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What is the study of Immunology, what does that mean? Immunology is the study of the physiological mechanisms that
humans and animals use to defend their bodies from invasion by other organisms. Bottom line: immunology is how we fight infections
to keep healthy. What is an infection?
Pause for a minute and really think about what you think this is instead of just reading on to find the answer.
An Infection is a disease caused by microorganisms that have the advantage of reproducing and/or evolving faster than their
hosts. This makes sense because your body is fight microorganisms all the time without you feeling any effect: the only time you do
notice is when you are sick, which basically means that the bug managed to beat the system and stay alive inside of you. This leads
us to the question: What is the purpose of the immune system? There are three general purposes of the immune system:
So, youre body has now recognized that something should not be there, great. What next? Say hello, ask about its trip?
No, do something about it!
You want your body to immediately recognize it and start attacking it
In doing so it prevents it from spreading, which will make the infection much harder to fight, not to mention spread the
damage of fighting the infection
Fighting an infection is like fighting a war, yet you kill the bad guy and you feel better, but not without paying a price
Okay, youve successfully recognized and killed your host, what is the next step? Thats right, clean up.
Youve got all these dead bacteria and cells hanging around. Do you really want them floating though your body?
No, they need to be cleaned up before they block something up.
They tend to accommodate to hostits not in their best interest to kill the host because then they have nothing to live off
from. Microorganisms are just like you and me, all they really want to do is live, grow, and replicate. I think Jackson Browne
put it best in The Pretender
Im going to rent myself a house
In the shade of the freeway
Im going to pack my lunch in the morning
And go to work each day
And when the evening rolls around
Ill go on home and lay my body down
And when the morning light comes streaming in
Ill get up and do it again
Amen
Say it again
Amen
There are four main pathogens: bacteria, fungi, viruses, and parasites -- all of these can cause an infection
Your book uses this term a lot, pathogen, when it discusses eliciting an immune response
However your immune system does respond to a WHOLE pathogen, it responds to a piece
of the pathogen, that piece is called an antigen.
An Antigen is a substance that causes a specific immune response and reacts with the products of that response
This is a piece of the pathogen that the immune system recognizes as foreign and what actually causes an immune response
Another definition is a complex molecule of high molecular weight that the immune system recognizes as foreign
Antigenic and immunogenic are interchangeable terms that describe the effectiveness of initiating the adaptive immunity
Now we get to an Epitope, this is the piece of the antigen that the immune system is actually going to bind to during an immune
response
This is the physical area where the antibodies bind and what the T cells recognize
So we have three levels here with increasing specificity
The pathogen enters the body, it is a foreign object immediately recognized by the immune system.
On the pathogen are many antigens, pieces of the pathogen: there can be many many different antigens on one pathogen
and each one can elicit a different response, but they all initiate an immune response
On each antigen are epitopes, the specific pieces that interact with the pieces of the immune system
Most of the time we will use the term antigen as that is the level that is initiating the immune response
While all antigens will initiate and immune response, all antigens are not created equal
Lets look at what makes a good antigen
Chemical Complexity
Here we mean variation in the chemical components; how many different building blocks
are we
looking at?
Polysaccharides contain only a few building blocks, however in proteins there are over twenty
that can be rearranged
Are there repeating subunits of the same thing such as in sugars? This will not be highly immunogenic
Large
Sorry, but size does matter when it comes to immunogenicity!
High molecular weight is what we are looking for here, usually >6 kilodaltons, lots of different pieces as well,
such as amino acids
They are:
o Extremely complex
o Very immunogenetic, especially if foreign
o Considered multi-determinant, meaning they can have more than one epitope
Includes enzymes and antibodies
*These are the best of the best as far as antigens go*
Polysaccharides:
Polysaccharides are macromolecules built from repeating monosaccharides. Lets see how they measure up
First they are very large, thats a plus
Second, they are very foreign, good, still what we are looking for; this is a very promising candidate
But, they arent very complex and are only considered immunogenic when they are attached to a protein
complex, bummer
*They have some things going for them but just dont measure up to proteins*
Nucleic Acids:
Nucleic acids are, of course, DNA and RNA
These are not typically immunogenic, except in autoimmune disorders
Can anyone think of why that might be? Lets think about what they are made of and where they are found
They are made sugars and bases (only four), typically they are found in a nucleus, even when they do
manage to make it out they are quickly broken down into small pieces
*Bad, but not the worst*
Lipids:
Lipids are organic molecules; fats and triglycerides
They are
o Components of living self cells, strike one
o Composed of repeating units, strike three
o Not wildly complex, strike three, youre out!
