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Introduction
Noor, Dima, Basma Ziad Elnasser Sunday, 3/7/2011

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Immunology - Lecture 1 Sunday, 3/7/2011 Done by: Noor, Dima, Basma

Dear colleagues Here we go again! A new beginning with a new spirit =D InshaAllah it will be a great Summer =) It's a pleasure for us doing this 1st lecture in the Immunology Course ! Hope you ENJOY it =D

Course Introduction
Good Morning =) Today, we start the immunology course :) We'll have five lectures per week; 60-minute each! We're going to have two mid-term exams; the first will be on the 23rd of July and the second on the 13th of August. For this course, we're going to use a very nice, easy-to-read book called IMMUNOLOGY FOR MEDICAL STUDENTS / by NAIRN. This book is so easy to read, it has beautiful colors =D, and some clinical cases as applications for the basic information we're going to teach you. I think the book is present in the book store over here; the latest edition is the 2nd one (2007). Hopefully, next year they'll have the new updated book; in any case, I'll let you know about any new information. This course is so condensed; every day, we will be taking a LOT of information. I want you to go over the material that we discuss day by day; not leaving everything till the END of the week! The information that we're going to take is comprehensive and a build-up like a series; the information you hear today, you'll use it to understand the coming lectures. If you miss the first 2 or 3 classes, you won't be able to understand the rest of the material! :/ The secret for scoring 100% in this course is to follow up the material! It's so easy, so nice! =) You'll see how I'm going to utilize the information to understand so many principles in medicine (internal medicine, pediatrics, surgery, and so on). We'll be using immunology terminology like the terminology we used in Microbiology. This terminology -that you'll learn this Summer- you'll be using it for the rest of your LIFE!
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Concerning the attendance, we'll be taking attendance based on the University laws and regulations; anybody who's absent more than 10% will not be able to sit for the final exam. So, each of you has to sit on his assigned seat.

General Introduction to Immunology

The science of Immunology is a NEW science. I always tell my students; when I took a course of Immunology in my PhD, my Professor was in his seventies! He used to tell me: In the fifties, when we used to look at a blood film and see a lymphocyte, we used to describe it as a cell without function! While today, 90% of the science of Immunology is lymphocytology! So, you can see how much information we have learned over the years The word Immunology comes from the Latin word: immunatus; it means to protect as defense. If you remember, in the Microbiology course, we talked about the formula of infectious diseases and how an infectious disease is going to take place. This formula equals: N*Z/H N: the number of microbes that enter our body (the infectious dose). Z: the virulent factors; the weapons that the organisms have to cause injury. H: the host factors (the immune system). We use the terms: Immune-competent: it means the immune system is functioning well. Immune-compromised (-suppressed, -depressed): it means the immune system is not functioning as it should be.

We said before that we have three lines of defense: 1st line, 2nd line, & 3rd line. And those work together to protect us against ALL the invading microorganisms (bacteria, viruses, fungi, protozoa, and helminthes). If our immune system is functioning well, we'll be protected. If it's not functioning well, then we are compromised and susceptible to infectious diseases.

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Sometimes, our immune system can go crazy :O! Like the diseases caused by over-stimulation of the immune system; like hypersensitivity, allergies that could sometimes lead to death, and auto-immune diseases where our immune system would attack our own tissue, destroy it, and cause injury. I always want you to remember: Anything that doesn't kill you makes you stronger! And we have in our ISLAM:

And our body works in the same way; it's designed to defend itself; so that the second time, the third time >> it will be stronger & stronger! Through history, people were trying to understand diseases and how the infectious agents cause injury and how our body is defending itself. You probably remember the experiment of Louis Pasteur and the rabies; where in the 19th century, they knew that rabies kills people. Louis Pasteur got a dog that died of rabies and got his spinal cord (he knew that rabies affects the brain and the spinal cord); he took some material out of it, and then he got a 12-year old kid who was bitten by a rabid dog (they knew at that time that anyone who's bitten by a rabid dog will get rabies and it's a matter of time that he'll die). So he got that material and injected it in the skin of that kid and he repeated that frequently, and that boy didn't get rabies! So by this, he managed to make vaccines. Do you remember the experiment by which they discovered vaccination? Vaccination comes from the Latin word: vaca; which means: cow! They used to have cow pox (which is vesicles that appear on the hands of shepherds when they milk cows); they noticed that shepherds who get cow pox don't get small pox! So, they tried to take the fluid out of the vesicles of cow pox and inject it in the skin of people; so those got protected against small pox. This is the idea of what we call vaccination. So, vaccination simulates a natural infection and prepares our body to defend against the wild strains of microorganisms.

