are can display protein fragments from any pathogen. As can have different binding motifs, and therefore can pres- you will see, antigen presentation is central to the func- ent peptides which have different kinds of amino acids at tion of the adaptive immune system, with the cells that their ends.
Moreover, although MHC I molecules are picky about binding to certain amino acids at the ends of The structures of class I and class II MHC molecules have the peptide, they are rather promiscuous in their selec- now been carefully analyzed, so we have a good idea tion of amino acids at the center of the protein fragment. When mRNA is translated into protein in the cytoplasm of a cell, mistakes are frequently made.
In addition, proteins suffer damage due to normal wear and tear. Within the human popula- in the cytoplasm that function rather like wood chippers. In contrast to class I MHC molecules, cut proteins up into peptides.
Most of these peptides are the binding groove of class II MHC molecules is open at then broken down further into individual amino acids, both ends, so a peptide can hang out of the groove.
As which are reused to make new proteins. Further, for class II MHC molecules, the crit- sack-like structure inside the cell from which most pro- ical amino acids that anchor the peptides are spaced along teins destined for transport to the cell surface begin their the binding groove instead of being clustered at the ends.
Immunologists call these endogenous proteins. They MHC I include ordinary cellular proteins such as enzymes and MHC I- structural proteins, as well as proteins encoded by viruses Peptide and other parasites that may have infected the cell.
For Complexes example, when a virus enters a cell, it uses the cellular Golgi Stack biosynthetic machinery to produce proteins encoded by viral genes. Almost every cell in the human body expresses class I molecules on its surface, although Once inside the ER, some peptides are chosen to be the number of molecules varies from cell to cell.
In addition, the amino acids at the ends that can be checked by CTLs to determine whether it has of the peptide must be compatible with the anchor amino been invaded by a virus or other parasite and should be acids that line the ends of the groove of the MHC mol- destroyed. A typical human cell has about , class I ecule. So as you can imagine, the chippers in these expressed exclusively on cells of the immune system.
As a result, some of the peptides ing proteins that are manufactured inside the cell, so the will be appropriate for MHC presentation, but most will ubiquity of class I molecules gives CTLs a chance to check not be. In contrast, in cells such as macrophages that spe- most cells in the body for infection.
On the other hand, cialize in presenting antigen, this chipping is not so ran- class II MHC molecules function as billboards that adver- dom. Why, cytoplasm and are injected into the endoplasmic reticu- you ask? Because the TAP transporter and MHC I mole- lum where they bind to a third protein called the invariant cules both favor peptides that have either hydrophobic chain.
This invariant chain protein performs several or basic C-termini. So in antigen presenting cells, stand- functions. First, it sits in the groove of the MHC II molecule ard proteasomes are modified so they will produce cus- and keeps it from picking up other peptides in the ER. If these protein of peptides they make, and since the magic number for fragments were loaded onto class II molecules, then class class I presentation is about nine amino acids, you might I and class II MHC molecules would display the same imagine that the ER would be flooded with useless pep- kind of peptides: However, it in the cell.
Since the goal is for class II MHC molecules turns out that the TAP transporter has the highest affin- to present antigens that come from outside the cell, the ity for peptides that are 8—16 amino acids long. Once candidate peptides have been Another function of the invariant chain is to guide transported into the ER, enzymes trim off excess N-terminal class II MHC molecules out through the Golgi stack amino acids to make the peptide the right size for binding to to special vesicles in the cytoplasm called endosomes.
Conse- the cell are enclosed in a phagosome, and brought into the quently, most peptides displayed by class I MHC mole- cell. This phagosome then merges with the endosome, and cules are derived from newly synthesized proteins, mak- enzymes present in the endosome chop up the exogenous ing it possible for the immune system to react quickly to proteins into peptides.
During this time, endosomal an infection. But this is not of the MHC molecule. Amazingly, although the exogenous enough. It must also receive a second, co-stimulatory sig- proteins and the invariant chain are hacked to pieces by nal.
