Body Wars

There is a war going on. Each side is trying to kill the other side. Millions of lives are at stake.  The dead and dying are being continually carried off the battlefield, and fresh new recruits are taking their place.  

Nobody knows how long this battle has been going on, but it is at least 1.5 billion years old and it perhaps extends back to the beginning of life itself, about 3.4 billion years ago (reference 1).  And just like in any arms race, each time one side invents a new way to invade, the other side invents a way to counter it. 

When you get invention after invention of new types of weapons by the attacker, you will also get invention of new, innovative defenses against those weapons by the defender. These defenses get incorporated and passed down and remembered over billions of years of battling. You can expect to see incredible complexity as a result.  And that is, indeed, what you get when you study the human immune system.

This age-old battle, and the continual invention of new, innovative types of defenses is happening inside your body.  Right now.  24 hours a day. 7 days a week. 

My task recently, since we have been cooped up, has been to learn about the human immune system.  In this blog post, I will share some of my findings with you so we can perhaps better unravel what is happening with the Covid-19 disease and more fully understand the innovations that are being created to fight it.

Two Systems

Humans have two separate and distinct immune systems that are always working side by side, in coordination with each other.  It's kind of like when police respond to a crime in progress - the county sheriff is often the first to arrive and then, if the situation merits, the state police take over the investigation.

The more ancient of the two systems  - the county sheriff of the human body - is billions of years old and is called the innate immune system.  In humans, these are the soldiers that are first on the battlefield, bearing arms, ready to fight.  The second system - the state police of your body - is called the adaptive immune system.  It is extremely potent but it takes a while to get going.  The adaptive system arose on the scene with jawless fishes about 500 million years ago and is present in all vertebrates (reference 2).

The Innate Immune System

The Innate system is the body's first line of defense.  

Phagocytes

The innate system consists of a group of "white blood cells" that can find and engulf microbes.  A few examples of these cells are macrophages, dendritic cells, mast cells, basophils and eosinophils.  

Figure 3: a phagocyte

These cells collectively are called phagocytes.  Once the phagocyte "eats" the microbe(s), it will confine it in a vesicle and then attempt to kill it with oxidants and nitric oxide (refer to Figure 3 above and reference 5).  If this doesn't work, the cell will commit hari-kari in a very violent fashion, blowing up itself and all its contents.  All for the sake of the body.  

Antigen Presentation

Some types of phagocytes become antigen presenting cells.  What does this mean?  Once the very proud "sheriff" cell has engulfed and killed the microbe, it presents a piece of its kill (the antigen) on its surface... a silver platter of sorts.  Cells from the adaptive immune system (the "state police") then circle by, attempt to recognize this antigen and get to work on it  (reference 6).

Figure 4: Antigen presentation by a phagocyte

This is the connection between the two systems, sort of like the radio connection between the local sheriff and the state police, giving a be-on-the-lookout (BOLO) alert for a certain dastardly type of person - an accomplice to the original crime that will be wearing the same uniform.  We will discuss how the adaptive immune system (the "state police") processes the antigen once it is presented in the next section.  

Other aspects of the Innate Immune System

There are a few things about the innate immune system that we won't cover today.  Physical and chemical barriers such as your skin, mucus membranes, and the acid in your stomach are actually considered part of your innate immune system.  It also includes of the cilia in your lungs (tiny little hairs that transport foreign particles up and out). These barriers all attempt to prevent microbes from entering your body to begin with.   Other aspects of the innate system that we won't cover are Natural Killer Cells (reference 4) and the Complement Immune System (reference 7).  We will discuss these in another post.

The Adaptive Immune System

Your body is continually challenged by microbes that it has never encountered.  These clever little devils may have figured out how to disguise themselves from attack by the innate immune systems - for example, by coating themselves with various molecules that make them look similar to human cells or that otherwise fool innate immune mechanisms.  Or, alternatively, they might have been recognized by the phagocytes and simply overwhelmed them by sheer numbers.

How do you recognize that one of these little buggers has outsmarted or overran your innate system?  And once you've seen it, how do you remember it so it can't attack you again?  This is the fundamental set of problems that the adaptive immune system has solved in an amazingly innovative way.

Lymphocyte (B and T cell) Production

The adaptive immune system produces several types of cells collectively called lymphocytes (aka B and T cells).  There are millions of lymphocytes that are continually produced in your bone marrow.  After they have been produced, the B type of lymphocytes further mature within the bone marrow and the T type of lymphocytes migrate to your thymus to mature.

As each lymphocyte cell matures, an antigen-binding receptor is created on the surface of the cell.  (These are illustrated as the little stick-figures that are sticking out of the circles in the middle of the diagram above.)  During the maturation process, random mutations are deliberately introduced in the part of the lymphocyte's DNA that creates this antigen-binding receptor.  

