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Why The Immune System Is the Best Protection Against Infections

If you want to understand how vaccination works, you have to start with the immune system.

You will find that the immune system is a very impressive and very potent weapon against all types of microbes that cause infections.

The role of vaccination is just to help the immune system react faster.

In this chapter we’re going to dive into the different layers of the immune system and see how they relate to each other.

You will learn in this chapter:

  • How the 3 lines of defense of the immune system complement each other
  • Why the secondary immune response is much more effective than the primary one
  • Why immunity lasts a long time
  • What is the link between vaccination and immunity (conclusion)

Dogs and cats are mammals, as we, and many other species, are.

In normal circumstances, the body of mammals harbors many bacteria in its peripheral regions: the skin, or the epithelial cells of the gut, the vagina, and the respiratory system. These microorganisms live, feed and replicate there without causing any harm to their host.

This is natural and healthy.

Moreover, some of them are essential to their host’s life because they help regulate vital functions such as digestion. It’s now accepted that there are more bacteria in(on) the human body than body cells!!

In our environment there are also very many microorganisms surrounding us that would love developing within our body. The problem arises when they are harmful microbes and they succeed in crossing our natural defenses. They may be bacteria, viruses, worms or protozoans. They are called pathogens.

The body defends itself against pathogens in 3 different ways:

  • First layer of defense: the skin and epithelia are barriers that very few microorganisms can cross. This is especially true for the skin which is almost unbreakable unless there is an open wound, an insect bite, or a penetration by a worm. The epithelia are very effective too. But very active viruses or bacteria can destroy epithelial cells and make their way into the organism.
  • Second layer of defense: the innate immune system consists of specialized white cells: dendritic cells, macrophages, killer cells… that are naturally able to differentiate foreign cells from the body cells and neutralize them.
  • Third layer of defense: the adaptive immune system is very potent. Its only weakness is that it needs a few weeks to “learn” about the pathogen. Once it “knows”, it is insanely effective. It is responsible for the immunization process.

The role of vaccination is to help the adaptive immune system “learn” faster.

Now we're going to see what “learn” actually means.

the 3 lines of defense of the immune system  
1

The first line of defense: the epithelia and the skin


There is no way a pathogen can enter the body other than through epithelia i.e. the skin or different types of mucous membranes.

The skin is a thick structure. Usually no microorganisms should penetrate this way.

It’s pretty safe. But wounds or insect bites can cause a breach in this wall. Here, pathogens can find their way towards the blood flow.

The other types of epithelium are the mucous membranes. They are present in various parts of the body: intestines, the vagina, the stomach, the mouth cavity, the nose, the eyes…

Because they are thinner than the skin, mucosous membranes are more vulnerable to infection but their defenses are effective nonetheless.

As for the skin, the junction between the cells is quite tight and makes it impossible to breach without causing damage to them. The only solution for micro-organisms is to adhere to the surface and start destroying epithelial cells.

But epithelial cells can protect themselves.

First they are all covered with a thick layer of mucus. It prevents the attachment of pathogens to the epithelium. In some organs, such as lungs or intestines, the mucous membranes are also fitted with cilia that move the mucus layer, thus rendering bacterial attachment even more difficult (see animated image below).

mucosa-and-cilia-help-the-organism-protect-against-infection  

In addition, the mucus is loaded with many antibiotic chemical substances (enzymes, fatty acids) or peptides (defensins, cryptidins) that destroy many pathogens.

In the intestines the natural bacteria population has also a protective effect. It competes with pathogens for the nutritive substances they all need and some of them also have antibiotic properties.

Sometimes, because the host's body is weak, too old or very young – or because the pathogen is quite virulent – the infection can’t be avoided and germs can cross the mucous membrane and enter in the blood flow.

This is time for the 2 next mechanisms of defense to come into play.

 
2

The second line of defense: the innate immune system


Now that some pathogens finally entered the body they have to face internal defense mechanisms.

The innate immune system has the inborn ability to recognize foreign cells or substances and to destroy them.

It is made up of White Blood Cells (WBCs) also called leukocytes. They are produced in the bone marrow.

Innate Immune System's White Cells

Among them, macrophages lead the defense against the infection.