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Basic Concepts and Components of the Immune System

When we talk about the immune system, we talk about 2 main components: 1. Innate Immunity: This is the one we are born with. It is non-specific; which means that ALL the defenses that ALL of us have are almost the same (they act the same for everybody and against any microorganism). It's represented by the 1st line of defense; like the skin, physical barriers, and mucous membranes, and the 2nd line of defense which is the blood and its components (other than the lymphocytes): WBCs, phagocytic cells, complement, and inflammatory mediators. It doesn't have memory; it doesn't remember the organism that has invaded (it acts the 1st time as the 2nd time as the 3rd time). 2. Adaptive Immunity: this is a specific immune response and it has memory. It recognizes the microorganism the 1st time and remembers it when it invades the 2nd time. It is characterized by the following: Self vs. Non-self One of the major functions of the adaptive immune system is to differentiate our antigens; either self or non-self. The lymphoid cells go ALL over our body and keep sensing the antigens that are present; if they find a non-self antigen, theyll attack it in order to get rid of it. The differentiation of the immune system between self antigens and nonself antigens is a very important subject. If our immune system fails to differentiate between self antigens and non-self antigens, then were going to have an autoimmune disease. Well talk about the role of the thymus gland and the bone marrow in the differentiation between the self and the non-self antigens.

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 Antigen recognition molecules The adaptive immune system uses cells that have receptors for different types of antigens; the specificity of these receptors is determined by our genetic setup (so we are born with these receptors). We differ genetically; so if I get exposed to an antigen and I have the cell that has the receptor for that antigen, then Im going to get a response. If I dont have the cell that is specific for that antigen, then Ill be immune-compromised or Ill be weakened, so here the other mechanisms of resistance should be fired. So, the antigen recognition molecules are the molecules that will recognize the antigens; like the receptors on T-cells, immunoglobulins, and the major histocompatibility (MHC) antigens. Clonal selection So, when we talk about the specific immune response, we have a set of cells that have receptors that we are born with, but each cell has one type of receptors! When a person gets exposed to a specific antigen, that antigen will hook into the antigenic determinant of the lymphocyte and the cells will differentiate into what we call clones (the same copy of that lymphocyte), and then it will be active; either a killer, or it will give an antibody. Memory cells The process will end up by forming memory cells that will live for a longer period of time. So, the lymphocyte that is a memory cell lives longer than the non-memory cell one; it may live tens of years. This is the one that we need to make when we vaccinate; so the body remembers the infectious agent if we get infected with it later on. The innate immunity is faster than the adaptive immunity. The innate immunity is always there! While the adaptive needs interaction in order for the cells of the immune system (lymphoid cells) to produce specific cells, specific antibodies, and so on; so it will take longer time than the innate. The successes that are achieved in Immunology are: Production of vaccines Immunity to microbes Successful transplantation of tissues Production of monoclonal antibodies
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The failures that are associated with our immune system are: Autoimmune diseases Immunodeficiency Allergies Questions to be answered later on: 1) How does our body defend itself against pathogens? The person could be a responder or a non-responder. And in order for the organism to cause an infection, it has to succeed in penetrating the first, the second, and then the third lines of defense. So, it is a battle between the microorganisms and our immune defenses! 2) How does a pathogen succeed in breaching (breaking) the bodys defenses eliminated? When we get a burn, then here we breach the defense and we get the infection. When our phagocytic cells aren't in a good number or when theyre not functioning well, then we are weakened and immune-compromised. If I dont have specific lymphocytes to act against those pathogens, then Im a non-responder and Ill be weak, and so on. 3) How does our body remember a prior exposure? It remembers it by the production of memory cells. But what is the nature of those memory cells? How do they develop? How do they differ from other cells? How can they be increased in number and efficiency by vaccination?

