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BBasic Concepts and Components of the immune system

Amin Al-Baik Ziad Al-Nasser

Monday, 4/7/2011

Lecture # 2, chapter 2 Date: Monday, 4/7/2011 Done by: Amin Al-Baik

Basic Concepts and Components of the immune system

Review for the first lecture ((Ch#1 mainly))
Everybody got the Idea about Immunology course, and yesterday we have started talking about some of the concepts and terminology that we have been using in the science of Immunology. We talked about Louis Pasteur (who created the first vaccine for rabies and anthrax) and the vaccination against rabies which give you thing that doesnt kill you, but makes you stronger. and we talked about Edward Jenner who is considered as the father of Immunology for his discovery of the vaccination against the smallpox; where he noticed that shepherds, who got cowpox, they didnt get the smallpox, so he took from the vesicles of cowpox (lesion has a fluid), he took from that fluid and injected that to people, they expected to be getting the smallpox, but then they were protected. I told you that vaccination starts with vaca which means (cows) in the Latin language, so the terminology came from a cowpox vaccination by Edward Jenner, and we started talking about the main divisions of our immune system and its significance in defense; the nonspecific one = the innate , and the specific one = the adaptive . 1

And we said that: 1- The nonspecific (innate) is much faster, it is the one we are born with, (E.g physical barriers and mucus membranes), they make the bulk of the first line of defense. We have the second line of defense, (e.g. serum and its constituents, WBC other than T & b lymphocytes i.e. WBC which perform phagocytosis, and the complement system), about cells (e.g. neutrophils, phagocytic cells, natural killer cells, macrophages), all of them are nonspecific, and those cells can produce cytokines which are components trigger the cells; they interact with each other, some are upregulator (enhance) and some are downregulator (suppress). 2- Then we said on the other side about the specific of immune response, where we talked about specificity, and we talked about memory at the same time, and we talked about antigen-recognition molecules receptors and antigenic epitopes that have to fit into those receptors, and we said that we were born with sets of receptors on the surface of those T and B-cells, if those are there then we are responders, and if they arent there then we are not responders.

So when we talk about T cells, B cells, major histocompatibility complex (MHC), antibodies, memory cells, receptors and antigenic determinants (epitopes), We talk about adaptive immune response Then we talk about adaptive immune response, and we said also vaccination is the one of the successes of our immune system, and we will talk in details about it, and its program, and we will talk about transplantation, we have sometimes to transplant a kidney or a cornea or even blood! , blood transfusion is considered as a type of transplantation, and how we are going to keep that into perform the function, so sometimes we need to suppress the immune system in order for our body to accept that particular graft (the part which is transplanted), and also we said that it is so important for you to understand the molecular interactions, molecular reactions, biochemical pathways, which will take place, why?? Because if any defect happened during that pathway, then we are going to have immune 2

deficiency, or we can manipulate those by drugs to suppress the immune system. So we said sometimes in hereditary diseases, the enzyme could be defective, and loss enzymes expressed by genes, so in order to replace those genes we could do gene therapy and we will talk about it later.. and some of the failure of the immune system other than immune suppression , lack of these cells that we talked about, enzymes , genes and so on, sometimes our immune system could go over reactive and this result in hypersensitivity or Allergies; they could kill people; so we have to identify that, also we said one of the major specific function of the adaptive immune system is to recognize self from nonself, and we said this occurs in the major lymphoid organs, in the thymus gland, and in the bone marrow, any defect in this normal process, then we will have autoimmune disease , and these autoimmune diseases (e.g. systemic lupus erythematosus, rheumatoid arthritis), they could lead to death, we will see how to treat those later on.

For example look to this patient who has hepatitis B infection, it is chronic hepatitis caused by Hepatitis B virus, and these patients have jaundice. look to the *sclera here (figure #1), you can see yellowish discoloration of the sclera. So, one of the causes of jaundice is hepatitis B, and classical causes of hepatitis , hepatitis A , hepatitis B , hepatitis C. Hepatitis C is the most serious one, it could infect the health care workers , and kills a lot of people all over the world, in USA it kills more than one MILLION every year, they die by hepatitis. 3 (Figure #1)
*Sclera: is a white fibrous membrane which covers the eye.