Not immunogenic unless attached to proteins
*The bottom of the barrel*
Now that we have seen the general purpose of the immune system, lets look more at the specifics: how are we able to wage a
successful war against microorganisms?
There are two main parts of the immune system: the innate and adaptive
The innate immune system is your first line of defense; they are your front-line troops. The innate immune system is
based on inherited genes.
They recognize and kill anything foreign, no matter what it is, no questions asked
It includes cells and proteins, including the complement pathway (also known as the complement cascade; I know,
just what you wanted to hear after being tortured with the coagulation cascade!)
The adaptive immune is youre supporting troops; they are your special ops. These include B & T cells. The adaptive
immune response adapts to the infecting organisms and is based on genes that youve rearrange.
They recognize and kill pathogens, but not just any pathogens; they look for very specific targets
It takes time to call them up and make them active
o They are very specific and very effective, but also take time and energy to develop
These are your big guns; you only use them when you need to
In the end they are what develop the immunological memory, which helps prevent you from getting sick from the
same infection over and over
Before we break down our discussion into further detail about the innate immune system, lets spend a few minutes discussing how the
immune response is initiated.
Innate Immunity
As we said before the innate immunity is your bodys first defense against pathogens, were looking at the whole organism
here because it needs to get into the body and do some damage before we get to the specific immune response
Remember we said this was the non-specific arm of the immune system; doesnt matter what it is, as long as its foreign it will be
attacked therefore it is not going to develop any memory
The effectiveness of the innate immune system is dependent
Think about how often you get sick when you are under an enormous amount of stress? I know for me that is a big factor.
Or how about when you are run-down physically.
o When you give your body too many other things that it needs to focus on its going to spend less time
protecting the borders so to speak, its going to be much easier for pathogens to gain entry when the
troops are spread thin
What are the parts included in the innate immunity? Compared with the adaptive it is quite diverse
If you are a sports fan you may have hear the statement the best offence is a good defense, especially if you are a New
Jersey Devils fan. A huge part of the immune response is preventing the need to ever use it.
The innate immune system has a number of external
Cells are another big part, there are many cells involved in the immune response, much more than just the B and
T cells of the adaptive immunity
These are a group of proteins that function sequentially to form activated enzymes that split and build other
proteins that eventually leads to coating of the pathogen with protein (this helps the cells of the immune system
to recognize them) or it eventually builds a complex that will punch holes in the membrane of the pathogen,
killing it. We wont do more than mention it now; we will look at this system in more detail when we look at
antibody function
The process of inflammation is a big part of the innate immunity. This is your bodys defense against injury
and spread of infection; this is where the body tries to contain the initial invasion by a pathogen once it manages to
get past the physical defense
So lets start out with the Physical Defense of the Innate Immune System
Physical Defense
Intact Skin
Intact skin is your very first defense against pathogens. You will hear about this a lot in hospitals and medical offices
where hand washing occurs more frequently. I know, at least at the hospital I work in, there is a big push to use the
alcohol rub because there is less drying of the skin, therefore less chance for the skin to crack and break the physical
barrier of the skin where pathogens can enter.
The outermost layer of your skin is made of dead stratified squamous, keratinized cells, which means it
becomes thin and tough
Why does it inhibit microbial growth? As you will learn in microbiology it makes a very inhospitable
environment for microbial growth
o Dry, salty, oily, and fatty acids are not characteristics bacteria are looking for in a good home
o Exfoliation is the slothing or peeling off of skin cells; you are constantly loosing these guys and bacterial
cannot colonize if the foundation of the colony is constantly falling off
Some bacteria can survive in that environment, and, it may sound odd that we are preventing bacterial entry with
more bacteria but its true. The normal flora hangout and live on our skin without bothering us.
In return for us not bothering them, they crowd out any other bacteria that might come along and decide
they would like colonize there. The normal flora will out compete the other bacteria for growing room and
nutrients thus preventing bacterial entry
There are also a number of antibacterial substances that are produced by the epithelia
Sebum, which is produced by the sebaceous gland, is composed of fatty acids and lactic acid
Defensins are peptides that interfere with the membrane integrity of invading organisms (more about these
later)
Lysozyme, found in tears and saliva, breaks down the cell walls of bacteria
The skin gives way to mucosal tissues that are specialized for communication with their environment. These are not the
impenetrable barriers that the skin was, so they are a little more vulnerable to microbial infection
The mucous forms a thick fluid layer that contains glycoproteins, proteoglycans, and enzymes that protect epithelial
cells from damage and prevent infection
o
Mouth:
Stomach:
contains normal flora (also contains nasty bacteria that feed on the food stuck in your teeth and
cause cavities), saliva (and tears) contain lysozyme which is an antibacterial substance), also your saliva works
to flush whatever organisms that may have gotten in there into the stomach
contains strong hydrochloric acid; that stuff will eat through metal, need I say more?
