Fund 1: 10:00-11:00 Scribe: Kosha Shah

Fund 1: 10:00-11:00 Scribe: Kosha Shah

Thursday September 24, 2009 Proof: Myra Dennis

Dr. Barnum Basic Concepts of Immunology Page 1 of 6

I.  Introduction [S1]: [He talked about immunology in relation to dentistry and optometry with a couple slides that we don’t have]

a.  If you have questions, you can get me by email.

b.  I strongly ask you to ask questions if you get lost because immunology is a comprehensive topic and you will have a bunch of lectures over the next few weeks that will slowly build up.

c.  I hear that you want to be dentists and optometrists, so what do you care about immunology?

d.  But the fact of the matter is that most of the time when patients come to see you is because they have some sort of inflammatory problem that the immune system is contributing to. Whether it’s in their mouth.

e.  On the left side we have a nice, healthy tooth and gums and on the right (no problems here). But then you have periodontal disease (on the left) where you start having reduced bone, inflammation, pulling away of gums from the tooth, infection-all of that kind of stuff. That painful red swelling is due in part to the immune system trying to fight off an infection and damaging your own tissues.

f.  The same is important if you are interested in optometry. Beautiful fundus right here. No problems, everything looks good. Then you have someone who has toxoplasmosis infection-they have all kinds of scarring and additional vessels trying to grow here. All these problems. Or somebody that has a really nasty infection in the eye. It is the host pathogen interactions with these infections that are causing this horrific inflammation and all this kind of white puffy material here. These are immune cells that have crawled out of vessels into the site of infection to try to clear that infection.

II.  Title [S2] Immunology is important to you as a future clinician because:

a.  Immunology is important to you because most of the time when people come to see you they have an infection, they have trauma. Maybe they’ve been poked in the eye. A tooth has come loose because they were playing football in the backyard and they got hit. Or they’ve got an infection - cavity is an infection. Or an infection that was going around school or something like that. You are always going to see that kind of stuff.

b.  You have to understand a little bit about immunology because at least subset of your patients that you will deal with could be going through chemotherapy so their immune system is compromised because the chemotherapeutic agents are killing off their white cells so they’re susceptible to an infection. Maybe they are undergoing radiation therapy. Maybe they have AIDS-they’re immune system is compromised. Maybe they have some sort of congenital immune deficient. They don’ have T cells or B cells, so how you treat that patient is dependent on what the condition is. You don’t want to expose them to the greater risk of infection or greater problem.

c.  In addition, you have to protect your own self and your staff from infections. You don’t want to be known as Dr. Flu for someone who spreads disease around and that kind of thing because you don’t take care of things. And you don’t know the mechanisms because host and pathogen interactions that lead to disease or can prevent disease.

d.  Immunology is an old science. It comes from a Latin word called immunitas, which originally applied to politicians, which means they were immune to prosecution. But it didn’t take very long before you had a plague running through town, and some people were immune, meaning that everybody else was getting sick but that particular person or persons were not getting sick. It is because they have been exposed to the disease before, survived that infection and now they have an immune response to fight the immune response to fight that infection off very easily and never get sick.

e.  It quickly became associated with infectious disease, and the ability to fight off that infection. In fact, at one point, there was this suggestion that you might even be able to be immune to everything. Once you were immune to one type of bacteria or one type of virus. Of course this clearly didn’t happen, and you will understand as we go along.

f.  Maybe we should start with the basic definition of immunology and then we will move into the basic concepts of the system.

g.  Immunology is the study of the cellular and molecular events that occur where an organism encounters foreign pathogen (written on board)

h.  Do immune responses always happen only to foreign pathogens? No. Sometimes you have an autoimmune response where your system s misdirected to your own tissues. Examples: multiple sclerosis and lupus... The immune system can be misdirected to damage your own tissues, and in some cases, in life threatening ways.

III.  Title [S3] Immune System Components

a.  The immune system is made up of a variety of different organs. The thymus is where your t cells originate, mature and are released into the periphery so they can mediate their function and immune responses.

b.  Bone marrow, which is a critical site for the immune system, is where your B cells come from and all your phagocytic, neutrophils, white blood cells generate.

c.  There are secondary organs in the immune system: the spleen and the lymph nodes. The spleen sits on the left side a little bit behind the liver collection of B cells, T cells, that mediate responses primarily to pathogens that are found in the blood

d.  The lymph nodes, scattered throughout the body, are a collection of T cells, B cells. A type of cell called an antigen-presenting cell (APC) interacts with T cells to help educate them to the fact that there is a foreign pathogen present.

e.  You also have stem cells and their precursors from which T and B cells originate, and all the macrophages too.

f.  There are also macrophages and neutrophils. These are phagocytic cells that gobble up invading pathogens and kill them.

g.  Dendritic cells are also part of the family of antigen presenting cells, and their main function is to present antigens derived from invading pathogens to T cells so they can mount an adaptive immune response.

h.  Mast cells are involved in type 1 hypersensitivity allergic responses. Basophils, eosinophils-lots of different cell types, are present.

i.  You also have a lot of different types of proteins. These are molecules that are largely in solution, also part of what’s called the humoral/soluble system. These are soluble proteins that are found in the blood and basically in almost every tissue of the body-tears, urine, and saliva. You have all these soluble proteins to protect you against invading pathogens, particular antibody.

