Turned up to eleven: Fair and Balanced

Wednesday, March 20, 2002

Kathy Kinsley has given me a nudge to get on with the innate immunity post I promised (who is this "ed." guy, and how come he gets to insert comments into everyone's posts?-ed.), so here it is. Fair warning; this is pretty dry stuff for most people. If you don't like it, you know who to blame!

Innate Immunity (or how I learned to stop worrying and love a fever)

The innate immune system is a catch-all term for the various systems in the body that deal with non-specific threats to the system. It is difficult at times to separate out the systems of immunity (innate, adaptive), and in fact many of their operations are intertwined. A quick overview will be presented here, with emphasis on how the non-adaptive system functions, and how this might relate to bioterrorism defense, as mentioned in an earlier post.

The immune system is a complex, interrelated group of organs (spleen, bone marrow), tissues (lymph nodes, various mucosal layers and specialized cells), and blood cells (PMNs, macrophages, T and B cells) that work in a mostly concerted effort to recognize and eliminate foreign bodies from the host organism. As stated above, the system can be divided into two overlapping subsystems (it can be further subdivided, as we will probably discuss in the future) referred to as innate and adaptive immunity. The adaptive system is called that because it develops as we grow and are exposed to "immunogens," foreign bodies which can elicit a response from this system in the form of T or B cell development. This process (trust me, you are not interested in the details of immune cell maturation and differentiation) results in the wide variety of specific immune cells, which respond to one specific antigen, defined by a receptor molecule on the surface of the immune cell. The innate system is the system that we are born with, and the key to this system is that it is fairly non-specific. It recognizes foreign objects in essentially two ways. The effector cells, that is, the cells that do the dirty work of innate immunity, are the PMNs (polymorphonuclear leukocyte, sometimes also called a neutrophil), and macrophages (the immature form is called a monocyte, and you will sometimes see the terms used interchangeably). These cells are called phagocytic, because they are able to envelop and swallow up foreign objects in a process that is called, of course, phagocytosis. How do these cells know that there is a foreign body to be attacked? In the case of PMNs, they detect a string of amino acids called fMLP, which stands for formyl-methionine-leucine-phenylalanine, which is specific for bacteria (but not any particular bacterium). Macrophages can detect either opsonization , which means covering something with antibodies, or complement (see below for description). After taking up the foreign object, they essentially destroy it in compartment called a lysosome, which is very acidic. This cellular approach is the first way that innate immunity works. The second way is through the activation of a cascade of enzymes known as complement. The complement system is the humoral (liquid) phase system, as opposed to the cellular system. This part is tricky, and if it is any comfort, go ask your local physician to explain how the complement activation pathway works. The blank stare you get will make you feel better about this. I only remember it vaguely, but I will try to explain it. Essentially, this system is activated by two different sources, and these are known as the classical and alternative pathways (a pretty good overview of the systems, in relatively non-technical terms, can be found here). One pathway involves antibodies, which come from the adaptive immune system, while the other involves detection of bacterial debris from an infection.

At this point, you might ask yourself, 1) why am I reading this? and 2) what does this have to do with bioterrorism? Both are good questions, but I can only address #2. The reason that this came up was that I commented that I didn't think trying to augment the innate immune system was a very good idea, and I haven't yet explained why. To understand that, you need to understand at a basic level what the system described above is used for. Essentially, the innate immune system has two functions. One is to protect infants that haven't developed very much adaptive immunity (especially true in animals, but fairly accurate in humans as well), and the other is to provide a first and a last line of defense against infection. What I haven't told you about the innate immune system is that the effector cells named in the previous paragraph don't just swallow up foreign objects. When they do this, it stimulates them to release chemicals that are called pro-inflammatory cytokines. The most important of these are Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha). The release of these factors has several effects, including recruitment of more phagocytic cells to the site, activation of immune and phagocytic cells, and inflammation. The last one of these is the most important for our discussion (it is also the source of my title, along with Dr. Strangelove). If you want a great pictorial, hyperlinked guide to inflammation, here it is. In any event, we learn in grad school that the symptoms of inflammation are tumor (swelling), rubor (redness), calor (fever or heat), and dolor (pain). Localized inflammation is an important part of the healing process, either from a wound, or bacterial infection. The problem comes in when this becomes a systemic response, due most likely to overproduction of the pro-inflammatory cytokines. High, prolonged fever is a serious concern, and systemic pro-inflammatory response, including activation of phagocytic cells throughout the body, is a great way to kill someone. In fact, one of the biggest killers in the U.S. is septic shock, also called septicemia or sometimes bacteremia (this is a bit different, but the symptoms are the same). This disease is caused by the presence of bacterial cell envelope (lipopolysaccharide, or LPS) in the bloodstream, which provokes a systemic inflammatory response.

You might now ask yourself, ok, but what does this have to do with bioterrorism? Well, the article that Kathy cited was about boosting the innate immune system to create a "supervaccine." There is a critical difference between the two systems, however, that I have alluded to, and hopefully communicated somewhat clearly. The innate system is not specific for any organism (although it first and foremost targets Gram-negative bacteria). It is activated, in fact, by non-infectious processes such as a cut in the skin, to a limited extent. It probably has a homeostatic effect, making sure that our body as a whole stays equilibrated while a localized injury or infection heals. It is likely, IMHO, that attempting to boost this system will have horrific side effects. Lets take the septic shock example given above. This reaction to bacterial LPS (also called endotoxin) is probably a side effect of the surveillance function of the innate immune system. Our gut is filled with bacteria, and they happen to be mostly Gram-negative, that is, they have this LPS in their cell envelope. The body is very, very sensitive to the presence of this molecule in the bloodstream, probably as a way to detect any kind of damage to the intestinal wall. As a by-product, the presence of even small quantities of LPS in the bloodstream can be deadly. This is mediated almost entirely by the innate immune system. Boosting this system seems very likely to me to make us even more sensitive to the presence of LPS. I greatly fear that the effort boost this system would only have the effect of making septic shock more deadly and more common.

The above is just an example of the pitfalls of this type of approach. Of course, there is a mechanism of trial and error that works well to test for these things. One word of caution; don't get your hopes up if you see that someone has created a vaccine that boosts innate immunity in an animal model. Animal models of inflammation are notoriously tricky; the experiments are hard to control, and because of differences in the types of bacterial flora in the guts of animals, the results are very difficult to translate to humans (I worked on some of this in grad school, a rabbit model of endotoxin shock). I would never suggest that the experiments shouldn't be done, that would be an unscientific approach. I just don't think that this is the way to go.