This is presumably because the These are the antigen presenting cells APCs. MHC molecule is cleverly folded so that the enzymes can- Because the job of antigen presenting cells is to activate not gain access to their favorite cleavage sites. Does it seem to you that immu- room for the peptide.
HLA-DM competes with potential nologists just like to make things confusing? Anyway, to keep this straight, just remember ing that only peptides that bind tightly will be presented. All of these are white molecules. It is this separation of loading sites and blood cells, and since new blood cells are made continu- pathways that allows the class I billboard to advertise ously, APCs can be replenished as needed. It is important to note that these cells are very Before a killer T cell can kill or a helper T cell can help, different from the plasmacytoid dendritic cells pDCs it must be activated.
In fact, pDCs are not even shaped like a point, phagocytosis ceases, and the pathogen-activated starfish. They are round like plasma cells. It is its ity. II MHC molecules. And by skin. Also during its journey, the DC upreg- of defense. In normal tissues tissues that have not been ulates expression of its class I MHC molecules.
Conse- infected , DCs resemble wine tasters. Although they can quently, if the dendritic cell was infected by a virus out at take up about four times their volume of extracellular the battle scene, by the time it reaches a lymph node, frag- fluid per hour, they mostly just take it in and spit it back ments of viral proteins will be on display on the dendritic out. Finally, while traveling, the atively low levels of MHC molecules on their surface.
DC increases production of B7 co-stimulatory proteins. So As a result, these resting dendritic cells are not good at when it reaches a lymph node, the mature dendritic cell presenting antigen to T cells, especially to virgin T cells. Finally, dendritic cells have pattern-recognition receptors e. Typically, a DC remains in the tissues for about six hours after activation, collect- ing a representative sample of battle antigens.
Of course. There response will be in proportion to the severity of the the traveling dendritic cells activate those virgin T infection. After all, you want DCs to mature, travel to nearby lymph nodes. There they initiate the travel to lymph nodes, and present antigen only if a bat- adaptive immune response by presenting antigen tle is on.
Acti- Once a DC reaches a lymph node, it only lives for vated DCs are short-lived, and the rapid turnover of about a week. However, dendritic cells can interact with hun- recruited will depend on the severity of the attack.
In addition, by the invasion. Can you imagine a more ingenious after a dendritic cell has been activated, but before it system? There is another reason for the short lifetime of den- dritic cells. In Lecture 2, I mentioned that it is very impor- Activated macrophages tant that the magnitude of an immune response be in pro- Macrophages also are sentinel cells which stand guard portion to the seriousness of the attack.
The short lifetime over areas of our body that are exposed to the outside of DCs helps make this happen. In a resting state, macrophages are good at If the attack is weak, relatively few battle cytokines will tidying up, but they are not much good at antigen pres- be produced by warring macrophages, and only a small entation.
This is because macrophages only express number of dendritic cells will be dispatched with their enough MHC and co-stimulatory molecules to function cargo. On the other tors ligated by invading pathogens.
Reticulum In contrast, macrophages are heavily armed soldiers ER who must stand and fight. Nevertheless, their lack of mobility raises an Complex Phagosome interesting question: Once they have been activated by dendritic cells, T cells exit the lymph nodes, circulate through the blood, and enter inflamed tissues to help with the battle. Because a threshold number of T cell receptors rophages mainly function to re-stimulate experienced must be crosslinked by presented antigen before a Th cell T cells.
A virgin B cell is not antigen around. Presentation of antigen by B cells is also much good at antigen presentation, because it expresses very fast.
As a result, an experienced B cell the B cells which could recognize that particular invader is able to act as an antigen presenting cell for Th cells. B are virgins, so the important APCs are activated den- cells do not function as APCs during the initial stages of dritic cells. However, later in the course of the ring T cells to keep them pumped up. Later in the infec- infection or during subsequent infections, presentation of tion, or if this same invader is encountered again, expe- antigen by experienced B cells plays an important role.
