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THE IMMUNE SYSTEM

NEW DEVELOPMENTS IN RESEARCH PART 1

WEEK 1
INTRODUCTION TO IMMUNOLOGY

TRANSCRIPT

INTRODUCTION

Hello, I am Masa Miyasaka, welcome to OsakaUx, The Immune System, New Developments in
Research.
Do you know how your own body protects you from viruses and other pathogens?
Would you be surprised to hear that cancer may also be controlled by your immunity?
Every day immunology research aims to understand the mysteries of our bodies and seeks out
the seeds for medical application.
This course introduces wide ranging content in general immunology fields from basic knowledge
to front line research.
In particular, I hope that from this course you gain necessary understanding of the new world
of immunology, the world opened up by the illustrious immunologists of the past, and the
unexplored mysteries that are yet to be explained by experiencing a part of the front line
research currently in progress.
In this lecture series, we will be learning how the immune system works, in particular how the
components of the immune system interact with each other, and how the failure of the immune
system leads to various diseases.
We will also be learning how knowledge of the immune system can be in a clinical setting, and
we will hear about cancer immunotherapy and the therapy of autoimmune diseases including
rheumatoid arthritis.
Now, as the very first speaker of this lecture series, I will give you an overview of immunology
so that you will get a rough idea as to what is the immune system all about, what kind of players
act in this system, and how they interact with each other to fight against pathogens.

Alternatively. elimination of non-self. Or. viruses. this system is not perfect. Second. such as newly introduced substances or molecules. our immune system may sometimes attack our own body components by mistake. Third. we have an amazing protection mechanism called the immune system. and substances. First of all. But nowadays. which is one of the most common type of allergy in developed countries. If this happens in your respiratory tract. which means exemption from military service. toxins and parasites. However. tax payments and other public services. These immunodeficient people can become infected very easily and often die of such infections. a condition called "immunodeficiency". which is designed to defend us against millions of bacteria. in order for the immune system to function well. Tissue grafts are normally rejected. you may develop rheumatoid arthritis. Now. First of all. our immune system is actually a collection of many different organs. and sometimes it fails. because it works as defense against newly arising transformed cells. immunity is defined as resistance to disease. our immune system may overreact to certain antigens such as pollens. As you may realize by listening to my talk. fungi. the immune system is important. but not a single entity. if this happens in your joints. In other words. This word actually derives from the Latin "immunis". which collectively help protect you from infections and other diseases. For instance. The fact that the immunodeficient patients are also prone to develop various types of tumors underlines the importance of the immune system. So. specifically infectious disease. a germ can sometimes invade successfully. or tissue grafts is another important task of the immune system. such as malignant tumor cells. making us sick. let me remind you what "immunity" means. the immune system is important because it defends us against infections. immunity means more like exemption or protection from disease. let us look at the importance of the immune system. it requires balance and harmony among the various cell types and humoral factors that comprise the immune system. So. this tells us how important it is to have an intact immune system. because the recipients' immune system attacks them and .INTRODUCTION TO IMMUNOLOGY (VIDEO 1) Inside our body. One important thing to remember concerning the immune system is that it is a system. This point becomes clearer if you look at the people who have been born with problems with their immune system. you may develop hay fever. special cells. instead of getting rid of pathogens.

However. Finally. such as measles. this clearly shows the strength of the immune system. as you will see in the case of allergy and autoimmune disease. mumps and polio. subsequent to the development of specific vaccines against them. if the recipient is given immunosuppressive drugs to blunt his/her immune response. However. it leads to tissue injury or inflammation. tissue graft rejection is delayed or sometimes completely inhibited. rubella. This is particularly the case with childhood diseases. and you hardly see them among properly vaccinated children. which were highly prevalent among children some decades ago. By properly stimulating the immune system using part of pathogens or vaccines.finally eliminates them. This slide shows you an amazing capability of our immune system. So. . indicating the importance of the immune system. if the immune system works excessively. we have been able to dramatically reduce the incidence of certain infectious diseases in developed countries. these diseases are declining very rapidly.

