The immune system

Inflammation can be both mechanically stimulated, such as a cut or a burn, or endogenously stimulated by the immune system to respond to foreign molecules within the body. Inflammation is necessary to detect, fight, and destroy these potentially harmful molecules. Moreover, the inflammatory response can lead to the formation of stronger mechanisms to combat a specific virus or bacteria in the future.

In large, inflammation begins with the activation of Mast cells.  Mast cells are white blood cells that are found under the skin near blood vessels and other vital areas in the interstitial area. The interstitial area is simply just the fluid filled areas underneath the skin (subcutaneously) and around blood vessels and other organs. 

Mast cells in the interstitial space are used for a few different things. They can respond to damaged tissue like a cut or a burn or respond to pathogens within the interstitial space. Pathogens are simply just molecules that should not be in the interstitial space. Most commonly, these are things like allergens and bacteria. However, in a scenario of intestinal permeability,  mast cells will react to  undigested food that has exited the gut through a compromised gut barrier. 

Mast cells contain histamine granules, which are likely the most prominent and important inflammatory mediator. An inflammatory mediator is a broad definition for molecules that evoke what are commonly referred to as inflammatory response. 

Inflammation is not a step by step process, rather a cascade of simultaneous events. The process begins when a pathogen is recognized, typically by a mast cell. Pathogens will have specific molecules on their surface that are called antigens. Antigens are recognized by a mast cell. 

Mast cells produce granules, most notably   histamines, leukotrienes , and prostaglandins. 

In addition to mast cells, if a tissue is damaged, such as a cut or a burn, these granules can be naturally produced. Cell membranes of every cell are made of phospholipids, and an enzyme called phospholipase a2 (PLa2).  PLa2 is located on the phospholipid bilayer of a cell and turns damaged phospholipids, from damage to the cell membrane, into arachidonic acid. COX-1 and COX-2 enzymes can take arachidonic acid and convert it into a leukotriene (COX-1) or  prostaglandin (COX-2). 

All of these inflammatory mediators, histamines, leukotrienes, and prostaglandins, alter the state of the endothelial cells. Endothelial cells are the cells that line the blood vessels, and an alteration in their structure and function allows for fluid and immune cells within the plasma to move into the interstitial space. 

Swelling 

The granules bind to receptors on endothelial cells and cause the cell to contract. The result is the formation of small gaps between the cells, allowing for immune cells to permeate from outside of the blood vessel to the inside. Further, the plasma within the blood vessels can leave the blood vessel and travel into the interstitial space between the skin and the blood vessels. This accumulation of plasma is referred to as adema, or swelling. Symptom number 1 of inflammation

Pain

Additionally, the interstitial space has a large amount of pain receptors, referred to as nociceptors. As the fluid increases, it begins to stimulate the receptors and cause feelings of pain. Symptom number 2!

Heat and redness

These inflammatory mediators can also bind  onto smooth muscle cells, causing them to relax. The result is vasodilation of the blood vessels. This reduces blood pressure, allowing for more blood flow at a specific site of inflammation. Since blood is thermogenic, the area begins to heat up.  Moreover, due to the color of blood (red) the area will begin to turn red. Symptoms number 3 and 4!

Why you get a fever

When an  immune cell begins processing an antigen, it will begin to secrete interleukin-1 and tumor necrosis Factor alpha (TNF alpha). Interleukin-1  and TNF alpha stimulate endothelial cells to produce more selection proteins on their surface and stimulate the movement of more immune cells into the site of location. Furthermore, Interleukin-1 and TNF alpha also   stimulate the production of PGE-2, in the brain. Through a series of mechanisms, PGE-2 will increase body temperature and lead to a fever. A fever increases metabolic processes, thus stimulating greater immune system function and activity, allowing for even greater pathogen fighting ability. Symptom number 5!

As these symptoms arise, the immune cells are busy terminating the pathogen! 

The battle ensues

Upon binding to the endothelial cells, inflammatory mediators stimulate granules inside of the endothelial cells, called WPB's.  This stimulates p-selectins to travel to the surface of the endothelial cells, exposing them to the plasma within our blood vessels. Within the blood plasma we have a multitude of immune cells, the most abundant being neutrophils and monocytes. These cells have sugar molecules on their membrane that will bind to p-selectins. Through a series of mechanical processes,  p-selectins allow the immune cells to pass through the gaps of the endothelial cells, into the interstitial space. 

The inflammatory mediators in the interstitial space will bind to receptors on the immune cells. However, they bind only on a specific side of the receptor,  signaling the sight of inflammation. triggering it to travel to the location of the pathogen.  This is called positive chemotaxis. 