B cells can concentrate antigen for presenta- small amounts of antigen for presentation. For contrast, when a protein is chopped up into short pieces starters, we need to ask the question: This is really a two-part question, since we understand, but why are MHC molecules so polymor- are talking about two rather different displays: After all, there are so many different forms in the class II.
So long as pathogens remain outside I MHC proteins. Now imagine what might happen if a of our cells, antibodies can tag them for destruction by virus were to mutate so that none of its peptides would professional phagocytes, and can bind to them and pre- bind to any of these MHC I molecules. Such a virus might vent them from initiating an infection.
Since each plasma wipe out the entire human population, because no killer T B cell can pump out about 2, antibody molecules per cells could be activated to destroy virus-infected cells.
Imagine imum number of different class I MHC molecules six how terrible it would be if uninfected cells happened to live significantly longer on average than do patients who have debris from dead viruses stuck to their surface, and have genes encoding only five or fewer different class I killer T cells recognized this un-presented antigen and molecules.
Why six, not ten, genes for class I MHC most proteins made in a pathogen-infected cell remain molecules? So without class I display, many pathogen-infected cells would go undetected by killer T cells. But what about class II presentation? What must be actually are at a disadvantage. The reason is that most appreciated, however, is that many pathogens do not proteins must be folded in order to function properly.
As infect human cells: If antigen tors might recognize are unavailable for viewing — because presenting cells could only display proteins made by path- they are on the inside of a folded protein molecule.
MHC molecules. The best studied of these presented antigen? However, in contrast battle is going on, and helper T cells are screened to be to classical MHC molecules, which have grooves that are sure that they do not react against our own proteins. So compartments within a cell, and can present these mol- the requirement that helper T cells only recognize ecules on the surface of antigen presenting cells, where presented antigen insures that the decision to deploy they can activate T cells.
Consequently, it has been postu- the potentially deadly adaptive immune system is not lated that these non-classical MHC molecules give T cells made by a single cell.
As a result, the number of proteins. The consequence of this expanded nize fragments of proteins presented by class I and class number of targets is a stronger, more diverse immune II MHC molecules. Obviously, CD1 presentation of lipids reaction in which many different helper T cells will be to T cells is an exception to this rule. Be aware, however, that this may change as more research is done on CD1-presented lipids. Such an unlawful use of setting of organ and tissue transplantation.
Transplanta- the class I display has been termed cross-presentation. In those days, tumors were usu- out a way to avoid infecting antigen presenting cells, ally induced by rubbing some horrible chemical on the yet could still infect and reproduce in other cells of the skin of a mouse, and then waiting for a long time for a body, cross-presentation would give the immune system tumor to develop.
Because it was so much trouble to make a chance to activate CTLs against this pathogen. So far, these tumors, biologists wanted to keep the tumor cells the rules that govern cross-presentation have not been alive for study after the mouse had died. They did this clearly defined, and it is not known whether cross- by injecting some of the tumor cells into another, healthy presentation by class I MHC molecules of antigen taken mouse, where the cells would continue to grow.
What up from outside an APC is an important feature of the they observed, however, was that the tumor cells could human immune system. This So the MHC molecules that we have been discussing provided the impetus for the creation of the many inbred in the context of antigen presentation are the very same mouse strains that immunologists depend on today.
By destroying these vessels, CTLs cut the two mice were from the same inbred strain. In con- off the blood supply to the transplanted organ, usually trast, when this experiment was tried with mice that were resulting in its death. For this reason, transplant surgeons not inbred, the transplanted skin turned white within try to match donors and recipients who have the same hours because the blood supply had been cut off and MHC molecules.
However, finding such a match is dif- invariably died. Immunologists figured this immediate ficult. Indeed, it is estimated that if you had access to graft rejection must be due to some genetic incompatibil- organs contributed by 10,, different individuals ity, because it did not occur with inbred mice that have who were not related to you, the chance of your find- the same genes.
So the diversity of mice to create strains that differed by only a few genes, MHC molecules, which is so important in protecting us yet which were still incompatible for tissue transplants. Clearly, the immune system did fying genes that were grouped in a complex on mouse not evolve with organ swapping in mind!