In the uterus of our mothers, were fully protected against the external environment, so ALL the defenses that were getting are from our mother. The uterus and the amniotic sac are ALL sterile. But if the mother is infected, then some of the organisms could pass from the mother to the baby, and the baby could be born with an infectious disease; like rubella, syphilis, toxoplasma, and so on. The minute the amniotic sac is opened and the baby gets to the outer world, the baby starts to be exposed to the external environment that is full with microbes, bacteria, fungi, viruses, protozoa, and so on. The immune system starts to defend itself and defend us against this external environment.
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Slide 4: It shows water that is contaminated maybe with fecal material of animals and humans, and it may have lots of coliforms. But about 97% of microbes that are ALL over the world are non-pathogenic. The air around is full of microbes; insects can bring microorganisms into babies, so theyll start to be exposed to the microbial world! Those babies are born with some defenses; if these defense mechanisms are efficient and protective, then they will enable them to survive in this world. Those babies who survive living in developing countries -in which there are many infectious microorganisms- are well protected and have a good immune system, and their chance of being infected later will be much less than a person living in the developed countries! If a person is living in the USA and he is not vaccinated against polio virus, then the chance of getting poliomyelitis is much higher than in those living in the third world country. Now, people are asking why Escherichia coli is more in Europe, it is for the same reason! Here in the 3rd world countries, we are exposed to many microbes; so by nature, we are more protected against infectious agents than others. What you are seeing here is a classical example of how much the immune system is effective in protecting us against infectious diseases. Of course, Im not asking you to go to such dirty water =P ; for sure, the chance of getting diseases is much higher when you do so!

The Innate Immune Response (Non-adaptive)

As we said, it's not specific, doesnt have memory, and it's the fast one. The 1st line of defense: The skin (the biggest organ in our body) and the mucus membranes help us to be protected against the external environment. If these physical barriers are affected, then well get infected. So, remember that burns result in breakage of physical barriers causing death due to dehydration and infection. The 2nd line of defense: The phagocytic cells (like neutrophils and macrophages) are part of the 2nd line of defense. Well be talking about these things later on. The complement and the interferons are also part of the 2nd line of defense.

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The first, second, and third lines of defense communicate with each other through substances called cytokines produced by cells. Well be talking about these cytokines; the cells that produces them, their types, and their function. Well talk later about the interferons; like interferon , , . And well talk about the interleukins; like interleukin 1, 2, 3, 4, and so on. The term "cytokine" has been used to refer to the immunomodulating agents; such as interleukins and interferons. Wikipedia Well be using these cytokines as molecules that communicate between cells. Some of these cytokines up-regulate (they stimulate) while other cytokines down-regulate (they suppress the immune system). Cytokines can even be used as medications. For example, we use interferon for the treatment of hepatitis. So, we should know when to suppress and when to activate the immune system, and so on. Slide 6: it shows a phagocytic cell engulfing bacteria. Well talk in details about that in the 2nd line of defense. So, this is a macrophage which is about 20 to 30 microns in diameter, and you can see the pseudopodia that have to adhere to the bacteria and it has to be taken inside. Well talk in details about the mechanisms of destruction of those microbes, and what happens if this process fails. It may fail because we dont have a good number of those phagocytic cells or because of certain defective enzymes in those cells that are utilized to make a reaction and kill these microbes.

The Adaptive or Acquired Immune Response

As I said, in the adaptive (specific) immune response, were talking about T and B lymphocytes and memory cells, and were talking about the cytokines that communicate between those cells. Well see the cytokines in both; the non-specific and the specific immune responses. In the adaptive immune response, we also talk about antigens. We define an antigen as a substance that has the ability to induce an immune response. Then, they have changed that into what is called an immunogen; which is a substance that induces an immune response, and the products of the immune response react with the immunogen!