Macrophages recognize cells that are obviously not part of the host body. They have to distinguish between the Self (=body cells) and Non-Self (=foreign intruders).

If macrophages were not able to sort the wheat from the chaff, the insiders vs the outsiders, they would destroy body cells (this kind of malfunction does exist in reality and cause autoimmune diseases that are a starting point for some chronic diseases such as diabetes, heart and renal failure, cancers and many others).

Macrophages recognize the general characteristics of cells or molecules they meet and decide whether it is enemy or ally. Some patterns make a foreign cell a suspect:

  • If the cell is a prokaryote. Prokaryotic cells do not have a membrane protecting their nucleus. Mammals cells are eukaryote: they do have a membrane
  • If the cell has a flagellum. Flagella help cells move in a liquid. No body cell should have one
  • If there are some molecules on the outer surfaces of the cell that are usually absent, or very unusual, in multicellular hosts

Macrophages are giant cells that can ingest and neutralize up to 100 germs in their life time. When they recognize an intruder, they also secrete various chemical substances (cytokines and chemokines).

Chemokines mobilize other and smaller types of white blood cells: neutrophils which account for more than 50% of the white cell population. Neutrophils gather in large quantities at the site of infection where they also phagocyte microbes.

In addition, neutrophils and macrophages receive the help of the complement system.

The complement system is part of the innate immune system. It is composed of about 20 types of proteins. When they encounter a foreign substance, they activate by cleaving in cascade in smaller and active molecules.

These small proteins then bind to bacteria’s membrane and mark (the scientific term is “opsonize”) pathogens for ingestion by macrophages. They attract more macrophages on the site of infection and may also start digging pores in the membranes of the microbe they’re on.

Unfortunately, this line of defense is generally not enough for the most virulent pathogens. And extra defense mechanisms are obviously needed.

 
3

The third line of defense: the adaptive immune response


This is the last step of the defense against pathogenic microbes. It is very specific, very effective but it is slow to react when confronted with a pathogen it has never met before.

Last, but not least, the adaptive immune system has a memory!! It is able to recognize a germ it had to fight with beforehand. And in this case, the reaction is very rapid and effective.

This is the one we want to activate in vaccination.

But first and before we start, we need to define what antigens are.

Antigens

Antigens are substances that are recognized by the immune system as foreign bodies. They signal the presence of pathogens and trigger the response of the adaptive immune system.

Antigens may be foreign cells, fragment of these cells or specific large molecules that signal the presence of a microbe.

Lymphocytes

The adaptive immune system is made of other types of White Blood Cells: the lymphocytes.

Lymphocytes are very important and numerous. Altogether, in humans, they weigh about the same as the brain.

There are 2 types of lymphocytes. They are named after the organ where they achieve their maturation:

  • Lymphocytes B also called B-cells are produced in the Bone marrow
  • Lymphocytes T also called T-cells are produced in the Thymus

Lymphocytes differ from each other by the unique antigen receptors they carry. Each of them carries thousands of receptors for the same antigen.

The thymus and the bone marrow produce randomly millions of different lymphocytes which can respond to a large diversity of antigens. A lot of them die there. Others migrate to the peripheral lymphoid organs: the lymph nodes and the spleen. They stay there as naive lymphocytes.

Dendritic cells

The next step of the development of a lymphocyte requires that it gets in contact with the antigen that corresponds to the receptor they carry.

It may get directly in contact if the antigen happens to be present in the lymph nodes or the spleen.

More often the antigen is presented to a lymphocyte by a phagocytic cell: a macrophage or a dendritic cell. Macrophages and dendritic cells are called Antigen Presenting Cells (APC).

Dendritic cells are the most important in this regard. They patrol preferentially in the peripheral regions of the body and occasionally collect pathogenic microbes. Once they encounter an antigen they develop dendrites and migrate to the lymph nodes where they present the pathogen or pathogen fragments to lymphocytes.

Lymphocyte activation

Once a lymphocyte has encountered its antigen, it can start its maturation either:

  • in an effector cell aimed at destroying the pathogens
  • or in a memory cell that can live for decades
  • or, in the case of T-cells, in a helper T-cell

Helper T-cells are essential for the maturation of lymphocytes in effector or memory cells.