Instead, the class II—invariant play what is going on inside a cell. There ery to produce viral proteins. Some of these proteins are they meet up with proteins that have been taken into the cut up into small pieces peptides by the proteasome, cell by phagocytosis and cut up into peptides by enzymes.
Those that are about nine amino acids the MHC—peptide complexes are transported to the cell in length with appropriate amino acids at their ends are surface for display to Th cells.
By this clever mechanism, bound in the grooves of class I MHC molecules, and are class II molecules pick up peptides derived from proteins transported to the surface of the cell. By scanning the taken in from outside the cell, but avoid peptides derived MHC I—peptide complexes displayed there, killer T cells from proteins made within the cell. Class II MHC molecules also are billboards, but they First, most viral proteins normally remain hidden inside an are designed to alert helper T cells that a battle is being infected cell and are not found on the cell surface.
There- waged. Class II molecules are assembled in the ER, just fore, these proteins would never be seen by killer T cells like class I molecules, but because invariant chain proteins unless they were advertised by class I MHC molecules. Consequently, MHC Macrophages, activated by danger signals, also can display greatly increases the probability that CTLs will function as antigen presenting cells. They stay put in the tissues and battle invaders. Both class I and class II MHC molecules are extremely Consequently, macrophages are most useful for present- polymorphic, and humans have multiple genes for both ing antigen after the adaptive immune system has been classes of MHC molecules.
Consequently, it is likely that activated. At that time, activated macrophages out in your MHC molecules will be able to display peptides from the tissues can keep experienced T cells fired up, pro- most pathogens, and that at least some people in the longing the time that they are effective in dealing with population will have MHC molecules capable of display- invaders.
The reason as well as co-stimulation. Th cells must wait to be activated by dendritic cells. There, the den- fired up. Consequently, relatively late in the initial infection cell out at the battle site.
In this way, the dendritic cell or early in a subsequent infection by the same attacker, B effectively takes a snapshot of what is going on at the cells play a major role as antigen presenting cells.
Give several reasons why antigen presentation by class I 4. Some peptides are presented more efficiently than others. What factors influence the efficiency of presentation by 3. Without vated. T cell receptors come in that only useful weapons will be mobilized. T cell acti- two flavors: RAG2 initiate the splicing of gene segments by making There are many similarities between the ways B cells double-stranded breaks in chromosomal DNA.
Consequently, it receptors of a traditional T cell recognize both the pep- would not be wise to stockpile B or T cells, because in tide and the MHC molecule and, unlike B cells, T cells our entire lifetime, we probably will never encounter cannot undergo hypermutation to change the affinity of the invader which a particular B or T cell could defend their TCRs for their cognate antigen. Indeed, an important feature of the adap- tive immune system is that its weapons are made on Non-traditional T cells demand: It has been proposed that NKT cells evolved as contact with the outside world.
This serves to remind us that so far as However, normal mice and mice that have been engi- the immune system is concerned, humans are not just neered to lack NKT cells are equally susceptible to infec- big mice. After all, human and mouse lineages diverged tion with TB, and, so far, it is not clear how important NKT roughly 65 million years ago, and humans are relatively cells are in protecting humans against bacterial infections.
In contrast, mice Because much more is known about traditional T cells are small and short-lived. And they are. For nucleus. Normally, this type of signaling across the cell example, it is not known where these cells grow up. As its name implies, this non-traditional T cell has some of the properties of the nat- ural killer NK cells of the innate system, and some of the Cell properties of traditional T cells of the adaptive immune Membrane system.
In humans, this signaling complex is In addition to the T cell receptor, there are two more made up of four different proteins: Please note, however, that added on these CD4 and CD8 co-receptors? T cell receptor. If any one of these pro- CD4 and CD8 co-receptors. When this hap- senting cell. Immu- vation signal is dispatched to the nucleus. But match with class I MHC molecules. The latest think- way! Conversely, if the TCRs are shaped properly munity. In contrast, if the CD8 co-receptor clips complexes.
