F*cking vaccines, How Do They Work - Part Two

Simon Loves Catfish And Hates Vaccine Preventable Illnesses

Following on the trails of my latest post I would like to delve a bit deeper into the mechanisms behind the working of vaccines starting by picking up a few loose ends that I left at the end of the previous post…

If you have not read that last post, go ahead, we will wait… *Ok, he is gone, get the beers! Get… * Oh, you are back! That was quick… Hello back!

Last minutes corrections.
Since my previous post went online, a helpful reader (*waves emphatically at Tom Sidwell*) pointed a few mistakes in my antibody structures… I wanted to spruce up my usual graphic, and more particularly, to illustrate the flexible hinge between the Fc and the Fab region and when the time came to label the picture, I put the wrong label on and marked it as a disulfide bond… It is in fact part of the protein…

I also ‘misunderestimated’ the exact size of the Fc region, that one was just a misremembering on my part… Thanks to Tom for pointing that out… Here is the corrected figure, with my apologies (I just hope Heidi does not feed me to the shark she keeps in her back-yard, especially as she just recently replaced the laser-beam on their head with chainsaws… that’s got to hurt).

Figure 1: The corrected diagram for the IgG molecule (click on the picture for full-size).

Loose ends, part 1: More on B-cell activation.

As I mentioned in the closing paragraph, there is a couple of important things I avoided talking about last time, the first one is the cell mediated immunity.

You see, there are three big groups of lymphocytes. The first one is composed of the lymphocytes B or B cell, so called because they mature in the Bone Marrow (or in bird, the Bursa de Fabricius. You too can become a hoot at parties by offering to show your Bursa de Fabricius to random strangers). The other one is called T-cell because, after they go and finish their maturation in the thymus…

The first two groups undergo the somatic recombination we mentioned earlier and both produce highly specific immunoglobulins that, when acting as cell bound receptors allows them to recognize antigens, once again, as mentioned earlier.

Were they diverge most is in their activation…

So, in broad brushes, the pathogen is floating around, it gets captured by a cell of the innate (non-specific immune system) that brings to the germinal centers, like a Labrador with a piece of smelly carrion. There, the dual presence of an antigen B-cell’s receptor and of signaling from activated T-cells will activate naïve B-cells (a naïve cell is one that has not been activated by the encounter with an antigen). Activated b-cells will maturate into a plasma cell and starts secreting free floating version of its immunoglobulins: the various antibodies… (the actual details of the activation are fairly complex and intricate and involve more receptors than just the ones I described; there is also some antigens that can activate the B-cells on their own without the help of additional signaling from the B-cells, we are simplifying A LOT, here).

Loose ends, part 1: More on T-cell activation and the cellular mediated immunity.

The T cells eschew such mundanities (I like to picture the B-cell as blue-collar factory workers: ‘gotta chuck out these antibodies!’ while the T-cells are snobby and high class. Also, they probably wear tiny monocles. The T-helpers are like managers while the cytolytic T cells are more like the evil English dude in Rob-Roy, the one played by Tim Roth that likes to duel. Also there are ninjas. They are riding velociraptors and the velociraptors have jet-packs, but I have not yet found a metaphor to put them in…).

As hinted, T-helpers are actually activated by presentation of the antigen through an MHCII and, upon activation, start secreting a bunch of various molecules (called cytokines) that serve in coordinating the immune response and, as mentioned, are often required for the activation of B-cells).

But it is the cytotoxic T-cells that really steal the show. They are activated by antigens presented through a different molecule, the MHCI. Essentially, the MHCI are present in all nucleated cells in the body. They bind fragments from other molecules produced within the cell (mostly degraded, deteriorated and misfolded proteins) and are translocated to the surface of the cell… That way, they present somewhat of a random sampling of the proteins the cell is produced. Normally, these will be normal proteins from the organism, of course, but if the cell happens to be infected, especially with a virus, some of the proteins synthesized will be viral ones… They will be displayed on the surface by the MHCI for the cytolytic T-cell to recognize them. This will signal to the lymphocyte that the cell has been compromised and, in turn, the lymphocyte will order the infected cell to enter apoptosis (or ‘programmed cell death’, basically, the infected cell will shut itself down rather than continue to produce pathogens) and, seriously, isn’t this mechanism like the coolest thing ever in the history of cool things?

Finally, there is a third group of lymphocyte, composed of natural killer cells. These do not undergo the somatic recombination and do not produce the antibody-like receptor we mentioned previously. Instead, they check the surface of passing cells for the presence of markers of self, including MHCI. If such markers are absent, it is a sign that something very wrong is going on inside… either the cell is infected by virus or it is cancerous… The NK cell will then either signal the cell to enter apoptosis or simply secrete molecules that will attack its cell membrane and lyse it…

Loose ends, part 3: The compartmentalization of the immune system.

The last thing I mentioned at the end of my previous post is the compartmentalization of the immune system.
And, before that, we also mentioned how the lymphocytes B made a circuit through various secondary lymphoid organs where they could be activated by exposition to antigens.

What we did not really touch upon is where these antigens came from. Basically, one can define three major compartments of the body and match them to particular secondary lymphoid organs. For example, the lymph nodes, are present located in small patches in the groin, armpits and neck (you know when you go to your physician for a fever and he palpates under your jaw? He is checking lymph nodes there). The spleen collects antigens brought there by the blood stream and all along the digestive and respiratory track you can find a bunch of Mucosa Associated Lymphoid Organs.
Now, naïve lymphocytes, lymphocytes that have not yet been activated by the encounter with an antigen, are released in the blood and, from there, circulate between the various secondary lymphoid organs. If the lymphocytes fail to get activated there, they will finish their route and return to the blood. However, if they get activated in a secondary organ, the surrounding signal will control the secretion of matching receptors called ‘lymphocyte homing receptors’. For example, if a lymphocyte is activated in the spleen, it will secrete receptors that will help it bind cells of the spleen. Similarly, if it is activated in a mucosal associated tissue, it will bind to other cells of the MALT. This phenomenon is called ‘homing’ of the lymphocyte and allows for the lymphocyte to remain in the compartment of the immune system it was activated in.
Such specialization makes sense, having your immune system trying to get rid of your gut flora, for example, is a recipe for disaster; the bacteria are an integral part of your digestion process. On the other hand, if you ever end up with E. coli in your bloodstream, you will want your immune system to get off its leukocytic butt and get rid of them as fast as possible…

These various compartments are not perfectly segregated, there is a bit of communication between them, especially from the lymph-nodes and GALT toward the blood-stream. However, this communication is limited.

Finally, while we are on the subject of the mucosal immunity, it is a good opportunity to mention yet another class of antibodies, in addition to IgM and IgG we mentionned earlier: the Immunoglobulin A (cf. figure 2). While IgM was pentameric and the IgG monomeric, the IgA is dimeric and is, if you want, composed of two immunoglobulin molecules linked together by a short polypeptide chain called the J chain (for joining chain).

Figure 2: The immunoglobulin A molecule.

There are two more immuglobulin types in mammals, the IgD and IgE, both monomeric, but neither of them are particularly important for the subject of vaccines, IgD is a receptor bound on the surface of naive B-cells that interacts with other immune cells, while IgE mainly plays a role in the defense against macroscopic elements (such as parasitic worms) and are involved in the allergic response… Interesting in its own right but not directly relevant here…

And now… look at that, we are already over my self-imposed limit of ‘around 1000 words’… this really took longer than I expected. But I think that most of the bases are posed by now and that we can build upon them in the next post in this series, focusing more on the vaccines proper: the various types of vaccines, their advantages and drawbacks.

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