to break down your food but whatever else may have come down with it
o
Large intestine:
Respiratory tract: contains ciliated epithelial cells that provide a defense mechanism by forcing
contain a protective mucous layer as well as a plethora of normal flora that help digest
your food, and produce gas; antibiotics can disrupt the protective flora and cause problems
particles upward, where they are swallowed or eliminated by coughing, called mucociliary escalator.
What a lovely compromise: you either cough out mucousy bacteria or you can swallow it where it
will upset your stomach!
o Urethral tract: urinating frequently has its benefits
The flow of urine through the urethra helps to wash
away bacteria that may latch on
This is a great mechanism for men, who
have long urethras, not so great for
women, whos urethra is significantly
shorter.
Even with flushing we still suffer
more frequent urinary tract
infections due to our short urethra
distance!
Inflammation
We will go more in-depth in this topic in chapter 3, now well just do a brief over view
Innate immune system has two main functions:
Recognizing pathogens: soluble proteins & cell surface receptors bind to pathogen and serum proteins are
altered
Then, the recruitment of effector mechanisms that kill the pathogen: provided by effector cells that
engulf bacteria, kill virus-infected cells, or attack parasites and complement (serum proteins that help effector cells by marking
targets)
The cells and proteins in damaged tissues send out cytokines (soluble proteins that interact with other cells to
trigger the immune response)
o
Hallmarks of Inflammation
The five hallmarks of inflammation are: redness, swelling, heat, pain, and loss of function
These symptoms of inflammation are not due to the
infection itself (the pathogen), but rather due to the
immune system responding to it.
So, heres how it works:
Cytokines change the properties of endothelial cells, making them more adhesive, allowing leukocytes to attach and
cell line and are derived from pluripotent hematopoietic stem cells.
They are derived mostly from one of the three lineages, the myeloid lineage. The lymphoid lineage gives rise to the adaptive
immune cells and the erythroid lineage gives rise to the red blood cells. Again, these cells are non-specific and have no
memory.
There are three main groups from the myeloid lineage:
Granulocytes: which include neutrophils, eosinophils, and basophils
A group containing monocytes, macrophages and dendritic cells
Mast cells which are in a category all their own
And one group from the lymphocyte lineage (still non-specific):
And natural killer cells
Well look at the granulocytes first.
Neutrophils
damaged tissue.
They contain a variety of surface receptors that are used in host defense,
well talk more about in chapter 3
Eosinophils
Eosinophils are found in most tissues, usually at the same sites as Mast cells.
They are the bodys main defense against parasitic infections,
especially helminths.
They recognize parasites via Fc of IgE (an antibody, more about that later too)
In response, they release major basic protein and eosinophil cationic
protein, both of which are toxic to helminths
This is important because helminths are resistant to the killing mechanisms of
phagocytes I.e. lysosomal enzymes and reactive oxygen intermediates.
Pretty gross, huh.
Basophils
degranulation.
Histamine makes small vessels leaky allowing immune cells to enter tissue
It does bind to the Fc region of IgE antibodies and crosslinks, causing degranulation
that releases histamine and other inflammatory mediators.
When released in excess, can cause anaphylaxis
Now well turn to the non-granulocytic cells.
Monocytes
Monocytes are much larger than granulocytesTheyre main function is to
Antigen-presenting cells are cells that endocytose antigens, break them down,
and display the pieces on their surface via major histocompatibility complexes (MHC)
They consist of macrophages and dendritic cells.
Their function is to chew up the antigens and display them on their cell-surface such
that cells of the adaptive immunity will recognize them.
They play a key role in the activation of the adaptive immune response
Macrophages
Macrophages are antigen-presenting cells
They are the mature form of the monocytes, found in almost every tissue, and
they are sedentary, unlike their monocytic precursor.
Macrophages are the scavenger cells of the immune system:
they phagocytose dead cells, cellular debris, as well as
microorganisms.