Interestingly, once a naive T cell has been acti- onto the class I MHC molecule, CD4 expression is termi- vated, the connection between the TCRs and the nucleus nated, and that cell becomes a killer T cell. As a result of this re-wiring, amplification of the TCR signal is not as important for an experienced T cell as it is for a virgin T cell. A the TCR is lost as it travels to the nucleus. If, how- complete activation of a naive helper T cell usually takes ever, while the TCRs are engaged, the T cell also receives several hours.
During this time, a number of important co-stimulation, the signal from the TCRs is amplified many events take place. First, adhesion molecules on the sur- times, so that fewer probably about fold fewer TCRs face of the dendritic cell bind to their adhesion partners must be engaged to activate a naive T cell. Although a num- on the T cell, helping to keep the two cells together. Next, ber of different molecules have been identified which can the CD4 co-receptor molecules on the surface of the T cell co-stimulate T cells, certainly the best studied examples are clip onto the class II MHC molecules on the dendritic cell the B7 proteins B7—1 and B7—2 which are expressed on the and strengthen the interaction between the two cells.
In surface of antigen presenting cells. T Cell Consequently, the Velcro-like adhesion molecules are extremely important for T cell activation. Although mature dendritic cells express MHC and co-stimulatory molecules e.
This requirement that two antigen will stick around long enough to help activate a cells the Th cell and the DC agree that there has been an lot of these T cells. So the interaction between a dendritic invasion is a powerful safeguard against the activation of cell and a naive helper T cell is not just one-way. The end result of this coop- Although the events involved in the activation of helper eration is that the dendritic cell becomes a more potent T cells are pretty clear, the picture of how naive killer T antigen presenting cell, and the Th cell is activated to cells are activated is still rather fuzzy.
Until recently, it was express the high levels of CD40L required for helping believed that for a naive killer T cell to be activated, three activate B cells. One tion, a single activated T cell can give rise to about 10, way this might happen would be for the dendritic cell, the daughter cells during the first week or so of proliferation. There This proliferation is driven by growth factors such as IL Consequently, the probability is quite small that a this cytokine.
In contrast, activated Th cells produce large helper T cell and a killer T cell would simultaneously find amounts of IL-2, and they also express receptors for this a dendritic cell which is presenting their cognate antigens. As a result, newly activated Experiments have now shown that in response to an helper T cells stimulate their own proliferation. This cou- invasion by microbes which can infect cells the microbes pling of activation to the upregulation of growth factor that CTLs are designed to defend against , T cell help is receptors is the essence of clonal selection: Those Th not required during the initial activation of killer T cells.
During this meeting, the factor receptors and proliferate to form a clone. Adhesion molecules mediate weak receive co-stimulation from that same dendritic cell. Receptor in a way that is analogous to the way a naive Th cell is engagement strengthens the adhesion between the two activated: The co-stimulation provided by invaders take over completely.
Consequently, helpless activation of Th cell surface as a result of activation. In invader advertised by the antigen presenting cell. Finally, relatively late in an immune response, there which can defend against a subsequent invasion by the will be many activated dendritic cells, Th cells, and killer same attacker.
This sequence of events, in which the DC and the Th cell meet first, and For either a naive helper T cell or a virgin CTL to be acti- then the licensed DC and the CTL meet later, would avoid vated, the T cell must first recognize its cognate antigen the need for all three cells to meet simultaneously.
This is true even It also has been demonstrated that when an activated for helper T cell-independent activation of CTLs. This helps insure that the powerful weapons of cell and a helper T cell typically lasts for several hours. Naive B and T matching gene segments. For the BCR, these recogni- cells also require co-stimulatory signals that are not anti- tion proteins are the light and heavy chains that make gen specific.
This two-signal requirement for activation up the antibody molecule. TCRs and propriate activation of B or T cells. For B cell activation, a BCRs have cytoplasmic tails that are too short to signal helper T cell can provide co-stimulation through surface recognition, so additional molecules are required for this proteins called CD40L that plug into CD40 proteins on purpose.