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The antigen is an antibody generating substance (anti-: antibody, -gen: generating), but it is not necessary that it will generate antibodies; it can stimulate lymphoid cells, killer cells, and so on. So, we use the terms antigenic and antigens for substances that have the ability to induce an immune response. The antigens have what is called the epitope or the antigenic determinant (its counterpart is called paratope); which is the most specific part and it has to fit into the receptor on the cell. And the antibodies that are produced are going to neutralize that antigenic determinant. Well talk later about the nature of those antigens, how they can stimulate an immune response, and how we can make a substance antigenic and vice versa. This process of the specific immune response takes time (7 to 10 days), while the non-specific immune response acts immediately; and this is why we need to measure the titer. You probably remember from Microbiology that we depend on the titer measurement (a 4-fold increase in titer) to determine the time that it takes the immune system to make the immune products. The differentiation between the self and the non-self antigens is an integral function of the specific (adaptive) immune response, and it uses the antigen recognition molecules for this purpose. The antigen recognition molecules are like the receptors on B cells and T cells, and you should know what those receptors are. If we talk about B cells, then were talking about IgM antibodies (monomers). While when we talk about T cells, then were talking about and polypeptide chains in different types of arrangements that form the T cell receptor (the antigen recognition molecule) on the surface of the T cell. In addition to the B and T cells receptors, the major histocompatibility antigens (MHC) are also antigen recognition molecules. Each one of us has a certain haplotype for the major histocompatibility molecules. So, my haplotype and your haplotype differ from each other, and that will determine how we are going to respond to different microbes. The MHC has two classes: class I and class II. We will tell you more about those; how they function as antigen-recognition molecules and their role in the activation or suppression of the immune response.

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We will be talking about immunoglobulins (or antibodies) in more details. Those are the byproducts or the outcome of B cells that have changed to plasma cells. Can a B cell produce more than one type of an immunoglobulin? The answer is NO! Each B cell is designed to produce one type. And one B cell has one type of receptor on its surface. This will lead us to what we call the clonal selection theory. And I will tell you more about the types of different immunoglobulins; IgM, IgG, IgA, IgD and IgE. What do we mean by clonally-distributed? The B cell that has one type of a receptor; when it matches the receptor with the epitope (the antigenic determinant), it starts to differentiate; it will expand to produce a clone from that particular cell. We start with one and we end-up with hundreds of the same specificity! And each one of those will produce antibodies of the same type. This is so interesting! =D If you have the originating cell, then you will have that clone; but if you don't have that cell, then you will not have that clone! Modification of self antigen and disease: we will talk in more details about self vs. non-self, the autoimmune diseases, and hypersensitivity. Memory and vaccination: we will talk in more details about how we are going to make vaccines and what are the manufacturers and ideas of making vaccines. We are going to use the same organisms causing the main disease; weakened, killed, or parts of the organism (the toxin for example). We will tell you more about how the pharmaceutical industries make vaccines. We have talked about influenza and the vaccination and how influenza virus is an extremely successful organism! Influenza is very evasive; it has the ability to deceive our immune system, but how? It has the ability to change its antigenic structure; so when our body recognizes that the first time, it reacts and develops memory cells against that type, then it changes its structure. So our body has to recognize that again as the first time, because no memory cells are there to counter-attack, and the body has to develop the memory cells again, and it may take 7 to 10 days; whereas if we already have memory cells, then our body will react so fast and effective. So, we will tell you more about influenza and what we did to minimize the effect of those organisms, do you remember? We have made upgraded vaccines; we add up all the strains that are discovered every year.
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So, we use seasonal vaccines; every year we use a vaccine between October and December that has ALL the common strains that were circulating ALL over the world, then we will be protected.