j.  You have a number of molecules called cytokines. These are a large group of particles that control every aspect of the immune response, from development to individual cell types, to initiation of immune responses, direction of how immune responses go, and then control and damping down of immune responses. You can’t let an immune response go uncheck. There is a tremendous amount of proliferation of T and B cells during an infection. If you don’t check that proliferation, you will become a walking bag of T cells and B cells, so you have to tamp that process back down, and cytokines help do that

k.  We will talk about a system of proteins called the complement system present in all your tissues and blood. It is very important for killing invading pathogens, viruses, bacteria, and parasites.

l.  A number of proteins that are called acute phase protein. If you have a really bad infection or trauma, such as if you break your leg or something like that, your body develops what is known as the acute phase response characterized by a variety of different cytokines and number of molecules whose function it is to eliminate invading pathogens, repair the damage, and return you back to homeostasis

m.  There are lots of enzymes that are involved in helping to chew up invading pathogens and their components such as carbohydrates, proteins, RNA, DNA, all of that kind of stuff. Enzymes are also involved in generating reactive oxygen species that are toxic to invading pathogens.

n.  Your body produces a lot of its own natural antibiotics-. These are molecules called defensins. They’re found all over the place-in your skin, guts. Their function is either bacteriostatic, to prevent bacteria from continuing to grow, or bacteriocidal. These are small molecules that are 20-20 amino acids that somehow insert into the lipid bilayer and screw up invading pathogens.

IV.  Title [S4] Innate versus Adaptive Immunity

a.  The immune system can broadly be broken down into what is called the innate immune system and the adaptive immune system. Even though we kind of consider these two aspects of the immune system as separate parts, they absolutely work together all the time.

b.  If you are missing a component by some genetic deficiency in the innate immune system, you will have lots of problems and infections and be susceptible to lots of diseases. Same if you are missing a component in the adaptive immune response. You can’t completely compensate for a deficit in the innate immune system by the adaptive immune system. They work best together.

c.  There are fundamental differences between the two systems.

d.  Response time: Innate immune system is present almost all the time and works immediately when you get an infection. Certainly within the order of minutes to hours, you will have that innate immune system trying to eliminate that invading pathogen. If it can, it will get rid of that pathogen, and you might not mount an adaptive immune response. Adaptive immune response takes days before it works. It is usually about a week or so before you develop decent titers of antibodies that can be detected in the blood to the invading pathogen. That response occurs faster the next time you encounter that pathogen. One is present all the time and works almost immediately and the other one takes a little time to develop.

e.  Specificity: Innate immune response is specific and very good at discriminating between the host and the invading pathogen. The innate immune system is very specific and it has a small set of receptors that allows it to recognize a large number of pathogens based on certain structural features. Lots of bacteria have things like peptidoglycan or LPS, or viruses have double stranded or single stranded RNA and DNA. Those are structural features that they can’t change without altering their ability to survive and replicate. The innate immune system uses a handful of receptors that recognize these features and allow it to recognize a lot of pathogens very easily. The adaptive immune response, in contrast to that, uses highly specific receptors that recognize only very small bits and pieces of an invading pathogen. That’s what allows T and B cells to distinguish between 90 different serotypes of Streptococcus because it’s just recognizing tiny bits and pieces. You have lots and lots of receptors that are recognizing small components on invading pathogens.

f.  Diversity- innate: These receptors are germ-line encoded, so you just have a few receptors to handle lots of different pathogens

i.  adaptive: it does something that no other part of your biology does. It does DNA gene rearrangement. This DNA gene rearrangement that the adaptive immune response uses is to generate these millions of different T cells and B cells, which are very specific for one bacteria, virus, or pathogen from one sort to another. The adaptive immune response generates lots of receptors for gene rearrangement. With this kind of rearrangement, you have the possibility that you might make a rearrangement that could be problematic because now you make an antibody to your own tissues. There are mechanisms that try to suppress that, so it doesn’t happen all the time. Even though you generate lots of receptors, antibodies, and T-cell receptors to release pathogens, there is a down side to that as well.

g.  Memory: Innate: has no memory. The next time it encounters the same bacteria, it handles it in the same fashion it did the first time-no faster, no more efficiently, no better; same as before, no memory

i.  Adaptive; It much better equipped the 2nd time its encountered this pathogen. Part of the reason for that is that the first time it encounters the pathogen, it takes a week or so to make decent antibodies, you have to get the right B cells and T cells. You have to activate the cells, They have to proliferate the antibodies. All of that takes a little bit of time. You only have a few number of B cells and T cells at any given time that are specific for an invading pathogen (maybe 5 or 10). But once you encounter that pathogen, those cells proliferate. Now you maybe have 5000 of those cells and that’s your memory. Those are the cells that have seated in your bone marrow and are waiting for the next time around for the invading pathogen. So instead of taking a week to find those cells, it occurs much faster. They are primed and ready to go, and you can make lots of antibodies. They will proliferate again and you will even have more of them.

h.  Discrimination: It is a very important point because you don’t want the immune system to attack you. You only want it to attack the invading pathogens; Innate immune system: The discrimination is basically perfect because you don’t have LPS or peptidoglycan in your cells, or all these different components that the innate immune system recognizes as foreign in your own tissues. The innate immune system won’t recognize you at all. Does that mean the innate system can’t cause problems for you? No. If you have an autoimmune disease and the antibodies are directed to your own tissues, part of the innate system called the complement system can be activated and damage your own system in that response. But in terms of recognition, it doesn’t see you. It sees the invading pathogens. The adaptive immune system: Is pretty good at that, but you do have the possibility of developing autoimmune responses. In that setting, you can have damage to your own tissues. But by large, it is specific for the invading pathogens, and you won’t have too much trouble with that all the time.