We need to have precautions and vaccination, because some of the health care workers could be infected when they are dealing with the patient with hepatitis, and everybody who comes to the hospital should be vaccinated with Hepatitis B, also hepatitis B could lead to liver failure , chronic hepatitis, hepatocellular carcinoma and death, this disease is sexually transmitted disease. Also we talked about influenza, and that its viruses are so evasive (they have ability to change their antigenic structure), so we could be infected with one of them frequently, and there is another example for the evasive viruses: Herpes Viruses which suppresses the production of major histocompatibility antigens, which are the major role in defense. However, Influenza could disguise with normal tissue covering itself with mucus plug, so we should know all the pathogens, their evasive mechanism and our counter measures to get rid of them. About influenza we told you that we use upgraded vaccine every year. This is the sneezing and cough, they are the way by which we get rid of respiratory particles, which next go into the air, floor, chair, and hands, then you shake hands with someone, and then pathogens will be transmitted to him and so on, this is the droplet of transmission. The most two important features of adaptive immune system are: specificity and memory. For example how we can modify our immune system in order to increase the number of memory cells; then will be protected against these organisms, and the classical example is the use of hepatitis B vaccination, we give three doses (sometimes we give two doses), between the first and the second dose there is a period of around one to two months, and the time between the second and the third dose is four to six months, so we give more than one dose, in order to increase number of memory cells. 4

the primary immune response is the response comes after first dose until second dose, in this period the antigen will be recognized (recognitive phase), the antigens bind through the receptors, the receptors through the clonal selection theory, you must have cells that will develop into clones, the clones will differentiate and proliferate increasing in number, and memory cells will develop and immunoglobulins.

After second dose (secondary immune response), there is an increase in immune response, and the period for the immune response to take place will be much shorter i.e. it is faster, because memory cells have already developed. And the type of the immunoglobulins that will develop is different, they are with high affinity binding, so strong, neutralizing antibodies. After third dose, the response will be much much higher, we will have huge amount of immunoglobulins in few months. The different between the primary and secondary immune response is that the primary takes longer period of time ends up with development of memory cells, but the secondary, the type of immunoglobulin of which is much better than the primary, they last longer, and the binding of them is so strong (high affinity), and we call the secondary immune response another name which is anamnesia which is in contrast to amnesia, anamnesia is the reaction that remembers, so develops memory cells. this patient has renal failure (figure 1.8, p5, ch1) , and you know when kidneys fail, there is no way to recover it except to do kidney transplantation, and kidney transplantation needs donor to give and the patient which is recipient, and we must have tissue match , in order the recipient to accept the donors kidney.

and the role of histocompatibility antigens , each of us has sets of haplotype, I

inherit half of genes from my father and half from my mother, this is called dominant type of expression , and those genes are the ones that stimulate the immune response and genes, and antigens which will respond immunologically , so if we have the same setup genes , that means same antigens = no immune response = graft will be accepted and vice versa, until now there is no way to reach 100% match, so we are going to do suppression of the immune response (by using immune suppressor drugs), so patient will accept graft, there is a lot of organs to make transplantation , e.g. cornea transplantation is the most successful types of transplantation .

There are some similarities and differences between adaptive and innate immune response : Innate is non-specific and adaptive is very specific. Innate is fast (minutes), while adaptive needs time to develop so it is slow (days). Innate is without memory, unlike adaptive which is with memory. The innate include natural killer phagocytes and secreted molecules; the adaptive has lymphocytes (B & T cells) and also secreted molecules. There are few pattern-recognition molecules in the innate (they develop as pattern for group of antigens) like a polysaccharide, and there are many Antigen-recognition molecules in the adaptive.