let us study the basic terminology to understand this issue. the innate immune system is immediately activated. T lymphocytes and B lymphocytes and their products. is activated. neutrophils. In addition.RECOGNIZING INVADERS PART 1 (VIDEO 2) So. Against these antigenic determinants or epitopes. The reason why activation of the innate immune system promotes induction of the adaptive immune system is because activated cellular components of the innate immune system such as dendritic cells and also cytokines produced by the activated cells act on lymphocytes to . they are able to recognize molecules or cells invading into our body. the innate system is natural or "innate" to the host. sugars or lipids. our immune system can be subdivided into two. and hence. how do we recognize such invaders? What kind of strategies does our immune system exploit to recognize them? Now. As I will describe later. Basically any type of immune cells has such sensors. First of all. Once pathogens invade our body by breaching the skin or mucous membrane barriers. they are proteins. and these structures are collectively called sensors. immune cells have structures necessary for sensing. Functionally speaking. Then. an epitope is the part of an antigen that is recognized by the immune system. This word originally came from ANTIbody GENerator. This system is highly specific and acquired in nature. our immune system is very effective in getting rid of pathogens or other types of invaders. the major cellular components of this system include macrophages. which is called the adaptive or acquired immune system. ANTIGEN. an antigen refers to any substance that provokes an immune response. If the innate immunity could not eliminate pathogens. The former. another immune system. the major players of the adaptive immune system are lymphocytes such as T cells and B cells. and specific immune responses occur. and is ready to respond to invasion and does not require a period of time for induction. dendritic cells and natural killer cells. One is the innate immune system that provides non-specific host defense against invading pathogens. these molecules have a number of determinants or epitopes. meaning that antigen is the molecule that can generate antibodies or the molecule that can induce antibody responses in the body. Pathogens normally have a number of such antigens on their surface. whereas the other is the adaptive immune system that provides specific and long- lasting immunity. Most importantly.

As you see here. and survival. IL-6. Cytokines. innate immunity starts to act immediately after pathogen invasion and continues to act for many hours.stimulate their proliferation. at least. Full-blown adaptive immune responses thus require several days. and are principal mediators of communication between cells of the immune system. such as G-CSF. three types of ILCs. Here I show you the major cellular components involved in innate immunity. Macrophages.. So. This leads to the recognition of the pathogen. When the invading pathogen is not satisfactorily eliminated. Following microbial invasion. dendritic cells. . This slide shows you what I just mentioned. here. They are called phagocytes and others act as effector cells. and some act as cytokine producing cells. in this system. plays a major role in pathogen elimination. and finally eradicates the intracellular microbes. They mediate inflammatory and immune reactions. When the pathogen invades the cytoplasm. which block infection and eliminates the pathogen. consisting of epithelial barriers. and also complement components that I will explain more later. neutrophils. Most . They all secrete cytokines that can activate immune cells including T and B lymphocytes. We know now that there are. you have many different kinds of cells and they secrete bactericidal proteins and cytokines. IL means interleukin. Some of them engulf pathogens. T cells recognize the pathogen with the aid of dendritic cells. innate lymphoid cells or ILCs. Here. dendritic cells. the innate immune system.. adaptive immunity ensues. B lymphocytes proliferate recognizing the pathogen antigenic determinants and finally produce antibodies. Quite few of them are called interleukins. neutrophils. you see the dendritic cell and this is a T cell. differentiation. IL-1. A recent addition to the innate immune system is a group of cells. macrophages. releasing bactericidal proteins or proteins that can kill microbes. natural killer cells and so on.

complement proteins are inactive until they are cleaved by a protease. Upon activation of complement proteins through these pathways. allowing the passage of ions and small molecules. Some of them induce promotional microbial phagocytosis and killing locally. converts the proteins into a protease. Here I show you an example of complement cascade activation by infection. which finally results in the formation of the membrane-attack complex or MAC on the surface of the pathogen. which cleave specific proteins to release cytokines. The MAC in turn functions as a channel. when a complement component C3 binds to the microbial cell surface. They are normally produced by the liver cells and circulate as inactive precursors in the blood. which leads to killing of microbes. and pathogens are killed at the site of infection. histamine release from mast cells. The end-result of this activation cascade is massive amplification of the response and activation of the membrane attack complex on the surface of the pathogen. Some of the products induce blood vessel dilatation. And the antibody bound to the pathogen can activate C1.RECOGNIZING INVADERS PART 2 (VIDEO 3) Let me now tell you about complement proteins. which activates C2 and C4. C7. Alternatively. In this system. . as you see here. and this amplifies a cascade of further cleavages. which causes osmotic swelling and killing of the pathogen or infected cells. in addition to the classical pathway and the alternative pathway. phagocytosis by the activated leukocytes is promoted. there is another complements activation pathway .the lectin pathway. which assist the ability of antibodies and phagocytic cells to clear pathogens from an organism. which activates C3 and C5. The complement system is made up of over 25 proteins and protein fragments. C8 and C9. binding of an antibody to a pathogen triggers the complement activation through the so-called classical pathway. recruitment of phagocytes. This is called an alternative pathway. which leads to the sequential activation of C6. Now. When infection occurs. microbial products may activate proteases in the system. now. you can see now how important the complement system is as a component of the innate immune system. which in turn. inflammatory leukocytes are recruited to the site of infection. this activates a number of other complement proteins in sequence. For instance. So.

