As an introduction, you will find a video recapitulating some of the critical steps of our immune response. It recalls that the immune response takes place in two stages: an immediate response after microbe infection called " Innate or Natural Immunity" provided by dedicated cells followed by a delayed immune response (delayed by a few days) called "Adaptive or Acquired Immunity" provided by specialzied cells, the lymphocytes. The molecular determinants found on pathogens and triggering the reaction of our body are markedly different for these two kinds of responses!
Video provided by GarlandSciences
Let's first introduce the actors (cells and organs) of our immune system.
|Some immune cells|
|NK cell (yellow) attacking a tumor cell|
Dendritic cells are cautious: at the entrance of the microbe, they leave the infected site and will move to specialized organs called secondary lymphoid organs, to alert potent cells of our immune system: the T and B Lymphocytes. These cells, once informed of the presence and identity of the microbe by dendritic cells,will take the time to equip themselves with the most suitable weapons to fight against the microbe in question. Then, we will leave the seondary lymphoid organ to move back to the site of infection and eliminate the microbe (when all goes well!). It takes a week before all this happens. These cells are also very important because they are the "immune memory" ie if the same bug again crosses our borders, these cells will remember the best way to eliminate it and make it in a much shorter time than for the first infection.
To become more familiar with the appearence of all these cells, you can watch a remarkable video describing the blood cells!
To test yourself on the immune cells, nothing but a quizz!(sorry it is currently in french...)
|White blood cells analyzed by flow cytometry|
|T and B cells at their right place!|
This lovely film shows the movements of an immune cell under the influence of a "chemotactic" stimulus ie by a chemical molecule called "chemokine" that triggers cell migration. You will be able to measure the real-time reactions to the displacement of the cell toward the source of the stimulus. In fact, the cell "search" for the stimulus source (ie it is directed towards areas where the stimulus is the most concentrated): it works the same thing in our body!
Another film shows how the chemotactic receptors work in response to these stimuli.
Let's see now how our innate immune system recognize and fight against germs .
|A Toll-Like Receptor|
|The complement system: initation of the cascade and function|
|Structre of the MHC class I and MHC class II molecules|
--> Two other films show you how antigen presentation by HLA class I and antigen presentation by HLA class II to T cells operates. Finally you can have fun identifying antigens yourself in proteins of your choice using the dedicated freeware SYFPEITH.
--> How can our T and B lymphocytes recognize all the microbes potentially present in our environment? Unlike cells of the innate immunity that have some PRR, each capable of recognizing many different microbes, T and B cells each have a receptor very specific for a molecular fragment of a given microbe. For B cells, this receptor is called BCR (B Cell Receptor), which is nothing else than an immunoglobulin anchored in the membrane of the B lymphocyte. For the T cell, the receptor is the TCR (T cell Receptor) which recognizes the antigen presented by MHC molecules on presenting cells. There are a large number of different T and B cells each carrying a different BCR or TCR that determines our ability to react against virtually any aggressor! One speaks of a "repertoire" of B and T lymphocytes circulating in our blood to describe the extent of the diversity of T lymphocytes and B having different antigenic specificity.
|Estimated size of the total repertoire of immunoglobulins and TCR|
In fact the final reperoire of T and B cells is teh result of an equation:
Total repertoire - SELF-specific repertoire = NON SELF-specific repertoire!
Here we are! Many different pathogens can now be recognized very specifically and in a safe way!
--> For thos of you who can understand french, you will find a very interesting lecture by Jean-Claude Weill on Canal-U explaining these notions in deeper details.
|Functions of classes and sub-classes of antibodies|
|Mechanism of CD8 T cell cytotoxicity|
--> A key feature of the adaptive response is that it differs qualitatively and quantitatively depending on the pathogen infects us for the first time or upon re-encounter of the same pathogen: in the first case, we speak about a "primary" response and in the second, about a "secondarye response. The secondary response is faster and more efficient. The greater efficiency of the secondary response is true for both the dynamics of antibody response and the T lymphocyte response. Why? Let's look at this question in the case of B lymphocytes: when encountering a pathogen for the first time, our B lymphocytes do not know the pathogen: those B cells that will recognize the pathogen (those with the appropriate BCR, which are very rare ...) are called "naive." Because these cells are rare and unexperienced they will have to first divide to become numerous enough and equip themselves with weapons for pathogen destruction. The process whereby the B cells are chosen to proliferate is called clonal selection; the antigen "choses" thos clones of B cells pre-existing in the famous repertoire and able to recognize it through the BCR. These lucky cells can now proliferate! In the case of B cells, the anti-microbial weapons are mostly antibodies.
|Dynamics of the antibody response|
--> This process of clonal selection requires a certain time: this correspond to about one week during which these events are not easily discernible: one the one hand, they take place in the secondary lymphoid organ nearest from the infected tissue and not in the infected tissue itself; on the other hand, those cells are not yet capable of eliminating the pathogen and acquire this capacity with time. After this week, the B cells will produce antibodies, and even more of these antibodies:during the primary response IgM are predominantly produced. The antigen-antibody reaction can take place! These IgM poorly recognize and are relatively ineffective against the pathogen. By cons, little by little, some B cells replace their production of IgM by IgG (or IgA or IgE, it depends): this is a process termed class switching (or isotype switching). These new antibodies (mainly IgG) display a much higher affinity for the pathogen and are more effective. Part of B lymphocytes that are activated become memory cells: these cells live for a very long time (several decades): they usually have switched their antibody and remain in a state close to the activation. It is those cells that are responsible for the efficiency of the secondary response: indeed, if we re-infect with the same pathogen, these cells will come into action quickly since they are pre-activated (latency will be from shortened to 1-2 days only) and it will be more immediately effective as high affinity IgG are being produced. It happens almost the same for T cells except that their weapons are called perforin / granzyme or cytokines instead of antibodies. By the way, you have understood the immunological basis and significance of vaccination! The vaccine mimics the pathogen but without the toxic effects and when injected, the vaccine triggers a primary response of our immune system which leads to the generation of T and B cell memory: we speak of vaccination or active immunization. If you now encounter the pathogen mimicked by the vaccine, an intense and effective secondary reaction is triggered against the pathogen, which is eliminated faster! Clever, is not it? We find very old historical origins for vaccination, much before the way it works, as presented above, was understood!
|Mycobacterium tuberculosis: the agent of tuberculosis|
|Plasmodium falciparum: the agent of malaria|
|HIV-1: the agent causing aids|
--> Our immune system also allows us to fight against tumors. Many vaccines against cancers are being tested at the moment! In contrast to those positive role, our immune system also plays us tricks: if our immune system is poorly "educated", it can attack our own tissues: this can lead to auto-immune diseases. You can also have allergic reactions (or hypersensitivity) such as asthma, which is also due to the immune system.
Finally, we must take into account the immune system when you want to transplant an organ to someone. The notion of NON-SELF does not only apply to microbes, but also to your brother or your sister or your parents, or whoever putative donor! That is why we are looking for a compatible donor for organ transplantation! The most compatible one is ...yourself (autograft) or your twin! In other cases, we must be careful and take drugs that weaken the immune system to prevent you from rejecting the transplant (Note: during this time you are very susceptible to germs!)
WANNA TEST IF YOU REALLY BECAME AN EXPERT IN IMMUNOLOGY? Test yourself with QUIZZ 1 and QUIZZ 2 proposed by the University of South Carolina, School of Medicine!