Chapter #2: Basic concepts and components of the immune system

About interactions between two immune systems look at the figure here : > > You require Antigen-presenting cell (APC) for the specific immune response or what we call thymus dependant antigens. However, About APC E.g. dendritic cells, interdigitating cells, B cells itself, and Macrophages could detect the antigens, process it and then present it with class 1 and class 2 of MHC. This process (presenting & Processing antigens) is required for the B and T lymphocytes to be activated, and requires complement chemotaxis and phagocytic process I.e. we will see that 1st line, 2nd line ,3rd line of defense and primary immune response all of those mechanisms will help each other in order to make the defense. For example , if you get a bacterial infection , then those bacteria will be taken by the APC , it is processed and then presented to T and B cells, and you know we have different types of T cells , and the most important one is T helper (the main (or the orchestrating) cell in our immune system). CD4 cells, is the T cell which has CD4+ antigen.

Note: Orchestra means: band composed of musicians of many different instruments. and we said that about T helper cell coz it produces cytokines which manipulate, activate, suppress, and regulate the rest of other T cells or B cells, the B cell without the cytokines which produced by T helper cell will not produce immunoglobulin as much as when the cytokines is present, so the importance of the APC is for activation of T and B cells, and production of immunoglobulin. 7

We talked that, Immunoglobulins when they develop, this is what we call humoral immune response, and this is required for neutralizing viruses, toxins and pass through the placenta... etc.

sometimes we require to kill in cell , and this is what we call cell mediated immune response , if you have a viral infection for example , and the target cell is infected , and the virus is inside the cell , so we need to activate T cells to kill that virally infected cell.

Part of cell-mediated immunity is done by adaptive immune response, and the cells which are involved we call it T cytotoxic cells, and the other part by the innate we call them natural killer cells. The mechanism of the killing in both is the same , but the difference comprise the recognition of the particles , i.e. the T cytotoxic cells recognize particles by the receptors that present on the surface of it , while natural killer cells do that by different mechanisms like antibodies that are going to bind receptors.

We will talk to you about the Major histocompatibility antigens and its major role, and the expression of those antigens on the surface of those cells will determine whether T cytotoxic cells will take an action and kill or the natural killer cells will do that, we can see that we have so many alternatives for getting rid of invading micro-organisms.

Again, there are similarities and differences between the innate and the adaptive immune response:

Innate immune response: The response time is fast. The pathogen (non-self) recognition mechanisms are few. There is no memory. There is no improvement, unlike the adaptive. Adaptive immune response: The response time is slow. The pathogen (non-self) recognition mechanisms are so many. It has memory. It has improvement by changing of the type of immunoglobulin that they will develop and this development will change even a binding affinity.

Innate immune response

1. Phagocytosis and MBL (mannan binding lectin) of the C (complement) system which is non specific, we will tell you more about that. 2. cells that are involved in non-specific :a)Neutrophils : those are the major cells that are involved in Phagocytosis, they are developed on daily basis , they have short half life ,they are present in huge number, neutrophils live less than 24 hours, and then it will expire, they are called by process called Chemotaxis, and chemotaxis require cytokines to be expressed or secreted, so they (cytokines) will call those cells (neutrophils) to come in the area, mainly they are called upon when I have bacterial type of infection, so when I see lots of neutrophils; I know this is what we called pyogenic infection, when the process is finished they turn to pus cells, they get expired by the act , and they have so many killing mechanisms we will talk about them later. b) Macrophages: they differ from neutrophils, Macrophages are larger, they last longer, but they are not high efficient; coz their number is less, they can phagocyte once, twice, and third. They dont expire by the act, unlike the neutrophils. c) Natural killer cells (NK): non- specific cells, they kill virally-infected cells and tumor cells, and they are the main surveillance cells of our body, they keep circulating in

our body, I will tell u more how they kill later.

Morphologically, when we look to them under the microscope they look like lymphocytes but the difference between NK cells and the lymphocytes that NK dont have specific receptors against Antigens. In fact they are used to be large granular lymphocytes, but in reality they are not granular: they are not lymphocytes, they look like lymphocytes and they develop from the progenitor cell of lymphocytes. Mechanism of killing: the initiation is difference, but the outcome is the same, both of them produce substances we call them cytotoxins and cytolysins that they will kill virally infected cell, they kill the virally infected cell or the tumor cell by convincing the cell to commit suicide we call that apoptosis. 3. Interferon: one of the most important cytokines produced from many cells. Alpha Interferon (), beta Interferon () and gamma Interferon (); gamma type is produced from T-helper cell. Alpha from WBC, beta from tissue, and the interferons provide protection of cells mainly against viral infection .they are excreted from cells which are infected with viruses mainly and provide protection to others against viral infection, I.e. the outcome is the destruction of the messenger RNA of the viruses.