recognize nucleic acids. . -7. So. depending on their localization. and cytoplasmic transcription factors including NF-κB and interferon-regulatory factors or IRFs are subsequently activated. these pattern-recognition receptors are expressed ubiquitously. So. -8. and cell wall components such as bacterial lipopolysaccharides. innate immune cells have sensors that detect pathogens. they are often called pattern recognition receptors. Because the innate immunity receptors recognize these structures conserved or shared among pathogens or damaged cells. and as a result.INNATE IMMUNE SYSTEM ACTIVATION (VIDEO 4) Next. uric acid crystals. various adaptor proteins are recruited locally. which are collectively called innate immunity receptors. and Toll-like receptors respond to various PAMPs and DAMPs. cytoplasmic NOD-like receptors and RIG-like receptors. For instance. S100 proteins. I would like to explain how the innate immune system senses microbes invading our body. RNAs. Typical examples are microbial DNAs. sensors of the innate system are pattern recognition receptors. which are all expressed on the endosomal membrane. whereas Toll-like receptor-3. Toll-like receptors or TLRs have been the most studied so far. the signals are transmitted intracellularly via the TIR domain. and purine metabolites such as extracellular ATP (Adenosine Triphosphate). The other is called damage or danger-associated molecular patterns. -5. Examples include high-mobility group box1 (HMGB1) proteins. One of them is called pathogen-associated molecular patterns or PAMPs. As I told you a while ago. -2. They are endogenous molecules produced by or released from damaged or dying cells. and -9. These Toll-like receptors all contain a ligand-binding domain composed of leucine-rich motifs and a cytoplasmic signaling domain or TIR domain. These receptors are activated by mainly two types of molecular patterns. and endosome-associated Toll-like receptors that recognize nucleic acids of ingested microbes. When microbial components bind to Toll-like receptors via the Toll-like receptor's leucine-rich like domain. There are at least nine different Toll-like receptors. which are structures produced by microorganisms but not mammalian cells. And. and -6 recognize microbial cell wall components. innate immunity receptors are expressed ubiquitously. -4. Toll-like receptor-1. They include cell surface-associated Toll-like receptors (TLRs) and lectin receptors that recognize microbial cell surface components. Among the pattern recognition receptors.

But activated caspase-1 activates IL-1 to induce acute inflammation. a typical proinflammatory cytokine. which is a multiprotein complex that mediates activation of caspase-1. which leads to activation of caspase-1. NF-κB activation induces expression of certain proinflammatory cytokines and adhesion molecules. both of which help promote acute inflammation. because IL-1 is. is activated by PAMPs or DAMPs. When NLRs are engaged. . NLRP-3. And Toll-like receptor signaling also enhances this process. NOD-like receptors or NLRs sense PAMPs and DAMPs in the cytoplasm. this process helps promote inflammatory responses. Once recruited. you have IL-1. NLRP-3 oligomerizes with an adaptor protein and inactive form of caspase-1.IRF activation induces production of type-1 interferons such as interferon alpha and beta. IL-1 is one of the strongest cytokines that can induce inflammation. IL-1 is constitutively produced in inflamed cells as inactive form. I will tell you more about costimulatory molecules later in this talk. IL-18. one of the NLRs. Among the innate immune receptors. TNF (tumor necrosis factor). and forms oligomers with an adaptor protein and an inactive form of caspase-1. upon sensing of PAMPs and DAMPs. thus inducing anti-viral states in the cell. And among these proinflammatory cytokines. So. and activated caspase-1 proteolytically generates the active form of interleukin-1 or IL-1 from an inactive precursor. which in turn activates IL-1. and Interleukin-6 and so on. caspase-1 is activated. In this slide. So. And IL-1 induces acute inflammation and causes fever. and cleaves pro-IL-1 (inactive from of IL-1). so called. to generate biologically active IL-1. it stimulates the formation of the inflammasome complex. NF-κB activation also induces expression of costimulatory molecules that are required for induction of adaptive immunity.