Think couch potato
Dendritic cells
Generally, they are the first cell type to sense an invading organism.
o They produce cytokines that are involved in the inflammatory response. Dendritic cells are the most
Mast cells
They act as cellular messengers that are sent to call up the adaptive immune
response, when needed
They have the ability to migrate from tissues with intact pathogens, take them to the secondary
lymphoid organs and activate the adaptive immune response
and in mucosal
epithelium.
They function mainly through histamine and heparin release during degranulation at
sites of infection that contribute to inflammation.
Complement activation of mast cells leads to production of anaphylatoxin, which induces degranulation.
Finally, we see the lymphoid cell.
Natural killer cells are the only innate immune cell type that is NOT of the myeloid lineage, they
are part of the lymphoid
lineage.
Typically they are found in circulation and in the secondary lymphoid tissue.
NK cells are important in the defense against viral infections and certain tumor
cells.
They prevent the spread of infection by killing virus-infected cells and secrete cytokines
Once a pathogen has breached the physical barrier and the innate immune cells start to respond, this leads
to inflammation.
So what happens if we cant clear the infection with the innate response? We move to the special forces!
We said previously that the adaptive immune response is the second arm of the immune system that is brought in when the innate
defense against one pathogen; this response is so specific that it would provide
very little resistance against another pathogen, like the innate immune system.
o There are specific receptor molecules that are basically the same type, which we will talk about, the subpopulation
of cells provide the specificity.
Once the specific subpopulation of receptor is recognizes the pathogen, that cell line is selected and clonally
waning, will develop memory cells that can immediately respond the next time the pathogen gets into the body
These cells are derived from the lymphoid lineage (like NK cells) and are sometimes referred to as small lymphocytes
Much of what we will talk about in the first half of the course is the specific of the adaptive immunity: how the cells develop and mature,
the source of the specificity of the molecules, how each piece fights infection, and how they work together to fight infections. Therefore
we will only briefly mention them here.
B lymphocytes (B cells)
B cells have immunolgobulins on their surface that function as a receptor. Each cell makes an immunoglobulin that
is specific for one epitope.
Once B cells are activated, they can mature into Plasma cells, which produce antibodies
o Antibodies are a soluble, free form of the immunoglobulins that are stuck in the surface of normal B cells
o Antibodies are considered the effector function of B cells, which basically means that antibodies are what B
cells do!
T lymphocytes (T cells)
T cells have T-cell receptors on their surface that function as a receptor. Each cell makes a T-cell receptor that is
specific for one epitope
There are a few different kinds of T cells, the two main categories are:
o Cytotoxic T cells
The effector function of these cells is to kill virally-infected cells
o Helper T cell
Helper T cells secrete cytokines which trigger many effector functions
We will talk about each of these extensively throughout the semester. First we need to look at where the development and function of
the adaptive immune response takes place; these are called the lymphoid organs or tissues.
Lymphoid Tissue
What is lymphoid tissue?
It is specialized tissues (or organs) where lymphocytes congregate, remember that lymphocytes are B and T cells
The lymphoid tissues are broken down into two different types: Primary and Secondary Lymphoid Tissues
Primary Lymphoid Tissue is where lymphocytes develop and mature to a point where they can respond to a pathogen, no
pathogen contact occurs here.
o includes the Bone Marrow and thymus
Secondary Lymphoid Tissue is where mature lymphocytes become stimulated and
respond to pathogen; the first encounters with antigen occurs here
o includes all other lymphoid tissue
We will look at the function of all of the lymphoid tissues briefly, starting with the primary
lymphoid tissue.
Bone Marrow
Bone marrow is located in, you guessed it, the bone, specifically in the hollow of your bone.
It consists of red marrow (which contains myeloid tissue from which your rbc's, platelets, and wbcs arise from)
and yellow marrow (which consists mainly of fat and is where some wbcs develop)
This is the site for B cell development, maturation, and differentiation (B cell and Bone
Marrow, get it?)
It is also known as the Bursa Equivalent, now why the heck would they call it the Bursa Equivalent?
The Bursa of Fabricius is an organ found near the cloacae of birds and is the site of maturation of B cells in birds
(the fist animal in which this was discovered.)
o The Bone Marrow is apparently the site of B cell maturation in man therefore, Bursa Equivalent!
o Onto the Secondary Lymphoid Tissue!
Lymph nodes lie at the junctions of lymphatic vessels and are strategically
Lymphatic vessels (also known as the lymphatics) is a network of vessels that originates in the
connective tissue and collects the plasma that continually leaks out and forms the extracellular fluid
The lymph is the mixture of fluid and cells that flows through the lymphatics
Lymph flows in one basic direction through your body, we ensure this by placing valves in the lymph nodes that only allow
the fluid to move one way.
