Molecular knights and their horses
Immune system is our body’s primary defence mechanism, it protects us from hundreds of types of invading viruses, bacteria, fungi, worms and dozens of types of parasitic protozoa. In addition it also plays a key role in tissue clean up, wound repair, removing abnormal and malignant cells from the body.
However when it goes awry it is the same mechanism that is responsible for allergic reactions, autoimmunity, tissue and organ rejection in transplant cases and hemolytic reaction in blood transfusion cases.
How it works is absolutely astounding. It is all handiwork of tiny microscopic creatures and a handful of proteins that continue to operate round the clock in our bodies and orchestrate the mechanism that keeps the immune cells alert, looking for threats, warning their counterparts to be ready to fight, delivering important messages, recruiting armies of combat forces and eventually tracking and killing the invaders before they get a chance to spread and take over our bodies and minds.
Interesting enough that all these single celled microscopic creatures actually belong to one family and they originate from one type of mother germ line in bone marrow. As they mature they are dispatched to various body parts were they perform their specialised functions.
Even though they end up livings as individual entities for all their lives, the way they collaborate and cooperate is one of the marvel of nature. On the surface they may seem to float independently and freely in various streams of fluids flowing through our bodies but they continue to maintain a strong connection with their siblings. This monumental feat is achieved by chemical messages that pass signals from one cell to another as mediated by interaction of various molecules secreted by cells and the receptors that are embedded in cell membranes.
Our first line of defence is the dendritic cells (DCs), they form part of the innate defence mechanism of the body. These cells are present in tissues that are in contact with the external environment, such as the skin, inner lining of the nose, lungs, stomach and intestines. Here is an illustration of dendritic cell ( courtesy of wikipedia)
Movement of many cells of immune system including dendritic cells is mediated by a suite of chemicals called chemokines. Chemokines act as chemoattractants as they guide the migration of cells along their concentration gradient. Cells that are attracted by chemokines migrate in the direction of increasing chemokine concentration which directs the cells towards the source of the chemokine
There are two key chemoattractants (CCL20 and CCL21) that are expressed in different places in the body. CCL20 is highly expressed in peripheral blood lymphocytes, its expression is upregulated by presence of bacterial factors. CCL21 is highly expressed in lymph nodes. These chemokines are kind of GPS markers that advertise the site of attack as well as location of the command centre where the attack is to be planned and executed from.
So effectively it is CCL20 that moves the immune cells towards peripheral tissue, which is generally the site of infection and it is CCL21 that causes the cells to move in the other direction (towards the lymph nodes). It is the lymph nodes where dendritic cells visit to spread the message. As DCs come in contact with T cells they notify T Cells the kind of pathogens they have been exposed to. Once T cells are ready they march to the site of invasion and initiate the fight.
The way this works is that chemokines have ability to bind to their respective cell receptors. CCL20 binds to CCR6 and CCL21 binds to CCR7. Since these receptors are expressed on surface of different immune cells at different stages of immune response, it is the respective binding that determines which direction a particular immune cell will march towards and at what stage as shown in the diagram.
CCR6 and CCR7 expression is upregulated at different stages of immune cell maturation to ensure appropriate activation of the immune response. CCR6 mediates trafficking of immature Dendritic Cells to sites of pathogen stimulation, whereas CCR7 allows for trafficking of mature DC cells to the lymph node once they are activated.
In addition to CCR6 and CCR7 dendritic cells have numerous other receptors on their surface that recognise specific chemical signature patterns of molecules present in various microbes, viruses etc.
Dendritic cells are also called antigen presenting cells as their main function is to process antigen material and present it to the T cells of the immune system. Much like conveying the characteristics of the enemy to the command centre. When DCs come in contact with antigens they kill it, break it down using its cellular machinery and present the signature molecule on to its surface using a set of proteins called major histocompatibility complex (MHC) as if they are carrying trophies of hunt on their head as they march towards the command centre . These signature molecules act like the barcodes for T cells to recognise the presence of antigen inside the cells.
Once dendritic cells become active they start expressing CCR7 along with many other molecules that eventually determine their subsequent actions.
As the CCL21 binds to CCR7 receptors the mature DC cells change their course and start migrating towards lymph nodes where CCL21 is found in high concentrations. It is the lymph nodes where they meet the famous T cells and trigger the immune response following a process known as T cell activation.
Interesting enough T cells also have CCR6 and CCR7 receptors which not only attract naive T cells to lymph nodes but also dispatch armies of activated T cells to site of infection following exactly the same mechanism of moving towards high concentration of chemoattractant.
The T cell activation is another interesting story I think we should save that for another day.
To our dismay certain tumor cells also have CCR6 and CCR7 receptors on them which do create havoc in the body as they facilitate spread of cancer cells.
Hence the major challenge for immune system is to maintain a sufficiently large immune repertoire capable of recognizing all possible foreign antigens, whilst at the same time maintaining immune system in an unresponsive state towards body’s own antigens. At a molecular level it is achieved by maintaining a delicate balance between various ligands and their receptors.
So at end of the day our bodily defences are largely in the hands of these molecular knights and their horses be it the nexus between CCR6 and CCL20 or the one between CCR7 and CCL21.
Originally published at scriptgrandeur.wordpress.com on May 22, 2015.