OK. B cells express antigen specific receptors called B cell receptors or BCRs and consist of two major subsets. B1 and B2. they are very different in structure and different in the nature of the antigen they recognize. whereas.INNATE IMMUNITY VS. they can differentiate into several subsets. compared with those of the adaptive immune system. For instance. On the other hand. more potent than the innate immune system. so much for the innate immune system. and hence. Here I show you antigen receptors of T cells and B cells. . and thus their specificity is broad. First. and upon activation. basically. because lymphocytes respond to antigens on the principle of clonal selection. Both subsets have the potential to produce antibodies but of different properties. both of which are encoded by genes that undergo gene rearrangements and somatic mutations. T cells express specific antigen receptors called T-cell receptor. each lymphocyte expresses a unique receptor. a B-cell receptor is tetramer consisting of four polypeptides. more adaptable. a T-cell receptor is alpha-beta heterodimer and recognizes only peptides with the aid of dendritic cells. This is also underlined by the fact that the innate immunity receptors are encoded in the germline and do not mutate as frequently as B-cell receptors and T-cell receptors. In contrast. while both types of receptors can discriminate self from non-self molecules. all cells have more or less the same innate immunity receptors. as I will explain to you later. Th17. Treg and Tc. They are similar in a sense that they are polypeptides recognizing a specific antigen. Th2. the major cellular components of this system are T and B lymphocytes. innate immunity receptors have limited diversity compared with antigen-specific receptors of the adaptive immune system. such as Th1. As you see here. However. As I will explain to you later. These subsets are diverse in terms of how they are activated and what kind of cytokines they produce. innate immunity receptors recognize PAMPs and DAMPs. Therefore. ADAPTIVE IMMUNITY PART 1 (VIDEO 5) Here I summarize some important properties of the innate immune system. a T-cell receptor recognizes so-called peptide-MHC complexes presented by dendritic cells. namely two heavy chains and two light chains. I will now focus on the adaptive immune system that is more specific. So.

it normally does not react with self antigens. it remembers this and shows a more rapid and more effective response. Here I summarize important properties of the adaptive immune responses. . because the responses are mediated by lymphocyte clones expressing specific antigen receptors. The adaptive immune responses are self-limited and decline as the infection is eliminated. This is an important point.A B-cell receptor can recognize such antigens as proteins and sugars in the absence of dendritic cells. I will tell you more about clones a little later. When the adaptive immune system is exposed to the same antigen it has encountered before. Helper T cells eliminate phagocytosed microbes by secreting cytokines and activating macrophages. In the adaptive immune system. T cells and B cells have their individual function. and this is why vaccines can confer long-lasting protection against infections. In contrast. T cells mediate cell-mediated immunity in response to microbes or parasites that are internalized into or synthesized in cells. self-reactivity is normally down-regulated so that no concomitant tissue injury occurs when this system responds to foreign antigens. although it can respond to a whole variety of microbes and other foreign antigens. As you will hear later in this lecture series. The adaptive immune responses can also generate memory. The responses are highly specific. B cells mediate so-called humoral immunity where B cells respond to extracellular microbes by producing antibodies that can neutralize and eliminate these molecules such as microbes and microbial toxins. The adaptive immune responses are also highly diverse. which makes the adaptive immune system to respond to a large variety of antigens successfully. The last not least important property of the adaptive immune system is that. whereas cytotoxic T cells kill infected cells and eliminate reservoirs of infection.

INNATE IMMUNITY VS. For instance. They are immunologically inexperienced. this concept is called the clonal selection theory. lymphocytes respond to antigens at the clonal level. These clones are derived from a single precursor cell. The lymphocytes that are seeing antigens for the first time are called naïve cells. when a B cell clone specific for antigen X encounters this the antigen X. . here I show you three different clones for example. is called clonal selection theory. that is. they mount a so-called primary response in which activated B cells secrete antibodies specifically reactive against antigen X. but upon encounter with a specific antigen. We have within our body many clones of lymphocytes that are specific for different antigens. showing the specificity of the adaptive immune response. for instance. memory B cells are now activated. T cells also respond to antigen in an identical manner. that is. anti-X antibody. I will tell you about lymphocyte clones. it evokes only the primary response. except that they require antigen presentation by dendritic cells. When a different antigen comes in. Similarly. or secondary immune response. So. antigen X. Here I show you the way how the adaptive immune system responds to antigens. They have the ability to respond to a specific antigen and proliferate subsequently. And this concept: a specific clone is selected for proliferation by antigen. So. developing a much stronger and much more long-lasting response. after some rounds of cell division. anti-Y antibody. B cell clones with irrelevant specificities do not get activated and produce no antibody. What I mean by clone here is a population of lymphocytes expressing identical antigen receptors and hence identical specificities. when a B cell clone specific for antigen Y encounters the antigen Y. Basically. it gets activated and differentiates into the cells that can produce specific antibody against Y. which is called the secondary response. the antigen-responding cells. produce antibodies and antibodies produce membrane-bound antigen receptors they are secreted as antibody molecules from plasma cells. This response declines with time. which was initially put forward in the 1950s and eventually yielded several Nobel Prize winners. as I will describe later. A particular antigen selects the clone to be activated. In the case of B cells. ADAPTIVE IMMUNITY PART 2 (VIDEO 6) Now. it gets activated and differentiates into the cells that can produce a specific antibody against X. but when the same antigen X comes in for the second time. which are called plasma cells. However.

