How does the immune system work? How do we “instruct” the immune system with vaccines?

 

Vaccines have recently been target of attacks concerning their safety for human beings and many scientists and physicians are doing a good job trying to convince people about the safety and the importance of vaccination, especially for some invalidating diseases.

I believe that the best way to convince people is to explain how it works, so that they can realize themselves the importance of vaccination.

Vaccines use the endogenous defence of the body, teaching the immune system how to behave in presence of a specific pathogen (a bacterium or a virus causing a disease.)

First of all,

HOW DOES THE IMMUNE SYSTEM WORK?

The immune system is the ensemble of cells and proteins taking care of the body response against external pathogens.

Immunity (the ability of the body to defend against pathogens thanks to the immune system) is either innate (or aspecific, meaning that each person is born with it) or acquired (specific against the different pathogens).

 -        Innate immune defence is represented by physical/chemical barriers, or cellular/protein factors like phagocytes, NK cells, cytokines (soluble free molecules), alternative complement pathway.

 -        Acquired immune response is mediated by antibodies, cytokines, cytotoxic cells, complement pathway (classical and lectin-activated).

 

Innate immunity.

Innate immunity represents the first barrier against pathogens that may cause infection. The natural immune response is triggered few hours after the body gets in contact with exogenous particles (not necessarily a pathogen).

Barriers are the first components of innate immunity, such as the skin, preventing pathogen entry inside the body; enzymes present in mucosae and tears, degrading putative harmful molecule; pH, for instance the very acidic environment of the stomach represents itself a barrier, being incompatible with the functionality of many proteins.

In case pathogens go through these barriers, the cellular/protein components of the natural immune system respond: NK (Natural Killer) cells, phagocytes and complement proteins pathway are activated.

NK cells recognize a cell (eg a bacterial cell) as exogenous by evaluating the expression level of a protein complex expressed on bacterial cell surface, named MHC. Once activated, NK cells kill target cells by releasing proteins such as perforins, which lead to cell lysis* of target cells making pores in the plasma membrane, and granzymes, initiating an intracellular signalling leading to cell death (apoptosis). NK cells release also cytokines to call phagocytes* that take part in pathogens removal. NK cells are also able to recognize stressed cells and tumor cells that often downregulate the expression of MHC complex.

The complement pathway is a defence of the immune system that, acting through a number of proteins, amplifies the stimulus elicited by microbial infection, ending with infection removal. Proteins of the complement pathway can be differently activated: the alternative activation, which is part of the innate immunity; and classical and lectin activation, which are part of the acquired immunity and will be discussed later.

The “key” protein of the complement pathway is called C3. This protein undergoes a spontaneous cleavage (cleavage is the cut of a protein in a specific region). The cleaved, activated C3 protein (now called C3b) binds to the microbe membrane and to other proteins, making a complex that 1) will amplify the signal by activating other C3 proteins (by cleaving them); 2) will release molecules responsible of inflammation* 3) will, in turn, activate C5 protein. Activated C5 will recruit the other proteins required to form the MAC (membrane attack complex) that will attack the plasma membrane of a microbe, causing lysis and cell death.

In case the cleaved (activated) C3 protein will not find a microbe, it will be simply inactivated.

 

Acquired immunity.

Once stimulated (by bacteria, viruses,… ), different types of acquired, specific immune responses can be activated:

 

1)     The humoral response.

 

2)     The cell-mediated response.

 

3)     Complement pathway

 

1) The humoral response involves white cells called B lymphocytes. Receptors expressed on B lymphocytes surface bind bacterial or viral proteins present in human fluids and, recognizing them as exogenous, stimulate the immune response (primary response).

After immune response stimulation, activated B lymphocytes proliferate and differentiate into plasma cells and memory cells. Plasma cells are antibodies-producing cells. Antibodies are proteins having the same structures of the B lymphocytes receptors that recognized the antigen in first place (antigen is the exogenous protein, eg a viral or bacterial protein, that triggers immune system response). Antibodies are then released in the blood flow and bind the antigen, forming a complex that is easily recognized by phagocytes and eliminated. In parallel, B lymphocytes also differentiate into memory cells, which will express the specific receptors for that particular antigen and will remain “quiescent” making the body ready to respond in case of another infection due to the same antigen (secondary response). 

Antibodies, also called immunoglobulins (Ig) are classified in different types: IgG (representing 75% of circulant Ig. They cross the placenta providing a protection for the first months of a new-born’s life), IgA (mainly present in saliva, tears, mucus of respiratory apparatus and digestive tube, are important for local response), IgM (first antibodies synthesized right after immune system stimulation, they are successively degraded), IgD, IgE (controlling allergic response). In the primary response, firstly and mainly IgM are produced and only later IgG. In the secondary response, IgM production is followed by a huge amount of IgG production.

2) The cell-mediated response involves white cells called T lymphocytes.

T lymphocytes can be subdivided in: T-killer (or cytotoxic, actively killing infected cells and tumor cells), T-helper (secreting cytokines after antigen stimulation. They can also activate B Lymphocytes), T-regulatory (responsible of shutting off the signal at the end of an immune response).