This is what I was talking about. Here we have B cells, each one of those cells with one type of specificity; here everyone has a different shape. And when we are exposed to an antigenic determinant, then in order for the immune response to take place you must have a match and then a clone is going to develop. So, you can see here; this cell, for example, its shape matches the specificity of the receptor, so here the condition has been matched and clonal expansion is going to take place and these cells start to divide. This is so interesting! =D These cells match the shape of the antigenic determinant then they will react; they start to divide, then B cells change to plasma cells, and plasma cells produce antibodies of the same specificity. So, we develop here a clone and memory cells, of course, will develop regarding that particular B cell. So, here we have B cell producing immunoglobulins. When immunoglobulins are produced, how can our bodies utilize those immunoglobulins? Y3ni how are the antibodies that you have just seen here going to defend us against infection? The immunoglobulins have developed here with a matching specificity of the antigen, so they are going to go and bind these antigens to neutralize them; preventing them from binding to specific receptors on cells to inflict injury. If those particles, for example, represent toxin, we call these antibodies now anti-toxins; these anti-toxins will neutralize the toxin, so the toxin has been neutralized and it will not act on specific receptors.
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In our bodies, this is one branch; we call it the humoral immune response which means antibody-mediated; immunoglobulins and B cells related to that. Sometimes, we have foreign cells or we could have viruses inside the cells. I could get infected with a virus and the virus is inside the cell, or some of my cells could get modified to develop into tumor cells; those tumor cells are modified self-cells and they are foreign to my body now. If I'm lucky, my immune system is going to identify those as foreign and get rid of them. But if I'm unlucky (if I don't have a matching cell against those foreign cells), then those will proliferate and then they can inflict injury and cause cancer. Slide 10: You can see these cells here. For example, if this is a tumor cell, tumor-cell antibodies will not be enough to neutralize them; we need cells to kill those tumor cells. So, we have certain types of cells we call them Tcytotoxic cells and these are specific for certain types of antigenic determinants present on the surface of those tumor cells. We have another type of cells called natural killer cells (NK). Those have the ability to bind and recognize those foreign cells and secrete substances to convince those tumor cells to commit suicide! These processes occur on a daily bases; every day we have cancerous cells in our bodies, every day we have transformed cells in our bodies; but if I'm lucky and my immune system is functioning well, it will take care of those and destroy them. And if I'm unlucky, then I will develop cancer. The adaptive part we call it acquired immune response; it will develop and it will get activated after the stimulant enters our bodies. So, the acquired immune response is either humoral: antibody-mediated, and those antibodies can function to get rid of toxins, bacteria, viruses in a process we call neutralization, or cellular: cell-mediated; which is specific if those cells are Tcytotoxic cells with one type of a receptor on the surface, or it could be nonspecific if we are talking about natural killer cells, macrophages, or neutrophils that have the ability also to kill these foreign cells.

So, now you have an idea about how our immune system is working.

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Medical Successes in Immunology

Vaccinations Remember: what doesn't kill you makes you stronger! And we will help in making you stronger by giving you vaccines. You have to remember ALL the vaccination programs that we do and against which organisms. Organ transplantations We will talk about organ transplantations. And we need here to educate people to donate their organs; donation of organs can help other people; they call it " ." In the US, they always say: donate your organs; you are not going to use them in heaven! Last week, the head of ophthalmology was complaining that we do not have the culture of donating our organs; each one of us has to write if I die, I can donate my corneas, my kidneys, for example, for others to utilize. When you transplant an organ to another patient, what is going to happen? Either this graft is going to be accepted and then it will function as it should be OR it is going to be rejected. The story here is that I'm putting foreign antigens in my body, so by default my body is going to reject that, so what am I going to do to make that graft accepted? We will tell you more about the process of transplantation. Blood transfusion is a form of transplantation; we are transfusing foreign cells and our bodies are going to respond to those foreign cells; WBCs, RBCs, platelets, serum. How am I going to react against that? What am I going to do to make this grafted cells and tissues accepted? Treating hereditary defects in the immune system We will see the mechanism of responders vs. non-responders. You will understand the immune mechanisms at the molecular level; how a B cell is going to be stimulated to produce an antibody and how a T cell can be stimulated to produce cytokines or to kill. How this immune mechanism is going to take place? It is so interesting for you to know; because these immune mechanisms if they are defected in the process or an enzyme is deficient because a gene is deficient, then we will be immune compromised, so what am I going to do?

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You will see in gene therapy we can replace those defected genes, so those patients change from immune-compromised to immune-competent. So, we're going to concentrate on the immune mechanisms at the molecular level to understand how a B cell is going to be activated in complicated biochemical pathways to produce antibodies, or a T cell to produce cytokines or to be activated to kill. You have to understand that because you will understand how we are going to block this process if I want to make the patient immune-suppressed where we can use immune suppressive agents OR to activate that by using cytokines or to replace the genes that are defected. Drugs that control allergies How we are going to control allergies? First, you have to understand how allergies or hypersensitivity is taking place; what makes me allergic to pollens and doesn't make you allergic to pollens! Two weeks ago we had a patient who had a disease called angioneurotic edema (Angioedema) and he died in the hospital after taking one tablet of antihypertensive drug! It was really horrible! We will tell you how to act with those, and how to help people and save their lives! :")

and that was it! =)

Done By: (: Noor Abu-Farsakh, Dima Bani-Eisa, Basma Deeb :)

~ Happy are those who dream dreams, and are ready to pay the price to make them come TRUE! ~

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