and they respond there. such as those in the skin. they are called primary lymphoid organs. and hence. If lymphocytes see antigens in the secondary lymphoid tissues. the spleen captures antigen and immune response takes place there. or the respiratory tract. Whereas those that enter the blood vessels. the gastrointestinal tract. whereas T cells are produced and mature in the thymus. are transported to the spleen. Now. These stem cells reside in the bone marrow. Upon encounters with antigens. in the case of lymphoid antigens. only mature cells leave and enter the circulation. Thus. These are naïve T and B cells you find in the blood and lymphoid organs. They may encounter specific antigens in the secondary lymphoid tissues. microbial antigens are displayed in peripheral lymphoid tissues for T cell recognition. antigens are delivered into lymphatics. They sense the pathogen-associated molecular patterns or PAMPs of the microbes and become activated to produce proinflammatory cytokines. and other peripheral lymphoid tissues. Dendritic cells are abundant in these areas and capture the invading microbes and their products. In the case of blood-borne antigens. Microbes enter the body usually by crossing the epithelial barriers. where they mature. All lymphocytes are derived from stem cells. From these organs. So.The way T cells respond to antigens is very similar to this. one may wonder how antigens get into these tissues. and where they respond in the body. finally a lymph node captures these antigens and T cells respond there. They then lose adhesiveness to the tissue and move into the lymphatic vessels or blood vessels. So. but T cells produce cytokines but not antibodies. spleen. let us look at the issue of where lymphocytes are produced. The bone marrow and the thymus are thus the places where these cells are produced. Antigens that evaded uptake by dendritic cells also move into the lymphatic vessels and blood vessels. and continue to circulate throughout the body. Subsequently. B cells are produced and mature in the bone marrow. naïve lymphocytes differentiate into effector cells and memory . So. such as the lymph nodes. the microbes and their products are transported into the peripheral lymphoid tissues and are subsequently recognized by T cells and B cells. antigen that enter the lymphatic vessels. are transported into lymph nodes.

and memory cells have the following properties. but have no effector function. In contrast. because dendritic cells process the internalized antigen and present it as antigenic peptides to T cells. Naïve cells are quiescent. In contrast. Here. and this step is called antigen presentation. live long. meaning not cycling or dividing. They have no effector function and migrate mainly to lymph nodes. B cells can recognize native antigens in the absence of dendritic cells and differentiate into plasma cells to secrete antibodies or into memory cells that can respond to the same antigen more rapidly and more vigorously upon a second encounter. whereas helper T cells secrete cytokines. memory cells are quiescent. and cytotoxic T cells can kill microbe-infected cells. T cells then proliferate and differentiate into cytokine-secreting effector cells or memory cells. effector cells and memory cells. Activated B cells secrete antibodies. effector cells are usually cycling and live only for days. Naïve cells. you see naïve cells. On the other hand. migrating through the lymph nodes and bone marrow. T cells recognize antigens only with the aid of dendritic cells. effector cells. . and live for weeks to months.cells.

signal 1. thus providing another signal. and as a result. which is antigen-specific. However. So. The activated dendritic cells can also stimulate T cells by secreting cytokines. . which can provide strong binding between dendritic cells and T cells. binding of MHC-peptide complex with T-cell receptor alone can provide only signal 1. now B7 is appearing on the surface of dendritic cells.HOW DO T CELLS RECOGNIZE ANTIGEN . they are captured by dendritic cells. The binding of MHC-peptide complex with T-cell receptor alone provides only one of the signals required for T cell activation. In order for a T cell to respond to an antigen properly. However. they are lacking in costimulatory molecule expression. when both T-cell receptor-peptide-MHC interactions and costimulatory molecule interactions take place. When a T cell has an appropriate T-cell receptor that can recognize the peptide. let us move on to the subject of antigen recognition by T cells. they show increased expression of costimulatory molecules. Let us look at this issue a bit more closely. When microbes are coming into the tissue. whereas interactions among costimulatory molecules provide signal 2 to T cells. T cells require dendritic cells for antigen recognition. T cells can recognize antigens successfully. costimulatory molecules that are expressed by dendritic cells and T cells must bind to each other. So. When antigen-presenting dendritic cells are unstimulated. At the same time. So. the T cell makes a conjugate with the antigen-displaying dendritic cells. which is called signal 2. The microbial products enter the cleft of major histocompatibility complex or MHC molecules and displayed as peptides to T cells. although T cells always express costimulatory molecules such as CD28. this alone is not sufficient for T cells to recognize an antigen successfully. T-cell receptor-MHC-peptide interactions provide only signal 1. they become activated. no effective T cell responses occur. such as B7. This is antigen uptake and degradation by dendritic cells. In the absence of costimulatory molecules binding between dendritic cells and T cells. How do T cells recognize antigens and how is it different from antigen recognition by B cells? As you see here. they are degraded into peptides in endocytic vesicles and transported to the cell surface.PART 1 (VIDEO 7) Now. which alone is not sufficient for T cell activation. when dendritic cells have been activated by microbes and/or by their products sufficiently. This is antigen presentation. which is not antigen-specific are both required. that is essential for proper T cell activation. and signal 2.

