The immune response

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I have this compulsion to talk about the immune system. In part this is because it is grant season and I have been writing a lot about it in my latest grant proposal. It is such a beautiful and strange thing that I want to display some of that strangeness and beauty to you. Also, it is fundamental to understanding Type 1 diabetes and the efforts we are making towards finding a cure. Come to think of it, one part of the immune system – namely the part that produces inflammation is pretty important for type 2 diabetes as well as type 1. So, as I said, I feel this compulsion. This is a problem because the immune system is really hard to explain. How hard? Let’s put it this way, Jessica, the founder of A Sweet Life has made me rewrite this post 3 times. She is a very good editor.

So, how can I explain this to you without turning you off? Hopefully you are reading a science blog because you want to know about this stuff. That will help. I think the best course of action is to first describe a garden variety immune response to a bacterial infection and then in subsequent posts get into how different parts of that response were made possible. Ultimately, the immune system has a huge design problem to solve – namely how to tell what is “self” from what is not self and therefore dangerous. As I mentioned in an earlier post, this is not a perfect process and autoimmunity arises from mistakes made along the way.

So you cut your finger.

The skin, that first line of defense, has been breached and the invader has entered. The invader is a bacterium which, upon finding itself in a nice warm nutritious environment, begins to divide. A sentinel cell in the skin tissue realizes something is wrong because some cells right next to the cut have realized that their neighbors are gone and are secreting a signaling protein to this effect. The sentinel is a kind of cell called a dendritic cell. Being quite mobile, it follows the signal back to the source and runs into some bacteria. Now the dendritic cell is literally touching everything as it goes and when it touches the bacterium something about it on the bacterium’s surface makes it realize that this is not a cell of the body but rather, an invader. The thing it touched is something we call a pathogenic molecular pattern or PAMP. Did I mention that scientists love acronyms? Dendritic cells have somewhere between 12 and 15 receptors that can mix and match and recognize around 100 or so of these PAMPs. The response of the dendritic cell to this danger signal is to engulf the bacterium in a process called phagocytosis. Did I mention that scientists love big words derived from Greek or Latin roots?  Inside the cell the bacterium gets broken down and bits of it get displayed like trophies on the outside of the dendritic cell. We are going to call those bits “antigens”.

The dendritic cell now feels a compulsion to find a lymph node. This compulsion is really the result of a new pattern of gene expression caused by the activation of those receptors that recognized danger. By the way this will be a huge theme in these posts: some receptor gets activated and it causes a bunch of new genes to make proteins and the cell gets reprogrammed. Anyway, the dendritic cell finds its way to the nearest lymph node. This is not hard to do because all paths lead to the lymph node. Lymph nodes are sort of like drainage junctions for handling the fluid that bathes tissues outside of the blood stream. Importantly, lymph nodes are military bases. They are chock full of two very important immune cell types: T cells and B cells.

The T cell is recruited.

Once the dendritic cell enters the lymph node it gets mobbed by T cells. Researchers have actually gotten videos of this (http://www.sciencemag.org/cgi/content/full/296/5574/1873/DC1). T cells have a particular receptor on their surface called the T cell receptor. The function of the T cell receptor is to recognize antigen. Indeed the T cell sees the world through its T cell receptor. It has many thousands of copies of the receptor but only one receptor. This is a really important point so I need to emphasize it. It’s going to be key to understanding everything that follows. Each T cell has a different T cell receptor that recognizes a different antigen. So only one T cell in that whole lymph node or maybe just a few T cells will recognize an antigen displayed on the surface of the dendritic cell.

The T cell that recognizes the antigen activates. As I mentioned above, this means a bunch of new genes get made into proteins and the cell gets reprogrammed. It begins to divide. One cell becomes an army. This army moves deeper into the lymph node into a region that has this other type of cell called the B cell. B cells make antibodies. Like the T cell receptor, the B cell receptor recognizes only one type of antigen. When a T cell finds a matching B cell, the B cell activates, begins dividing, and creates its own army. The two armies co-mingle and in doing so, the T cell “instructs” the B cell how to make antibodies that will recognize the antigen. Once this is done they all go racing out back to the tissue where the invasion is happening.

The battle.

B cells secrete antibodies and these antibodies bind to the bacteria. Antibodies serve two functions. Proteins in the blood, called “complement proteins” assemble around the antibody and create a structure called the “attack complex” that functions very much like a molecular drill. It drills holes in the bacteria and makes them “bleed out” – sort of. Phagocytic cells like macrophages find their way to the site and using the antibody bound to the surface of the bacteria sort of like Velcro, grab onto the bacteria and engulf them.

Your finger has gotten red and swollen around the cut. Liquid has entered the area to make it easier for all of those immune cells to access the area. We call this edema. Pus may form if it is a particularly bad infection. These are all of the dead macrophages, T cells, and B cells that have died fighting for your survival.

So to recap: dendritic cells and macrophages are examples of cells that engulf other cells. T cells and B cells are cells that recognize antigen. Each T (or B) cell has only one set of receptor genes and therefore expresses many thousands of copies of only one kind of receptor that recognizes only one antigenic shape. When needed one of these cells expands to create an army to fight that battle we call the immune response.

Since you are still here I guess you won. The bacterial invaders were killed. The T cells and B cell armies mostly died off but a few stuck around to give your body “memory” of that danger you just survived. The skin healed and importantly, macrophages stuck around after the battle to secrete growth factors to help in that process.

Meanwhile pathogens swarm about us. Waiting.

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[…] first consider what an immunologist would think of as a danger signal. Our immune system continuously patrols the body. Macrophages, like garbage trucks, are constantly cleaning up the […]

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[…] mentioned in a previous post that T cells hang out in military bases called lymph nodes. Each organ has one or more dedicated […]

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