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Introduction

Noor, Dima, Basma

Ziad Elnasser

Sunday, 3/7/2011

30

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

Dear colleagues

Here we go again! A new beginning with a new spirit =DInshaAllah 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 takingaLOTof 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 thisSummer- 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 toprotect 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: 1 st 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 ofLouis Pasteurand 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 thatanyone 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'tget 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, physicalbarriers, and mucous membranes, and the 2

ndline 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 hasinvaded (it acts the 1

sttime as the 2

ndtime as the 3

rdtime).

2. Adaptive Immunity: this is a specific immune response and it hasmemory. It recognizes the microorganism the 1

sttime and remembers it

when it invades the 2nd

time. It is characterized by the following:

Self vs. Non-selfOne 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 non-

self 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 moleculesThe 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 getexposed 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 selectionSo, 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 cellsThe 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 innateimmunity 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 bodysdefenses 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 systemstarts 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 intobabies, 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 coliis 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 2

nd

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 acertain 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 isNO! 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 upgradedvaccines; 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 beenmatched 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. Icould 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 T-

cytotoxic 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 T-cytotoxic cells with one type of a receptor on the surface, or it could be non-

specific 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

VaccinationsRemember: 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 transplantationsWe 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 notgoing 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 oftransplantation.

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 systemWe 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 complicatedbiochemical 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 allergiesHow 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 theirlives! :")

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! ~