So. but also costimulation. Costimulation is absolutely essential for T cell recognition. T cell activation requires not only T cell receptor ligation with antigen. .

Here you see an exception. just like a fingerprint. and more than 1. and they are called HLA-A. There are two major classes of MHC proteins. Given that MHC expression is co-dominant. we should understand what the MHC is. antigen presenting cells. let us look at the human MHC. So. Every cell in our body carries the same set of distinctive surface proteins that distinguish us as self. . We were 5 or 6 years old at the time. I am actually one of twin brothers. Masa. Similarly. HLA class I and class II proteins that I express are completely identical to those of my brother. and myself. every individual is likely to express HLA class I and class II proteins that differ from those of another individual. no two person's set of HLA markers are exactly alike except for identical twins. Between these two persons. is an immunologist. MHC proteins are completely shared.000 alleles for HLA-DR. and they are expressed only on certain types of cells. There are at least three different genes in the class I locus. So. that means that the alleles inherited from both parents are expressed equally. there are more than 200 alleles for HLA-DQ. These 2 photos are more recent ones. every person expresses at least six MHC class I alleles and at least six MHC class II alleles. This is a photograph of myself and my twin brother.500 alleles for HLA-A. to better understand the molecular mechanism underlying antigen recognition by T cells.000 alleles for C.PART 2 ( VIDEO 8) Next. and there are more than 1. Here I show you a schematic of the genes encoding the HLA complex. more than 2. and more than 150 alleles for HLA-DP. B. Because these alleles are inherited and expressed virtually in any combination. My brother Nobu is a rheumatologist. and C. One group is called MHC class I proteins.000 for B. So.HOW DO T CELLS RECOGNIZE ANTIGEN . The other group is called MHC class II proteins. This set of markers is called the major histocompatibility complex or MHC. Simply speaking. namely. There are also at least several genes in the class II locus. more than 1. which is called the HLA complex. These genes are all highly polymorphic. MHC is the marker of self. and they are expressed on virtually all nucleated cells.

They are dendritic cells. MHC I proteins are expressed by all nucleated cells.So. Here I show you how peptides. macrophages and in some cases. shown in yellow. So. but that each MHC molecule is capable of presenting . The left shows a 2-Dimentional structure. lie on the peptide-binding groove of MHC molecules and are available for recognition by T cells. As shown in the bottom panel here. these residues are called anchor residues. although Class I and Class II proteins are slightly different in subunit composition. In the case of Class I. Thus. Here I show you the structure of MHC proteins. where they interact with amino acids of the binding groove. Each MHC Class I molecule can bind a peptide consisting of nine amino acids. I am allergic to pollens but my brother is not. this is because T-cell receptor and B-cell receptor diversities depend mainly on somatic recombination of the DNA encoded segments in individual cells. I would assume that antigenic peptides presented by our MHC molecules would also be almost identical or very similar between these two brothers. whereas MHC class II proteins are abundantly expressed in antigen-presenting cells. and both can display antigens for recognition by T cells. Class II molecules also have a peptide binding groove. These anchor residues anchor the peptide into the pocket of the binding groove. called alpha and beta chains. MHC molecules are membrane proteins that can display peptide antigens for T cell recognition. here you see microglobulin and here is an alpha chain. because there is only one binding groove. I will come back to this issue a little later. each Class MHC class II molecules consist of two chains. whereas the right shows a ribbon diagram of MHC Class I proteins. Each Class I MHC proteins consist of an alpha chain noncovalently associated with a protein called beta2 microglobulin. which is formed by alpha 1 and beta 1 domains. This is probably because T-cell receptors and B-cell receptors we express are not likely to be identical. and can accommodate peptides of approximately 15. and they are actually 10 to 30 amino acid residues. Importantly. But an interesting thing is that our immune responses are not identical. Peptide binding to MHC molecules requires the presence of characteristic residues in the peptide. An important thing here is that each MHC molecule can present only one peptide at a time. they are very similar in overall structure. B cells. whereas each Class II molecule can bind a peptide consisting of 10-30 amino acids. the alpha 1 and alpha 2 domains form a peptide-binding groove or cleft that can accommodate peptides of 8 to 11 amino acids. Similarly.