So, remember that the Innate and the Adaptive immune response are interconnected through the cytokines, they perform dual function, they help each other and they work as a team.

Adaptive immune response

The adaptive Is specific , distinguishes self from non-self , it has Diversity of antigen recognition molecules and so many genes that are produced so, this is why your new response is different from mine ; it depends on the gene that you have inherited from your parents and gene that I have inherited from my parents which is going to determine the receptors on the surface of the lymphocytes so, if you have the same receptors as the ones I do, then you will react the same, if you have more than me, you will react better. More genes you have inherited from your parents more lymphocyte cell surface receptor more efficient reaction with antigen

The importance of diversity to you is to have more genes more receptors more different cells than mine, to encounter all the different pathogens that we could be exposed. - Which determines the diversity of genes is the inheritance of your parents. the ones they have what we call Intersanguineous marriages ; if my

mother and father they are so related to each other, then the types of genes that Im going *(( )) to get from my father and mother they are - - going to be the same .they arent going to be diverse as such compared if may mother and father are not related to each other, then the polymorphism and the diversity, they are going to be enormous So, I will have better chance of responding to pathogens and foreign cells than the Intersanguineous marriages. Then always we said : )) *((

We will keep talking about that when we come to the genetics of immunoglobulin and its diversity B-cell, T-cell receptor diversity. Somatic mutation: the change that occurs at the binding site of that immunoglobulin and what we call a better fit of an immunoglobulin compared to a weak fit. The nature of immunoglobulin will develop, so the somatic hypermutation occurs in the secondary immune response i.e. after primary immune response; cuz primary response is just to recognize, and the mutation in secondary is for make the binding sites better fit. Receptors prior exposure to antigens: this is what I want you remember we have born with receptors on cells, those receptors do not develop when antigens enter our body. I want u to remember this important information: receptors they are already there, they are determined with set of genes that we inherit from our parents, so when we are exposed to antigen; if you have the cells then interact, if you do not have, they will not interact. Receptors of antigen are determined by genes that we have inherited from our parents, and arent determined by antigen that is going to enter our bodies"

Clonal expansion: will take place. This what we call clonal selection theory, we mean by clonal selection theory that We are born with cells which have already receptors there, and the clone that is selected is going to be activated, and proliferated. Self receptors must be deleted or inactivated: why?? All the progenitor cells that they come from the bone marrow, they go to the thymes gland in order to develop into what we call T-cells ( T from thymes) or in the bone marrow into B-cell (B from bone marrow), the main function to those progenitor cell to do into thymes gland ( Tcell) or in the bone marrow (B-cell)is to get rid of the self reactive cells ; the cells that are supposed to react against self antigen should be deleted . If this process fail for

one reason or another we are going to have an autoimmune phenomena. I will tell u more about this autoimmune diseases, and how they develop and all the theories and what I mean by tolerance, and how the tolerance is broken out. This is what I was talking about, you have so many different B-cells we are born with; with much different specificities, i.e. in one cell we have one type of specificity. When we are exposed to non-self, so non-self it has to find its match , if the match is there, it is going to bind, this is going to expand, this clone will develop, proliferate and immune response going to take place. If non-self doesnt find the match, no immune response going to take place, and Im considered as an immune compromised.


