Monday, 4 May 2009

Volcanos and MHC

The volcano is getting restless. Quick, someone sacrifice a goat. I hear Mike Kelly's not busy anymore...

With the Swine Flu getting quite a bit of attention these days, I figure I could make a topical post by reaching back into my work experience and making a post about immunogenetics. Swine Flu is both important and overblown by the media; a very bright epidemiologist from Ames Iowa can explain two reasons why it's concerning far better than I could.

An important thing in fighting off diseased cells in your body is recognizing that they're infected. When a Virus infects one of your body's cells (or any cells), it injects its DNA (or RNA, a close chemical cousin of DNA) into the cell, and tricks the cell into using that genetic material. That DNA or RNA makes the cell produce new virus parts, which self-assemble (Easier than the Ikea crap) and sometimes hang around until the cell explodes, releasing all the new viruses. It's actually kinda smart.

If you're reading this, and you have a spine (Sorry, shellfish readers), you have tools to fight off viruses. This comes in the form of what is called the Major Histocompatibility Complex, or MHC. It was discovered in the early 1900s, when surgeons of the day had a problem. Sometimes, tissue grafts, especially skin grafts, would take just fine. Other times, it would be violently and horribly rejected, sometimes killing the person in the process. In the 1930s, a Scientist named Gorer discovered that he could isolate 4 blood antigens that would strongly influence whether the tissue was rejected or not.

The antigens were MHC. So is MHC just there to make doctor's lives difficult? Obviously not, because I said it has something to do with fighting off viruses earlier! MHC is a critical part of the antigen recognition process. What happens is that as viruses replicate, they produce protein. Some of that protein is degraded by what we call Proteinases - protein-chopper-uppers. Also, protein naturally degrades on its own, over time. This produces lots of little fragments of protein floating around inside your cells, and outside your cells.

MHC's job is deceptively simple. It grabs these little chunks of protein floating around, and puts it out on the surface of the cell. This allows T-Cells, an important component of your active imune system, to go through and see if they recognize the MHC+Protein fragment combination. If they recognize it, then it's foreign, and it triggers an immune response, ultimately killing off the cell. Crazy, huh? You can see it in the second figure of this post: the peptide is the green bit.

The whole process is made tricky because of a few reasons. First, your MHC only has two `docking points` that it can grab these little floating protein chunks And these docking points can only grab specific forms of protein parts. Without getting into too much chemical detail, different parts of protein have different building material. Using a building analogy, if a stretch of protein is made out of wood, your MHC might be able to recognize it, but if it's made out of cinder blocks, it can't grab on to it.

Second, you only have two docks for each MHC type. Luckily, you have one MHC type for stuff inside your cells, and one for stuff outside, but that's still only 4 docks. And there's no guarantees that you'll get different sorts from your parents. If you get an identical sort from your mother and your father, then you're limited in what your MHC can detect.

Third, it's important to know that viruses are wiley beasts, and they mutate like crazy. If they have a mutation in a part of the peptide fragment responsible for being scooped up by the MHC - using my building analogy again, if they mutate from wood to brick in part of the docking segment - then that fragment can't be picked up by whatever MHC receptor that was recognizing it, anymore. All the new T-Cells that were made to recognize the fragment+dock combination are now kinda useless, and the virus has some breathing room until a new fragment is found, shown to a T-Cell, and more of those sorts of cells are made.

Finally, the last tricky bit is the T-Cell recognition itself. I said that it'll recognize foreign stuff... but how's the T-Cell know that it's foreign? When T-Cells are maturing, they go through a little squishy bit of organ called the thymus. The thymus isn't a very impressive organ. It's incredibly easy to miss that it exists at all, in a lot of critters. I don't think there's a yup'ik word for Thymus - I'll have to ask, but I don't know any. It's that small and unremarkable. Except while in the thymus, T-Cells get schooled. The thymus presents pretty much everything there is to express in the body, and the T-Cells either recognize stuff, or they don't. Those that recognize the stuff in the thymus are destroyed, leaving only T-Cells that can detect non-self-stuff. The process is called thymic education.

And you thought our school testing was high stakes!

There's literally reams more I could write about MHC. It's important for a billion and a half things, some of which have nothing in the least to do with disease. And you can imagine why a wildlife biologist might be interested in genes that help critters fight off diseases! I've got no doubt that I'll return to MHC in the near future.

The first figure is an excerpt of a figure graciously provided to me by WK Potts. The second figure comes from the URL cited at the bottom of the picture, but comes via WK Potts again.

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