Why do this? Well, for starters we dont pump our lymph like we do our blood, second we want to keep the
pathogens that are pulled in from our tissues out of our blood stream
The lymph nodes basically receive fluids from infected sites
As the lymph passes through the node, macrophages filter out pathogens and other materials.
This prevents pathogens from enter the blood, provides a depository for
pathogens to activate lymphocytes, and provides a residence for dendritic cells to come and activate
T cells.
Filled with B and T lymphocytes
So it is basically jam packed with cells!
Structure
The lymph node is an encapsulated structure.
The lymph is brought in through the afferent lymphatic, passes through the inner layers,
and leaves via the efferent lymphatic.
The inner structure consists of a cortex,
interfollicular region
The Cortex contains the primary and secondary follicles, which are B-cell concentrated
areas.
o
o
A primary follicle is a small lymphoid follicle where the cells are quiescent.
A secondary follicle is a lymphoid follicle whose B cells have been activated and are proliferating
creating a germinal center (site where B cells undergo differentiation)
cells
regions are found in between the different follicles in the cortex and contain
T cells as well as antigen presenting cells (mostly dendritic cells)
The Medulla is the central portion of the node that consists of cord-like masses of lymphocytes,
plasma cells, and macrophages arranged in reticular fibers (these provide support as well
as a surface for the cells to adhere to). Next up, the Spleen
Spleen
The Spleen is located below the diaphragm on the left side of the abdomen behind the stomach.
10% of the population also has one or more accessory spleen, a small nodule of splenic tissue found near the
spleen that can be found attached to the spleen or independent of it
Blood flows through and is filtered by the spleen through two, almost
separate, compartments.
The connective tissue that surrounds the spleen divides it into two incomplete
components: the white and the red
pulp
White pulp
The White pulp functions to fight infections.
It contains lymphoid tissue that responds specifically to
The Periarterial
primarily B
o
cells.
The marginal zone contains B and T cells, as well as dendritic cells and
macrophages to aid inT cell presentation
Red pulp
The Red pulp functions in filtration.
It removes unwanted materials from the blood, especially
The sinusoids are channels filled with blood where the filtration of red blood cells and the
recycling of the freed hemoglobin takes place.
The splenic
cords, also known as Cord of Billroth, consist of fibrils and connective tissue
that contain a large population of macrophages.
The main difference is that the components are not encapsulated (as are both the lymph nodes and
spleen), Which means that it contains T cell, B cells, plasma cells macrophages, etc, everything you need to wage an
adaptive assault on an infection.
Some of the more widely known lymphoid tissues under the category of MALT are:
Peyers Patches, a small region in the lower portion of the small intestine where follicles are bundled
together. Because it is exposed to the external environment, it functions in immune surveillance of the intestinal
lumen. As discussed earlier, MALT is coated with M cells, which function to sample to antigen environment and
transport it directly to APC.
Peyers Patches is a part of GALT (gut-associated lymphoid tissue) a group within MALT.
The appendix may be a surprise to some as most believe it has no real function. However the large number of
lymphoid tissue found in the appendix lead it to be grouped within the immune system. Some researchers argue that
it functions to help train the fetal immune system by exposing it to antigens to induce antibody production. Others
have argued that it functions as a reservoir of good bacteria to help re-colonize the gut after illness that flushes
them all out, especially in areas with poor sanitation.
In addition to these, there is also
BALT (bronchus-associated lymphoid tissue)
NALT (nose-associated lymphoid tissue)
LALT (larynx-associated lymphoid tissue)
SALT (skin-associated lymphoid tissue)
VALT (vascular-associated lymphoid tissue. A newly recognized entity that exists inside arteries; its role in the
immune response is unknown. )
CALT (conjunctiva-associated lymphoid tissue in the human eye)
Finally, the last stop on our trip through the lymphoid tissue is the Cutaneous Immune system.
epidermis.
o They take up antigen and function as APC to the T cells present in the epidermis
T cells and macrophages are also present performing the functions that we have beat to death in this
discussion
In the dermis
Helper T cells, Cytotoxic T cells, and macrophages function in the dermis.
Phew! That concludes our journey through the wonderful world of lymphoid tissue. I know weve been at this for a while and you are
probably wondering if this lecture is ever going to end but, I just want to take a quick look at one more topic.
Now that we have a good idea of the parts of the immune system and their function, lets take just a minute to see how the immune
system as a whole is developed.