These are the antigen- recognition molecules and the specificity that is involved in adaptive immune response and in the innate immune response. innate immune response: we dont have many genes that are involved, thats why we dont have the specificity of the adaptive or specific immune response . Ancestral gene modern gene pattern recognition molecule

So, you can see on the surface of the macrophage a receptor, this receptor for so many antigens at the same time, this what we call it pattern recognition molecule .for example; antigen recognition molecule will recognize the lipopolysaccharides in all gram ve bacteria . While in adaptive immune response, so many genes are involved that we inherit from our parents , and those will be selected one at the type its so interesting, ones that are selected one at the type will end up on the surface of those cells for the clonal selection theory which we have talked about. Ancestral genes gene duplication modern gene specialization antigen recognition molecule. major histocompatibility complex antigen : that will give u major histocompatibility proteins, when we talk about major histocompatibility, we talk about class and class ; class :locus a , b and c ,and we have two allelic forms, that are present on every cell in our body: ones come from father and the 2nd come from mother so, if the mother and father are related to each other , for example ; a1 from father and mother has a1 as well we end up with a1, but if mother and father they are not related a1 and a2 then I will have a1 and a2 at the same time . A1 will look different than a2, so here the chance that Im going to have to be exposed to a variety of antigenic determinants will be much higher. So, these are we call specificity that comes by inheritance. again locus a ,b ,and c for class and d, r ,p and q for class and we require two; one from the father and one from the mother, so will end up with 6 minimum ; when mother and father are related to each other and have the same set of genes , and maximum 12, if the mother and father are different completely I will be more diverse. The mother gives 6 and the father gives six also, so we will have 12 if there arent any similarities (considered as maximum), if they are related, then there will be some similarities, and this will make it less than 12, i.e. may be 10, 8, and 6 as minimum The same thing in the T- cell receptors and Immunoglobulins, I will tell you what are the type of those genes that is going to make which types of proteins of immunoglobulin or the T or B cell receptors, so genes will determine specificity, if that gene is selected, that protein will appear on the surface of cell and that type of immunoglobulin is going to be excreted. The T-cell receptors on T-cells and Immunoglobulins of B-cells, all of them are called Antigen recognition molecules. There is single antigenic determinant or epitope which can be recognized by one of those T-cells, B-cells or immunoglobulin as we are


going to see. This in adaptive while in innate there is pattern recognition molecule for the whole group of bacteria, and so on. This is how self reaction could fail: if you have B-cells for example, by one of the mechanisms manage to escape the deletion in the bone marrow or the Tcells in the thymes gland and they managed as you can see here with many different specificities depends on the antigenic determinant that we have, and if we have self antigen could react here as you can see with the B-cells, and the B-cells are going to react and produce immunoglobulins and those immunoglobulin will attack our own tissue ,complement could be activated and that tissue is going to be destroyed. They think this is foe, and they are going to have autoimmune disease, this could happen, it is this unusual; it is a disease; I will tell you how this will develop and how we prevent that from taking place.


The component of our immune system

1. 2. 3. 1. 2. Very important points regarding the adaptive immune system:Specificity: I mean by that the antigenic determinants and receptors. Diversity: so many types, so many receptors, so many antigenic determinants that we have talked about, immunoglobulins and MHC antigens. Memory: second time is not like the first time. We are talking about cells specific and non-specific , Specific cells:-are T cell and B-cell. Non- specific: - we are talking about macrophages, neutrophils, eosinophils, basophils, mast cells and NK cells, each one has a deferent function. And we talked about soluble molecules like cytokines, for example for cytokines: interleukin and interferon, they are soluble mediator that the cells utilize and interact with each other, all of those cells and their function should be know all the cells I have mentioned that they play a role in our immune defense. Cell mediated immunity: - involvement of virally infected cell and tumor cell E.g. T-cytotoxic and NK cells. Humoral immune response antibody mediated cell:It is the immune response that uses immunoglobulins for defense, antibodies, B-cell and Plasma cell that are involved. And remember here the notion of antigen presenting cells ~APC~ and their function, and this is mainly for thymes dependent

antigens, the function of T-helper cells which will never accept to participate in the game unless the antigen is presented to her by APC. You should know what these APC are.
Cell meditated immunity: T cells which eliminate intracellular pathogens! Humoral response: B cells (antibodies) which eliminate extracellular pathogens.

APC: E.g. 1)

interd igitati ng cells, 2) macrophages 3) and B-cell itself has dual function.

