commit bbfc688fee164f6ddf65a11886b2a0b524045c9e
parent bb572e6d6ba71e2b9b7333f3a2d4e03a85839b37
Author: Beau <cbeauhilton@gmail.com>
Date: Fri, 22 Mar 2024 11:19:09 -0500
add cad-fish post
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+# Cold agglutinin disease: fish out of water?
+
+<time id="post-date">2024-03-22</time>
+
+<p id="post-excerpt">
+Cold agglutinin disease is a fascinating and strange phenomenon, and might happen because we're fish.
+</p>
+
+## CAD: a matter of degree
+
+CAD is a disease of the cells that make the immune system,
+in which they overproduce a protein called cold agglutinin,
+resulting in a cascade of unfortunate events that are typically triggered by the blood getting slightly too cold
+(going outside in the winter, getting ice cream out of the freezer, drinking a Slurpie, etc.).
+Red blood cells clump together and cause painful, blue fingers/toes/etc.,
+sometimes so severe the affected bits die and fall off,
+and an autoimmune attack on the red blood cells begins,
+resulting in some of them being eaten alive by the liver and spleen
+and others being (literally) exploded while still in the blood vessels.
+
+Everybody has cold agglutinins,
+these proteins that cause the clumping ("agglutination"), at some low level.
+They're a type of IgM, a class of large proteins that are a key part of the immune system.
+IgM is really good at sticking things together,
+which is exactly what you want to happen in certain infections, etc.,
+but which happens aberrantly, and sometimes dramatically, with red blood cells in CAD.
+
+All red blood will agglutinate at 0-5C.
+This has been known since, at the latest, 1903.
+Karl Landsteiner figured it out.
+He's the guy who won the Nobel Prize for discovering blood types,
+which was based on experiments with "iso-agglutination,"
+With blood typing came the ability to cross-match blood for safe transfusion,
+which resulted in a huge leap forward in our ability to help people who lose a lot of it, as in surgery and trauma.
+We think of Landsteiner as the blood typing dude,
+but it's probably more accurate and expansive to think of him as the dude
+who first exhaustively characterized the different situations in which blood agglutinates.
+
+Landsteiner's discoveries came just in time for the World Wars,
+and folks got to collecting blood in earnest, at a huge scale.
+We went from a few laboratory fridges with dozens or hundreds of blood samples for experiments,
+to blood banks worldwide, collectively full of hundreds of thousands of units of blood
+for use in the operating room and battlefield.
+Some oddities about human existence are only found when the numbers grow to this size:
+blood bank technicians found that some blood agglutinates all the way up to 25C (~77F, "room temperature").
+This resulted in difficulty with accurately typing blood, which led to a number of deaths.
+
+In 1946 Lubinski and Goldbloom at Johns Hopkins published a paper describing seven patients
+with blood that would agglutinate all the way up to 37C (98.6F).
+All of these patients had brisk hemolysis (red blood cell explosion).
+
+Putting it together, we have three categories of blood agglutination in response to temperature:
+everyone's blood will agglutinate in a freezer,
+a small but significant portion of people have blood that agglutinates at room temperature,
+and there are an unfortunate few who have blood that agglutinates while still (relatively) warm in their bodies.
+In all of these cases, it's a cold agglutinin, a certain IgM protein, that coordinates the clumping.
+
+As a doctor I can accept that sometimes the body does horrible things,
+about which the most that can be fairly said,
+despite all that science can provide, is that they are random.
+A person's blood deciding to turn on them at the slightest cold provocation
+is well within the realm of crazy things we deal with on a daily basis.
+I would love to understand why everything horrible happens,
+but often have to move forward only knowing that it does happen,
+and hope that there might be a thing or two I can do to offset the horribleness.
+
+I can also accept that unnatural environments lead to unnatural phenomena,
+such as blood clumping in a freezer.
+That's a physical/chemical situation that never happens in a living animal
+(at least, in vertebrates. Don't get me started on the Antarctic midge).
+There doesn't need to be an evolutionary justification for the clumping in this case,
+just a biochemical one.
+
+It's the room temperature thing that bothers me.
+In physiologic findings that are so clearly a matter of degree,
+with an obvious sliding scale,
+I wonder: what in our deep past created the affordance for this thing in the first place?
+Why do we have cold agglutinins at all?
+
+## Whence cold agglutinins? Probably fish. And fish are us.
+
+Sigbjorn Berentsen is a Norwegian physician and researcher
+(CAD is, as you might expect, much more common in colder climates),
+and is The Man when it comes to understanding and treating CAD in the modern era.
+
+A recent paper from him had this to say about the most likely possibility of the origin of cold agglutinins:
+
+> ...the physiological function of CAs has not been clarified.
+It is difficult to envision a functional role of antibodies with a temperature optimum way below body temperature.
+Comparative studies, however, have strongly indicated that the evolution of the adaptive immune system
+began with the jawed vertebrates.
+Cartilaginous fish,
+which are phylogenetically ancient and considered closely related to the first jawed vertebrates,
+have only one immunoglobulin class in common with humans: IgM...
+[T]he temperature optimum of CAs is much closer to the environmental and body temperature of non-mammal sea vertebrates.
+Furthermore,
+CAs can react with antigens other than RBC surface macromolecules,
+and structures closely related to the I antigen are present on some microorganisms
+such as Streptococcus and Listeria species.
+Thus, one might explain human CAs as remnants of a primitive vertebrate immune system.
+
+<https://doi.org/10.3389/fimmu.2020.00590>
+
+So, ancient fish, swimming in room temperature or colder water, had to fight certain bacteria.
+The fish are us, if you go back far enough.
+We happened to have held on to this ability, these proteins, an immunologic vestigial tail.
+Certain proteins on our red blood cells look an awful lot like the proteins on those bacteria,
+and, if you are unlucky enough that your vestigial tail grows out more than the average bear, friendly fire ensues.
+(That last sentence has a staggering number of mixed metaphors.
+Smiling, tongue firmly in cheek, he turned to you and said, "Humans *are* mixed metaphors.")
+
+
+## Conclusion, prefaced by an aside on Jaron Lanier
+
+Jaron Lanier is a computer scientist, ethnomusicologist, and all-around wonderful weirdo
+who was behind a lot of the early virtual reality experiments in the 70s-80s
+(and now works on VR with Microsoft when he's not putting on concerts showcasing Chinese mouth-organs).
+He would do this thing where he would create VR avatars with many more limbs than humans
+(lobster is a classic one)
+and attach sensors to the participants to allow them to control all the limbs
+with various subtle movements (hips, elbows, knees, etc.).
+They found that it didn't take long for the humans to achieve surprising proficiency
+acting as a >4-limbed creature,
+and he would wax poetic about the ancient phylogenetic compatibility
+still hidden in the motor centers of the brain,
+and other related, delicious ideas
+(maybe it's not four limbs and 20 digits that are mapped discretely
+and *a priori* into the human brain,
+maybe it's the capacity to map any number of prehensile bits that is inherent, etc.
+The therapeutic and geeky possibilities leading from this are way too much fun to contain in an aside).
+
+Anyway, the point it this:
+I love it when the answer is, "idk, maybe we're fish. What's a fish, anyway?"