For the BCR, these signaling proteins are called the B cell surface. For T cells, co-stimulation For B or T cells to be activated, their receptors must usually involves B7 proteins on an activated dendritic cell be clustered by antigen, because this crosslinking brings that engage CD28 proteins on the surface of the T cell.
When the density of signaling mole- activated without the assistance of helper T cells. Likewise, helpless CTLs do not proliferate been identified by the complement system as dangerous robustly, are short-lived, and do not kill as efficiently as T those that have been opsonized.
The CD4 co-receptor cells which have been assisted by helper T cells. For B cells, this co-receptor recognizes not been chopped up and bound to MHC molecules. This antigen that has been opsonized by complement. If the antigen can be a protein or almost any other organic mol- BCR recognizes an antigen, and if that antigen also is ecule e. Because the universe of many fewer BCRs need to be crosslinked by antigen that antigens recognized by the BCR includes proteins, carbo- has been opsonized by complement.
Th cells express CD4 of invaders than can T cells.
On the other hand, because co-receptor molecules on their surface, and CTLs express the TCR looks at small fragments of proteins, it can rec- CD8 co-receptors. When a TCR binds to antigen presented ognize targets that are hidden from view of the BCR in an by an MHC molecule, the co-receptor on the T cell surface intact and tightly folded protein.
This serves to strengthen Another difference between B cells and T cells is that the signal that is sent by the TCR to the nucleus, so that during an infection, the BCR can undergo somatic hyper- the T cell is more easily activated fewer TCRs need to be mutation and selection. Consequently, the cards they are dealt. What is the difference between a co-receptor and co- the game. Give examples and tell why each is important which begins when an LPS-carrying, Gram-negative bac- for B or T cell activation.
Why are cellular adhesion molecules important during T are produced that can recognize the bacterium. Can you give 3. What happens when dendritic cells and helper T cells several examples? Th1, Th2, and Th We will dis- ogists call effector cells. CTL is to kill cells that have been infected by viruses or Of course, all of this begs the question: How does a bacteria. Effector helper T cells have two main duties: Well, as any football fan knows, behind and travel from lymph node to lymph node, providing every good quarterback, there is a good coach.
Second, it is essential municate with the rest of the immune system. As the to determine where in the body the invaders are located. It is then up to the helper T cell. The dendritic antigen discern the type of invasion, and to decide which weap- presenting cell, of course! In fact, these cytokines imprint dendritic on. These are of two types. There are recognition receptors we discussed in Lecture 2. These two ways that the coach instructs the quarterback.
First, cellular receptors recognize conserved patterns that are the mixture of co-stimulatory molecules displayed on the characteristic of various classes of invaders.
For exam- surface of an activated dendritic cell will depend on the ple, Toll-like receptor 4 TLR4 senses the presence of type of invader the DC has encountered.
TLR4 also can detect proteins the surface of helper T cells to pass this information along. So the bottom line is this: Con- cells. And the particular combination of co-stimulatory sequently, the emerging picture is that different types molecules and cytokines which a dendritic cell offers of antigen presenting cells e. These signals of the immune system fired up until the invaders have activate the dendritic cell and imprint it with the special been defeated.
And when the ILpro- e. In the tissues that to a virgin helper T cell, that Th cell will be instructed line your intestines, a battle will be raging. Molecule However, macrophages only stay activated for a lim- ited time. IL-4 is a growth fac- to resting and garbage collecting.
So, rophages fired up and engaged in the battle. And IL stimulates the production of mucus in killing. In addition, IL-2 is a growth factor which stim- the intestines. So the Th2 cytokine will be available to deal with the attack.
Of course, once the the mucus. Nevertheless, the source of IL-4 initially required for Th2 commitment has not yet been identified. It appears that DCs tell If areas of the body protected by mucosal barriers are these helper T cells where to go, but not what to do. How- attacked by fungi e. For exam- gens the DC is presenting.