followed by antigen processing within antigen-presenting cells. and the MHC peptide complex is subsequently delivered to the cell surface. the first event is antigen uptake. Then. This is the MHC class II pathway. where do these peptides come from? These peptides are derived from protein antigens that are inside the host cells. This is the MHC class I pathway. and finally these peptides are presented on cell surfaces to be recognized by T cells. a T cell subset expressing CD4 recognizes the MHC-peptide complex. they enter the endocytic vesicle and are degraded into peptides in infected cells.many different peptides. here. the first event is. let me tell you a little bit more about antigen presentation. microbial proteins are degraded into peptides and bind to class I MHC in the endoplasmic reticulum or ER. a T cell subset expressing CD8 recognizes the MHC-peptide complex. when a microbe or microbes enter the cell. they bind to these peptides and are transported to the cell surface. antigen uptake. In the case of MHC Class I molecule. Now. And because MHC proteins are constitutively produced and enter the endoplasmic reticulum. So. whereas in the case of MHC Class II molecule. In contrast. Because class II molecules enter the same vesicles. So. the MHC and peptide meet and are delivered to the cell surface. As shown here. and peptide-MHC association. followed by antigen processing and then you have MHC biosynthesis. . In this case. once again. and finally presented to T cells. peptides derived from proteins that are taken up into intracellular vesicles bind to its groove. peptides derived from cytosolic proteins bind to its groove. when microbes are endocytosed. In this case.

Membrane-bound antibodies or B-cell receptors are used for antigen recognition and also signal transduction into B cells. as you see with secreted IgG. and after several rounds of cell division. IgA and IgM.HOW DO B CELLS RECOGNIZE ANTIGEN . this part. In the case of T cells. activated T cells produce cytokines. the proliferating B cells differentiate into antibody-secreting plasma cells. IgG. In this picture. IgD. IgE. you see two identical antigen-binding sites consisting of the V regions of the heavy chain and the light chain. As you see in this slide which I showed you before.PART 1 (VIDEO 9) So. And. a specific clone is selected for proliferation by antigens. as seen with membrane-bound IgM. The rest of the antibody molecule. each loop-like structure. So. So. lymphocytes respond to antigens at the clonal level. and can kill invading microbes and neutralize their products. respectively. T cells recognize antigens complexed with MHC molecule. On the N-terminus. one can say that antibodies exist in two forms – one as membrane-bound antibodies on B cells. This is the same with IgG. with each chain containing a variable region and a constant region. whereas secreted antibodies are also specific to antigens. Then. Both of them are immunoglobulins and have two identical heavy chains and two identical light chains. I show you membrane-bound IgM on the left and secreted IgG on the right. V and C mean variable and constant. The C-terminal end of the heavy chain may be anchored in the cell membrane. only the B cell clone expressing the B-cell receptor starts to proliferate. In this slide. and the other as secreted antibodies. The antibody molecules secreted from the plasma cells have the same antigen-binding site as the initial B-cell receptor. When antigens bind to a B-cell receptor appropriately. and eventually produces antibody molecules in the case of B cells. how do B cells recognize antigens? The way B cells respond to antigens is much simpler than that of T cells. As you see in this slide. the rest of the antibody molecule is required for structural integrity and effector functions. there are at least five different antibody or immunoglobulin isotypes. or it may have no such anchoring domain so that the antibody is produced as a secreted protein. you find quite a few of them on the structure of immunoglobulin. . this loop is called the immunoglobulin domain or Ig domain.

So.IgM found in plasma is pentameric. upon antigen stimulation. So. It is important to remember that. it is mainly helper T cells and also microenvironment that influence which Ig isotype to be produced at a given time during the course of immune responses. Then. and triggers histamine release from mast cells. IgM is produced first. IgG is the major immunoglobulin playing an important role in mid. IgE also causes an immediate type of hypersensitivity by inducing mast cell degranulation. This is isotype switching. whereas when IL-4 is provided. IgA is mainly found in the mucosa and prevents colonization by pathogens. Therefore. And they play an important role for early stage protection against pathogens. Both IgM and IgD are expressed on naïve B cells as membrane-bound. IgE is important for immune responses against helminths by inducing degranulation in mast cells. B cells switch to IgE. five-mers. IgG subclasses play an important role in Fc receptor-dependent phagocyte responses. when helper T cells are activated concurrently. IgA is important in mucosal immunity. IgA is transported through the intestinal epithelial cells and displayed in the intestinal lumen. various signals derived from the activated T cells determine which Ig isotype is to be produced.to late-stage protection against invading pathogens. locally produced cytokines such as TGF beta and BAFF help switch B cells to secrete IgA. For instance. However. how are these different Ig isotypes produced? Upon activation. such IgA is important for neutralization of microbes and microbial toxins. These immunoglobulin isotypes have different effector functions as you see in this slide. each isotype has distinct biological properties and effector functions. immunoglobulins are essential for protection against pathogens. B cells differentiate into plasma cells and usually secrete IgM. IgE binds to allergens or molecules that induce allergy. when Interferon-gamma is provided by helper T cells. . B cells switch to IgG subclasses. In the mucosal tissues. they also activate complements and play an important role in neonatal immunity. because IgG can cross the placenta. IgM promotes complement activation in the classical pathway.