The result is an extremely high variety of lymphocyte cells, each one with a differently designed antigen binding receptor - a receptor that is specific to that cell.  At this point, you have millions of lymphocytes, each one with a different antigen-binding receptor.  

Next, a sorting process takes place, where the cells that bind to the wrong antigen are killed.  For example you wouldn't want a lymphocyte recognizing your liver cells as a threat - they would destroy your liver.  The ones that remain are able to collectively bind to a highly diverse set of antigens, and are not able to bind to (and destroy) your normal cells.  These mature lymphocytes then circulate through your lymph nodes, your spleen and various mucosal and cutaneous tissues.

When the lymphocyte finds the specific protein it was designed for and binds to it, the immune system is activated.  That cell starts replicating itself (including the exact receptor) like crazy (called "clonal expansion"), and then it injects all kinds of signaling molecules into the bloodstream and lymph system.

Antibody Production

Everybody has heard of antibodies.  They are the Y shaped molecules that bind to foreign substances (reference 8).

As can be seen in the figure above, antibodies play several key roles in the immune system, and two of the most important are to neutralize pathogens and serve as an opsonin (= binding to bacteria to make it easier for phagocytes to recognize and grab on to them so they can ingest them).  A third role, also illustrated above, is to help out the complement immune system (which is part of the innate system, and will be discussed in yet another post!).

B Cell Activation

Where do antibodies come from?  They come from B cells. Let's take a closer look at them.

It turns out that the B cell receptor that we described in the last section is actually an antibody!  This antibody is bound to the B cell's membrane, with the bottom of the "Y" stuck in the membrane and the two arms (the receptor portion) sticking out, waiting to bind to an antigen.  As described above, this receptor / antibody is very specific to a particular antigen.  The B cell is activated when that specific antigen is encountered and bound to the receptor.   This activates the B cell.

There are two ways that a B cell can be activated - with or without the help of a T cell. (reference 9) Let's quickly discuss that next.

T-cell Independent B cell Activation

The figure above shows a B cell activation without a T cell. You can see the B cell receptor (the little "Y" attached to the cell) on the left diagram, binding to the antigen associated with a bacterial cell.  Once this happens, the B cell multiplies and switches into a plasma cell (circulating in the bloodstream).  At this point it can produce antibodies which leave the cell and circulate freely in the blood, in search of the antigen. It binds to these antigens and inactivates the pathogen, and/or allows the phagocytes to more easily grab onto and consume the pathogen.

T-Cell Assisted B-Cell Activation

They call them T helper cells for a reason.  These cells (shown in green in the figure above) give a big boost to the B cell activation process.  Here, the B cell binds to the antigen (on the receptor/antibody) as shown at the top of the figure.  The B cell then migrates to where it can find a T helper cell.  And in the meantime, the B cell has ingested a piece of antigen and displays it for presentation to a T helper cell.  (Note that this presentation is the same mechanism that was described above in the innate immune system for phagocytic cells.)

This antigen-presenting B cell must now find a T cell with a receptor that also binds to that antigen. (We discussed the receptor creation process earlier, which happens in the thymus - this is very similar for B cells and T cells - except the T cell receptor cannot turn into an antibody).  Once that exact T-cell is found it will also bind to the antigen that the B cell is presenting and all hell breaks loose. 

The T cell releases all kinds of signaling molecules called cytokines (you've heard of a cytokine storm - these are very potent and can actually kill you due to an over response of one's immune system, more on this in another post).  The cytokines cause the B cells to proliferate like crazy - a process called clonal expansion - making exact copies of themselves, including the B cell receptor/antibody.  

Next, a process called somatic hypermutation takes place. This is similar to the receptor creation process that happened earlier which created all the diversity in antigen recognition.  Somatic hypermutation further improves the B receptor/antibody: it makes the receptor/antibody even more specific to the exact pathogen that was detected as well as increases the binding strength of the antibodies. 

B cells can then undergo class switching, which allows them to create different types of antibodies as required by the type of pathogen. 

Finally, one more very important thing happens - the production of B memory cells.  You can see on the lower left of the diagram that memory cells are produced late in the infection cycle.  These cells will stick around for a long time in primary lymphatic organs and they have exactly the right receptor should this particular pathogen ever show up in the future. If that happens, they will immediately go into clonal expansion and switch into plasma cells which will rapidly produce millions of antibodies specific to that pathogen.  This will prevent that new occurrence of the infection from ever taking hold - and that human being will be effectively immunized against that pathogen.  A future post on vaccines will explore this topic more thoroughly.