Immune cells have the capability to form a complex around pathogens and, for lack of a better word, ingest the pathogen. The cell forms a vesicle around the pathogen called a phagosome. Inside the immune cells, there are hydrolytic enzymes in lysosomes. The lysosomes will form a complex with the phagosome, creating what is referred to as a phagolysosome. These enzymes will break down all of the structures within the pathogen. Except for one part… the antigens!

Adaptive immune system 

Macrophages are referred to as antigen presenting cells. In the macrophage, major histone comparability complex 2 (mhc-2)  will be created, and will bind to all of the antigens within the cell. Moreover, mhc-2 will be exposed on the membrane of macrophage. 

However, neutrophils, the other type of immune cells, are not antigen presenting cells. Thus they begin to exocytose, which is a fancy way of saying that neutrophils start to release the antigens from inside of the cell into the interstitial space. 

Antigens from neutrophils, and antigen presenting macrophages will both enter the lymph fluid, and enter into the lymph node. The lymphatic system is used to take the fluid that has built up in the interstitial space, and return it to the bloodstream. First, the fluid passes through lymph nodes, where the antigens and other bacteria are neutralized. 

In the lymph node, there are B cells. An antigen from the neutrophils will bind onto a receptor on the B cell, and "activate" the cell.  The antigen enters the B cell, where other mhc-2 molecules will bind to the antigen. The mhc-2, with the antigen attached,  is then presented on the surface of the B cell, which as discussed means the B cell is now an antigen presenting cell. 

I understand this sounds like a bunch of jargon. BUT, this is vital to our ability to protect against viruses in the future if we have already been exposed to them before. This is called adaptive immunity. 

At this point, we have antigen presenting B cells and macrophages present in the lymph node. 

The macrophage will interact with a T cell.  T cells will form a complex with the mhc-2 molecule, and the antigen, on the macrophage via a complex  on the T cell called TCR. 

After the two cells connect, there is a protien on the macrophage, called b7, will bind to a receptor on the surface of the T-cell called cd28. 

The last complex formed is between interleukin 1 on the macrophage, and a receptor on the T cell that stimulates the production of interleukin 2. Interleukin 2 is used to stimulate the production of interleukin 4 and interleukin 5.

The T cell will begin to divide into multiple T cells referred to as T2 cells. The T2 cells begin secreting more Interleukin 4 and 5. 

Well… what are Interleukin 4 and 5?

Remember that B cell that we were talking about? Well Interleukin 4 stimulates the B cell to begin to proliferate, which simply means to increase in number. The special component of these B cells is that they all have receptors that specifically bind to the original antigen, and the mhc-2/antigen complex expressed on the cell surface. This process is often called clonal expansion. 

Interleukin 5 stimulates some of the newly formed B cells to begin to differentiate, or change, into plasma cells and memory B cells. 

As the name might entail, memory B cells are cells with the specific receptor for the initial antigen. 

Plasma cells have the ability to secrete antibodies specific to the antigen as well. 

Antibodies are very important for our adaptive immune system. These antibodies are specific for the antigen present on the pathogen that caused this cascade of events. If the same pathogen is present in the future, antibodies can attach to the antigens on the pathogen, and inhibit it from damaging healthy cells. Antibodies are also vital to the complement system. 

Just when you thought it was over… I present the complement system 

Well, I guess we need to talk about the complement system. The liver is constantly synthesizing and releasing complement proteins into the plasma.  This is referred to as the complement system. Moreover, there are memory antibodies that have already been exposed to a specific pathogen in the past. These antibodies bind to the antigens on the pathogen (say that 5 times fast). These antibodies attract complement proteins. The first complement protein that will bind to the antibodies is called c-1. The next will be c-4 (for some odd reason). Then c-2, and then  c-3. However, c3 convertase will split complement three into two different portions. These are called c3a and c3b. C3a will essentially break off of the antibody. C3a will  act as chemotaxis molecules, which as we discussed cause more immune cells to travel to the site of inflammation. 

C3b will stay, and allow for the binding of c5b. Then, c6, c7 , c8, and c9 will all bind to this moiety. 

Stick with me here…

Then from c5b - c9 can break off from c1,2,3,and 4, and bind to the membrane of the pathogen. That structure is called a membrane attack complex (MAC). The MAC will begin to deteriorate the pathogen. 

Then, a Macrophage will bind to the complement proteins still attached to the antibody, and ingest the pathogen, inducing the same process as previously discussed. 

Moreover, c3b can bind to and can bind to the antibody and exude the exact same process without the presence of c1, c2, and c4.

The complement system simply just heightens the speed and veracity in which we can fight against pathogens that the immune system has already been exposed to.

Well, it's evident that immune system is extremely complex, and this is just the tip of the iceberg. I also like to know that all of this information is to my best knowledge as a 2022, and is definitely subject to change as emerging science and data is undertaken and published.