The very first rearrangement that occurs in lymphocyte DNA joins D and J segments. and 6 J segments. and these three segments are joined together in a random combination. and 6 J segments and that these three segments are joined together in a random combination. diversity of immunoglobulins and T-cell receptors is produced mainly by random combination of V. D. There are more than 100 V segments. I would like to briefly explain how antigen receptors or antibody diversity are generated. about 30 D segments. somatic recombination is the key to create diversity in antigen receptors.PART 2 (VIDEO 10) Next. So. about 30 D segments. OK. This is called combinatorial diversity. So. and J gene segments. Genes for antibodies and T-cell receptors are present in pieces that can be combined in many different ways in different lymphocytes. one D. this already allows more than 10. The primary transcript is spliced to yield a messenger RNA consisting of one V. which is called D-J joining.000 combinations at this level. which is realized by somatic recombination of different gene segments. The reason why such recombination occurs only in lymphocytes is because only lymphocytes . one J. The next rearrangement brings one of the V genes together with the DJ segments jointed previously. which results in V-D-J joining. the fundamental principle governing antibody generation is combinatorial diversity. The result is a transcription unit consisting of one V. Basically the same principle works in the T cell receptor genes. and one C segment. This is translated into a polypeptide corresponding to the complete heavy chain. this shows the germline organization of immunoglobulin heavy chain genes. and one C gene arranged in this order. This somatic recombination occurs not only in the heavy chain but also in the light chain. one J. which is the method by which functional antibody genes are created. Each different combination yields an antigen receptor with a different specificity. It involves the rearrangement of many gene segments that code for the heavy and light chain proteins of immunoglobulins or alpha and beta chains of T-cell receptors. one D.HOW DO B CELLS RECOGNIZE ANTIGEN . and possible combination arising on this recombination in this case is the order of 3 million. and it only occurs in lymphocytes. so the number of possible combinations goes up to the order of 1 million in the case of immunoglobulin. So. Given that there are more than 100 V segments. For instance.

So. The major cellular constituents would be phagocytes. and together with the function of the T-cell receptor. B lymphocytes proliferate recognizing the pathogen’s antigenic determinants and finally produce antibodies. you have CD3 molecule. adaptive immunity follows. the innate immune system plays a major role in pathogen elimination. They proliferate. which is about how they transmit signals into the cell. OK. In addition. T cells recognize the pathogen with the aid of dendritic cells. that is. antigen receptors are non-covalently attached to other invariant molecules the function of which is to deliver to the inside of the cell the activation signals that are triggered by the antigen recognition. the total potential repertoire of immunoglobulin is the order of 10¹¹ in the case of B cell receptors. and . And these signaling proteins are brought into proximity and close to the antigen receptors and trigger complex signaling cascades in the case of B cells. which block infection and eliminate the pathogen. which is an enzyme required for this recombination. Here in the case of T cells.express the VDJ recombinase. I will repeat that potential repertoire of immunoglobulin is the order of 10¹¹. neither a T-cell receptor nor a B-cell receptor can deliver a signal on its own. Finally. following microbial invasion. This mechanism is called junctional diversity and this is estimated to add up to 10⁵ fold to overall diversity. Ig-alpha chain and Ig-beta chain. and this is even larger with T-cell receptors. once again. And. Upon antigen binding. Full-blown adaptive immune responses thus require several days. please remember that innate immunity provides the initial defense against infections. Innate immunity starts to act immediately after pathogen invasion and continues to act for many hours. First. this diversity is further increased by adding or deleting nucleotides at the junctions. Therefore. you need complements and you also need NK cells. which is induced by imprecision of the joining. It is the associated invariant chains that can deliver intracellular signals. Subsequently. these are so-called signaling proteins. In contrast. dendritic cells and macrophages. Thus. you have effective signal transduction. neutrophils. this antigen receptor and CD3 signaling. Let me describe one more thing about antigen receptors. and this is even larger with T-cell receptors. I summarize my talk using two slides which I showed you before. and finally eradicate the intracellular microbes. so this is the very important issue in the generation of antigen receptor diversity. In the case of B cells.

so much for the general introduction. I hope that my lecture helps you build up fundamental knowledge about immunology and will also help you obtain a good understanding of the rest of the present lecture series. OK.adaptive immunity follows next to provide more specific and long-lasting infections. .