And remember secondary immune response and primary immune response that we have talked about, and why we use what we call it booster dose; dose two and dose three , sometimes we give more than that, for example in polio we give 5 doses at 2 months ,4 months ,6 months , one in half year pre-school. The main reason why we give booster dose is to increase the number of memory cells and to have a better fit, and better functioning immunoglobulin. If we give booster doses continuously, Our immune system will figure out that this is not needed and instead of having and activation of immune response, our immune system through the signals - we will talk about that later in the regulation of immune response -will give a suppression signals to T-cells to stop doing that. We can do that if I want to suppress the immune system. do you know the hyposensitization which is used to treatment of allergies and hypersensitivities ?? what do we do in order to treat allergy if we are allergic to olive pollens ?. the idea is not to be expose to the pollens of olives , but we cant do that if the patient live in the area with a lot of pollens in the air. So, how Im going to get rid that permanently once and for all; I will be exposed to the antigen of the olives pollen continuously so, here patients body will realize that this is not needed so, start to produce mechanism will tell u more that At the end, every time he will be exposed to olive pollens, the suppression of the immune response is going to take place. This is the idea why you should not give continuously booster doses. This was studied how many booster doses I should be given in order to have ultimate immune response that is going to protect me forever.

Cells of the Immune System 1. Innate :Neutrophils 66%:They have granulocytes which have granules, and these granules have enzymes like: myloperoxidasis, I will tell you more about those and how they get activated and how they produce cytocidal, molecules. And how they kill the bacteria and phagocyte.


Eosinophils 4% :We will see where eosinophils will be produced, and which type of infections in which we see eosinophils. Parasitic type of infection and in allergies . You know the percentage of eosinophils is 4%, so if I see eosinophils go up to around 40% then I know that I could be infected with parasite, or I could have allergy. The granules that are produced by eosinophils are so important for neutralization of vaso-active amines that are produced in allergies. Macrophages:They are considered as Phagocytic cells and antigen presenting cells. and Macrophages differ from neutrophils, i. ii. They dont get expired by Act. They can phagocytose once , twice , third, in fact we see those sometimes when we have immune complexes, if I have antigen antibody reactions, those immune complexes could develop and precipitate in tissues , if this happened the macrophages come and try to phagocytose immune complexes .If they are free in serum, macrophages could phagocytose immune complexes and clear our bodies from them, but if immune complexes bind into the tissues like basement membrane of the kidney, so the macrophages come and try to phagocytose those and they couldnt, bcz they are so adherent to the basement membrane of the kidney, what the macrophages will do is to release vaso-active amines over the basement

membrane, and they cause damage to the basement membrane, we called those frustrated macrophages. And this is the damage that occurs to the basement membrane, the joints and the others; this is bcz of the phagocytes .for example ; one smoker who have chronic bronchitis why ?. bcz the carbon molecules stimulate macrophages ,these macrophages release their enzymes into the cells , they damage the cilia , and stimulate the mucus cells to produce mucus and coughing and end up chronic obstructive lung disease. Mast cells:They are involved also in hypersensitivity types of reaction. Natural killer (NK) cell:It is looks like a lymphocyte but they are large, and have larger granular than lymphocytes, and the NK cells involved in virally infected cells tumor cells as well.


2. Adaptive :T- helper cell or T cytotoxic all of them look the same, and there are plasma cells that are differentiated from B-cells but if u look at the fig. down at these type of cells and what is the outcome of their activation; if you have Bcell and T-cell, morphologically they look the same, so how we differentiate between B-cell and T-cell if they are looking the same?? Based on the antigenic marker that presents on their surfaces:

B-cell: - have immunoglobulin on their surface IgM. T-cell: - have CD4+ and CD8+ . B-cell can be activated to change into plasma cell and then immunoglobulin will develop .while T-cell if it is T-helper as you can see T-helper has CD4+ when gets activated produces cytokines, thats why it is orchestrator cell .and if you look into the surface of the T-helper, there is one type of a receptor one shape we dont see 2 shapes in one cell, this is the clonal selection theory. And the T- cytotoxic cells has the same thing they have CD8+ as surface marker and I will stop here.