Why the Immune System Is the Best Protection Against Infections

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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 microorganism can cut across it.

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

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

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

As for the skin, the junction between the cells is quite tight. The micro-organisms can't breach it unless they 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 the lungs or the 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).

 

In addition, the mucus is loaded with many antibiotic chemical substances (enzymes, fatty acids) or peptides (defensins, cryptidins) that can 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 pathogen is extremely virulent, the infection can’t be avoided and germs can cross the mucous membrane and enter the blood flow.

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

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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.

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 bacteria 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 membranes 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.

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The adaptive immune system 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 this reaction we want to activate in vaccination.

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

Antigens

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

Antigens may be the entire pathogen, fragment of the pathogen or specific large molecules that identify its presence.

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 as much 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 type of receptor they carry on their surface. They carry thousands identical units of the same type of receptor.

This receptor is specific to (it recognizes) a single type of 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

Lymphocyte activation requires that it gets in contact with the antigen that corresponds to the receptor it carries.

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've absorbed a pathogen, they develop dendrites and migrate to the lymph nodes where they present the pathogen or fragments of the pathogen to lymphocytes.

Lymphocyte activation

Once a lymphocyte has encountered the antigen corresponding to its numerous receptors, 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 both humoral immunity and 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 circulating 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 Helper T-cell that had been in contact with the antigen (either directly or via an antigen presenting cell - dendritic cell or macrophage).

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, 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.

Antibodies mode of action

The antibodies released in the circulation 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 can be:

• Lyse the pathogens
• Neutralize the pathogens by aggregation or agglutination: antibodies 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 the 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 a common characteristic of any cell that can on special circumstances initiate 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 lifecycle 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 identifies and destroys 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' resources to replicate.

Viruses are encapsulated sequences of DNA (or RNA) that hold on to target body cells. They then inject their DNA (or RNA) and reprogram the cell so that it can produce numerous new viruses. They are released upon cell disruption.

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

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).

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This is the important part!

This is where you will understand the mechanism of vaccination.

But, you first need to know about the 2 types of adaptive immune response: the primary and the secondary.

Primary adaptive immune response

The primary immune response swings into action 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 an additional week for the primary response to reach its maximum efficacy.

In the case the pathogen is virulent and/or is inoculated 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 is activated 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!

Source: Claire-Anne Siegrist - Vaccine immunology - 2013

But why is secondary response so much better?

It's not so easy to answer. This issue is not yet fully understood by scientists.

But there are still some explanations.

At the second and following expositions to an antigen, 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 are only waiting for the signal of Helper T-cells to activate.

When activated, memory cells react very quickly. They replicate, differentiate in effector T-cells and in antibodies-releasing plasma cells (B-cells). Memory cells also have a higher 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 entered.

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 also can link the pathogen to a macrophage.

Immunity duration and immunogenicity

Immunity duration mainly depends on the strength of the reaction of the immune response at the time of the first exposure to an antigen and on how many times it was exposed to this same antigen afterwards.

This strength of reaction is called immunogenicity. Immunogenicity comes from the antigen nature (its immunogenic potential), the quantities of antigens inoculated, and other factors amplifying the inflammatory response at the time of infection (example: adjuvants in vaccines).

A strong immune response produces a large number of memory and plasma cells. Long-lived plasma cells can keep on releasing antibodies for years or decades.

 

Immunity in oldest and youngest

The description of the immune system we’ve made so far applies to 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's antibodies.

At birth, the body is exposed to infections, while the immune system is not mature yet. Fortunately some antibodies, the immunoglobulins A (IgA), are still provided to the newborn by the mother via her milk.

The defense of the newborn relies mainly on the innate system, even though neutrophils response is weak. The adaptive immune system is very tolerant to foreign antigens it often 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 the immune system maturation, it is very difficult to define the optimal moment for vaccination. This is why younger pets are vaccinated several times within the very first months of life.

Immune system when aging

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

With time, the adaptive system 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.

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Mammals can be infected by numerous microorganisms: bacteria, virus, fungi and parasites.

In adult mammals, the immune defense against infections 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 push microbes back.

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 which reside 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 or 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 what vaccination is all about. Vaccination exposes the body to a 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.