Differently from B lymphocytes, T lymphocytes target cellular antigens. What does it mean? Viruses, bacteria, bacterial products (eg toxins) are “swallowed” (endocytosed) by a cell, processed and parts of these proteins are re-expressed on the cell surface. This process is called “antigen presentation”. Different cells can make antigen presentation, such as macrophages, dendritic cells, or B-Lymphocytes. According to the antigen-presenting cell type, a different T-lymphocyte subtype is involved and a different signalling is triggered. For instance, B Lymphocytes and macrophages activate T-helper, producing cytokines that in turn will activate effector cells, such as macrophages, T-Killer, or antibody-producing B-Lymphocytes. Antigen-presenting dendritic cells activate T-killer that will directly destroy the pathogen. Dendritic cells can also phagocytose entire cells infected by the pathogens, process pathogen proteins and express them on the surface to activate T-Lymphocytes.

Activated T-lymphocytes duplicate, in order to be able to efficiently respond to pathogen infection, and differentiate into memory T-Lymphocytes that, as well as B-memory lymphocytes, will be ready to respond to another future infection.

3) The complement pathway in acquired immunity is activated through the classical pathway or the lectin pathway. The classical pathway is triggered by the binding of C1 protein to the antibody/antigen complex. After the binding, C1 protein is activated and in turn activates another protein: C4. Active C4 binds to the microbe surface and activates C3. As mentioned for the innate immunity, activated C3 (C3b), will be part of the protein complex that, through the activation of C5 protein, will be responsible of recruiting the components for the MAC (membrane attack complex) to kill the microbe through lysis.

The lectin pathway is activated when lectins in the serum recognize and bind mannose (a carbohydrate present on microbes’ membranes) and some proteins structurally and functionally similar to the C1 protein of the classical pathway, which will start the cleavage cascade described above for the classical pathway.

Acquired immunity can be either active or passive.

 ● Serum* injection of someone that already developed the antibodies against a specific antigen (eg a virus, a bacterium, a toxin, etc.) provides a fast but not long lasting immunity. Indeed, after antigen neutralization, antibodies are degraded, without leaving trace. This is called passive immunity, and it does not protect from a future infection with the same antigen. The most common example is the snake poison. After a bite, there is need of an immediate protection to avoid the effects of the poison, so there is no time for the immune system activation to take place. For this reason, the “antidote” is the injection of serum containing antibodies ready to neutralize the toxin.

 ● Active acquired immunity, instead, takes place when the subject is injected with an antigen (eg an inactivated virus, a membrane protein fragment of bacterium, …), leaving time to the immune system to respond and make its own antibodies. The immune system response requires some time, but afterwards, the body will be ready to respond to future attacks from the same pathogen.

HOW DO WE INTERACT WITH THE IMMUNE SYSTEM WITH VACCINES?

With vaccines, instead of a disease-causing pathogen, the immune system is stimulated by something mimicking the pathogen. For example, the vaccine against the hepatitis B virus is made by using a portion of a protein expressed by the virus. Viruses are complex. They have nucleic acid (DNA or RNA) enveloped in proteins. The whole ensemble of DNA and proteins work together to enter the host (the human body) and cause the disease. Only one of these proteins alone is not able to cause the disease, missing key information to enter/act inside the human body. So, when a single protein fragment is injected in the human body with vaccination, even if unable to trigger a disease, it will be recognized as an antigen by the receptors expressed on the cell surface of B-lymphocytes. At this point, the immune system will start the cascade previously described. Although there is not a disease and a pathogen to fight and destroy, antibodies producing cells and memory B cells will differentiate (see image, right upper panel). The latter ones will stay quiescent, ready to respond in case of pathogen attack.

 

Vaccines may have some side effect, like many drugs do, and these are accurately studied by researchers before commercializing the vaccine. Side effects may be annoying, but it makes me think about helmets for motorbikes: they do ruin your hairstyle, but in case of accident, they save your life.

 

GLOSSARY

Serum. The blood is made of a cellular component -meaning white cells, red cells and thrombocytes- and a non-cellular component. The non-cellular component is called Plasma and it is a fluid containing proteins (mainly albumin), lipids, ions, sugars,… Plasma deprived of Fibrinogen (Fibrinogen is the inactive form of the protein responsible for coagulation: Fibrin) is named Serum. Serum contains antibodies and the antigens activating the humoral response.

Antigen: any molecule inducing an immune system response, eg some proteins expressed on the surface of pathogens.

MHC (major histocompatibility complex): protein complex responsible for recognizing a protein as self or non-self.

Self means being part of the body, while non-self means exogenous, such as a microbe.

Phagocytes: cells that “swallow” pathogens or dying cells in their cytoplasm and kill them.

Inflammation: biological response of the body to pathogens, aiming at protecting the body.

Lysis: cell disruption following membrane breaking down, for instance due to the loss of cytoplasmic components through pores in the plasma membrane.