Because they play a symmetrical role in humoral immunity and in cell-mediated immunity,Helper T-cells can be considered as the pivot of the adaptive immune response.

Lymphocytes B and Humoral immunity

The humoral immunity is the part of the adaptive immunity that fights against pathogens present in the blood or in the lymph, outside body cells.

This is B-cells' job.

B-cells are activated either directly by the antigen or, more frequently and more effectively, by a an activated T-cell Helper that was activated by antigen presenting cells carrying the antigen.

B cells activation in secondary immune response

Activated B-cells rapidly transform into plasma cells or in memory B-cells.

Plasma cells secrete a great number of antibodies (2,000 per second). The antibodies are released from the lymph nodes or the spleen into the general circulation, blood or lymph and reach the site of infection.

Plasma cells die after several days, but memory B-cells continue to live and release antibodies into the blood for years.

Antibodies are also called immunoglobulins.

Action of antibodies

The antibodies released in the blood reach the site of the infection where they bind to the pathogens. They may exert there different types of action. The list is impressive and shows how potent the adaptive immune system is:

  • Lyse the pathogens
  • Neutralize the pathogens by aggregation or agglutination: they bind the pathogens together and make them inactive
  • Immobilize or slow down the pathogens: fewer can reach body cells and attach to them
  • Inhibit the pathogenic potential of microbes by blocking their receptors
  • Induce pores in the pathogens membrane and eventually kill them
  • Prevent the attachment of the pathogens on the membranes of body cells or interactions between body cells’ membranes and pathogen’s
  • Mark (opsonize) pathogens for destruction by the complement system, macrophages or neutrophils thus increasing the efficacy of the innate immune system
  • Induce suicide (=apoptosis) of the pathogen. Apoptosis is common characteristic of any cell that can on special circumstances trigger its own destruction

Cell-mediated immunity

Cell mediated immunity is the part of the adaptive immunity that fights against pathogens that have already infected body cells.

All viruses and some bacteria are obligate intracellular pathogens: they must accomplish part of their lifecylce inside the cells of their host.

Some other bacteria may choose to enter body's cells on certain circumstances. They are facultative intracellular bacteria. See more about pathogens localization

In this case, the immune system needs to adapt its response: it has to identify and destroy infected body cells, thus preventing further multiplication of the infective microbes.

This is what Effector T-cells do.

This is effective for any type of invading microorganisms, but especially against viruses. Viruses need body cells to replicate.

Viruses are encapsulated sequences of DNA (or RNA) that hold on to target body cells. They then inject their DNA (or RNA) in the body cell where it adds up to the DNA (or RNA) of the body cell. The body cell is then “reprogrammed” to produce many new viruses.

Once activated by an antigen, T-cells look for the pathogen that carries this antigen and infect body cells.

T-cells activation in secondary immune response

Unlike B-cells which continuously release antibodies in the blood, T-cells have to be present close to the site of infection. They attach to the infected body cells and then kill them either by lysing them or by triggering apoptosis (=body cell suicide).

 
4

Primary and secondary immune response


This is the important part!

This is where you will understand the mechanism of vaccination.

You first need to know there are 2 types of adaptive immune response: the primary and the secondary.

Primary adaptive immune response

The primary immune response occurs when the immune system is presented with an antigen for the first time.

The primary immune response is rather slow and weak. It usually takes one week or so for the first antibodies to be released and another week to reach its maximum efficacy.

In the case the pathogen is virulent and enters the body in large quantities, the response is not effective enough and the host eventually gets sick (or even worse).

 

Secondary immune response

The secondary immune response occurs on the second and following expositions to the antigen. The secondary response is very different from the primary. It is both very quick and very powerful. The microbe doesn’t get a chance to develop!

The body is now immunized!

Primary and secondary immune responses comparison

Source: Claire-Anne Siegrist - Vaccine immunology - 2013

But why is secondary response so much better?

It is not so easy to answer this question and the issue is not fully elucidated by scientists. But there are still some explanations.

At the second and following infections, memory cells are already present and much more numerous than initial naïve lymphocytes. Approximately 40% of B-cells in human adults are memory B-cells. They wait for the signal of Helper T-cells to activate.

