cad-fish.md (7699B)
1 # Cold agglutinin disease: fish out of water? 2 3 <time id="post-date">2024-03-22</time> 4 5 <p id="post-excerpt"> 6 Cold agglutinin disease is a fascinating and strange phenomenon, and might happen because we're fish. 7 </p> 8 9 ## CAD: a matter of degree 10 11 CAD is a disease of the cells that make the immune system, 12 in which they overproduce a protein called cold agglutinin, 13 resulting in a cascade of unfortunate events that are typically triggered by the blood getting slightly too cold 14 (going outside in the winter, getting ice cream out of the freezer, drinking a Slurpie, etc.). 15 Red blood cells clump together and cause painful, blue fingers/toes/etc., 16 sometimes so severe the affected bits die and fall off, 17 and an autoimmune attack on the red blood cells begins, 18 resulting in some of them being eaten alive by the liver and spleen 19 and others being (literally) exploded while still in the blood vessels. 20 21 Everybody has cold agglutinins, 22 these proteins that cause the clumping ("agglutination"), at some low level. 23 They're a type of IgM, a class of large proteins that are a key part of the immune system. 24 IgM is really good at sticking things together, 25 which is exactly what you want to happen in certain infections, etc., 26 but which happens aberrantly, and sometimes dramatically, with red blood cells in CAD. 27 28 All red blood will agglutinate at 0-5C. 29 This has been known since, at the latest, 1903. 30 Karl Landsteiner figured it out. 31 He's the guy who won the Nobel Prize for discovering blood types, 32 which was based on experiments with "iso-agglutination." 33 With blood typing came the ability to cross-match blood for safe transfusion, 34 which resulted in a huge leap forward in our ability to help people who lose a lot of it, as in surgery and trauma. 35 We think of Landsteiner as the blood typing dude, 36 but it's probably more accurate and expansive to think of him as the dude 37 who first exhaustively characterized the different situations in which blood agglutinates. 38 39 Landsteiner's discoveries came just in time for the World Wars, 40 and folks got to collecting blood in earnest, on a massive scale. 41 We went from a few laboratory fridges with dozens or hundreds of blood samples for experiments, 42 to blood banks worldwide, collectively full of hundreds of thousands of units of blood 43 for use in the operating room and battlefield. 44 Some oddities about human existence are only found when the numbers grow to this size: 45 blood bank technicians found that some blood agglutinates all the way up to 25C (~77F, "room temperature"). 46 This resulted in difficulty with accurately typing blood, which led to a number of deaths. 47 48 In 1946 Lubinski and Goldbloom at Johns Hopkins published a paper describing seven patients 49 with blood that would agglutinate all the way up to 37C (98.6F). 50 All of these patients had brisk hemolysis (red blood cell explosion). 51 52 Putting it together, we have three categories of blood agglutination in response to temperature: 53 everyone's blood will agglutinate in a freezer, 54 a small but significant portion of people have blood that agglutinates at room temperature, 55 and there are an unfortunate few who have blood that agglutinates while still (relatively) warm in their bodies. 56 In all of these cases, it's a cold agglutinin, a certain IgM protein, that coordinates the clumping. 57 58 As a doctor I can accept that sometimes the body does horrible things, 59 about which the most that can be fairly said, 60 despite all that science can provide, is that they are random. 61 A person's blood deciding to turn on them at the slightest cold provocation 62 is well within the realm of crazy things we deal with on a daily basis. 63 I would love to understand why everything horrible happens, 64 but often have to move forward only knowing that it does happen, 65 and hope that there might be a thing or two I can do to offset the horribleness. 66 67 I can also accept that unnatural environments lead to unnatural phenomena, 68 such as blood clumping in a freezer. 69 That's a physical/chemical situation that never happens in a living animal 70 (at least, in vertebrates. Don't get me started on the Antarctic midge). 71 There doesn't need to be an evolutionary justification for the clumping in this case, 72 just a biochemical one. 73 74 It's the room temperature thing that bothers me. 75 In physiologic findings that are so clearly a matter of degree, 76 with an obvious sliding scale, 77 I wonder: what in our deep past created the affordance for this thing in the first place? 78 Why do we have cold agglutinins at all? 79 80 ## Whence cold agglutinins? Probably fish. And fish are us. 81 82 Sigbjorn Berentsen is a Norwegian physician and researcher 83 (CAD is, as you might expect, much more common in colder climates), 84 and is The Man when it comes to understanding and treating CAD in the modern era. 85 86 A recent paper from him had this to say about the most likely possibility of the origin of cold agglutinins: 87 88 > ...the physiological function of CAs has not been clarified. 89 It is difficult to envision a functional role of antibodies with a temperature optimum way below body temperature. 90 Comparative studies, however, have strongly indicated that the evolution of the adaptive immune system 91 began with the jawed vertebrates. 92 Cartilaginous fish, 93 which are phylogenetically ancient and considered closely related to the first jawed vertebrates, 94 have only one immunoglobulin class in common with humans: IgM... 95 [T]he temperature optimum of CAs is much closer to the environmental and body temperature of non-mammal sea vertebrates. 96 Furthermore, 97 CAs can react with antigens other than RBC surface macromolecules, 98 and structures closely related to the I antigen are present on some microorganisms 99 such as Streptococcus and Listeria species. 100 Thus, one might explain human CAs as remnants of a primitive vertebrate immune system. 101 102 <https://doi.org/10.3389/fimmu.2020.00590> 103 104 So, ancient fish, swimming in room temperature or colder water, had to fight certain bacteria. 105 The fish are us, if you go back far enough. 106 We happened to have held on to this ability, these proteins, an immunologic vestigial tail. 107 Certain proteins on our red blood cells look an awful lot like the proteins on those bacteria, 108 and, if you are unlucky enough that your vestigial tail grows out more than the average bear, friendly fire ensues. 109 (That last sentence has a staggering number of mixed metaphors. 110 Smiling, tongue firmly in cheek, he turned to you and said, "Humans *are* mixed metaphors.") 111 112 113 ## Conclusion, prefaced by an aside on Jaron Lanier 114 115 Jaron Lanier is a computer scientist, ethnomusicologist, and all-around wonderful weirdo 116 who was behind a lot of the early virtual reality experiments in the 70s-80s 117 (and now works on VR with Microsoft when he's not putting on concerts showcasing Chinese mouth-organs). 118 He would do this thing where he would create VR avatars with many more limbs than humans 119 (lobster is a classic one) 120 and attach sensors to the participants to allow them to control all the limbs 121 with various subtle movements (hips, elbows, knees, etc.). 122 They found that it didn't take long for the humans to achieve surprising proficiency 123 acting as a >4-limbed creature, 124 and he would wax poetic about the ancient phylogenetic compatibility 125 still hidden in the motor centers of the brain, 126 and other related, delicious ideas 127 (maybe it's not four limbs and 20 digits that are mapped discretely 128 and *a priori* into the human brain, 129 maybe it's the capacity to map any number of prehensile bits that is inherent, etc. 130 The therapeutic and geeky possibilities leading from this are way too much fun to contain in an aside). 131 132 Anyway, the point it this: 133 I love it when the answer is, "idk, maybe we're fish. What's a fish, anyway?"