When activated, memory cells react very quickly. They replicate, differentiate in effector cells and mature in antibodies-releasing plasma cells (B-cells). Memory cells also have a greater affinity to the antigen

As memory T-cells already circulate in the blood, they can quickly come close to the site of infection and fight pathogens just after they break through.

Moreover, the antibodies of the secondary immune response are different. Plasma cells of the primary immune response release mostly Immunoglobulins M (IgM), whereas IgG are dominant in the secondary response. Both IgM and IgG activate the complement system. IgG, in addition, can link the pathogen to a macrophage.

Secondary immune response

Duration of Immunity and Immunogenicity

Immunity lasts as long as memory cells persist. Long-lived plasma cells can keep on releasing antibodies for years or decades.

Duration of the immunity also depends of the immunogenic potential of the antigen (its ability to trigger a very strong response from the immune system). The immune response of the body is different according to the nature and the quantity of the antigen. The immunogenicity of an infection is measured by the quantity of antibodies produced.

An antigen that mobilizes the innate immune system triggers a more vigorous reaction of the adaptive immune system. This is the reason why vaccines often include adjuvants in their formula.

 

Immunity in oldest and youngest

The description of the immune system we’ve made so far concerns healthy adults. But it’s not so for either youngest or aging individuals where the immune system is not fully effective. They are much more susceptible to infections.

It will have some consequences on the vaccination strategies as we’ll see in the next chapters.

Immune system in the early life

In utero the fetus is protected by the mother antibodies. The immune system is tolerant to the mother’s antibodies.

At birth, the body is exposed to a very hostile environment, whilst the immune system is not mature. Fortunately some antibodies (IgA) are still provided to the newborn by the mother via her milk.

The defense of the newborn relies mainly on the innate system, although neutrophils response is weak. The adaptive immune system is very tolerant to foreign antigens it fails to recognize. It does not produce potent IgG antibodies.

Overtime the immune system matures and strengthens.

But as there are some major individual variations in the speed of maturation, it is very difficult to define the optimal moment for vaccination. This is the reason why younger pets are vaccinated several times within a short period of time.

Immune system when aging

Similarly, almost symmetrically, the immune system weakens in aging population.

Nevertheless, with time, the adaptive has built up a strong database of antigens, and is able to recognize easily many pathogens.

But the innate system is less effective. Neutrophils and dendritic cells are less active. New pathogens the body has never met before are less rapidly identified and lymphocytes response is weaker.

 
5

Conclusion: innate and adaptive systems work together


Mammals are the prey of many infesting microorganisms: bacteria, virus, fungi and parasites.

In adult mammals, the immune defense against infection is very effective.

Very few pathogens have the opportunity to enter the body thanks to the barrier provided by the skin and the epithelia made of cells bound together with tight junctions. On many epithelia, mucus containing lysing enzymes prevents cells attachment. Cilia mechanically disperse away microbes.

If germs succeed in entering the body, they are confronted with the innate and the adaptive immune systems which work in close cooperation.

The innate immune system has the capacity to naturally understand if the cells the body harbors are foreign or not, self or non self. Macrophages, neutrophils and Natural Killer cells (NK) destroy or ingest these pathogens.

Some macrophages or dendritic cells will present the microbes, or part or their structure (antigens) to naïve lymphocytes that resides in the lymph nodes or the spleen, thus activating the adaptive immune system.

The first reaction of lymphocytes is rather slow and leads to the maturation of effector and memory lymphocytes.

The effector T-cells destroy the body cells infected by the pathogen from which they got the antigen.

Effector B-cells (plasma cells) release very large quantities of antibodies that either kill the pathogen or assist the innate immune system by making the pathogen “more digestible” for macrophages and neutrophils or by marking them for destruction.

Memory cells can survive for years and can replicate and differentiate in effector cells when the antigen they are specific for comes in again.

When a pathogen enters the body for the second and subsequent times (secondary immune response), the adaptive immune response is both quicker and greater. More antibodies are produced, and they are more effective.

This is the basis for vaccination. Vaccination exposes the body to the selected pathogen a first time in order to induce a primary immune response. The following exposure to same pathogen, i.e. the actual infection, would trigger a much stronger and quicker secondary immune response.