index.html (9471B)
1 <!DOCTYPE html> 2 <html lang="en"> 3 <head> 4 <link rel="stylesheet" href="/style.css" type="text/css"> 5 <meta charset="utf-8"> 6 <meta http-equiv="Content-Type" content="text/html; charset=utf-8"> 7 <meta name="viewport" content="width=device-width, initial-scale=1.0"> 8 <link rel="stylesheet" type="text/css" href="/style.css"> 9 <link rel="icon" href="data:image/svg+xml,<svg xmlns=%22http://www.w3.org/2000/svg%22 viewBox=%220 0 100 100%22><text y=%22.9em%22 font-size=%2290%22>🏕️</text></svg>"> 10 <title></title> 11 </head> 12 <body> 13 <div id="page-wrapper"> 14 <div id="header" role="banner"> 15 <header class="banner"> 16 <div id="banner-text"> 17 <span class="banner-title"><a href="/">beauhilton</a></span> 18 </div> 19 </header> 20 <nav> 21 <a href="/about">about</a> 22 <a href="/now">now</a> 23 <a href="/thanks">thanks</a> 24 <a class="nav-active" href="/posts">posts</a> 25 <a href="https://notes.beauhilton.com">notes</a> 26 <a href="https://talks.beauhilton.com">talks</a> 27 <a href="https://git.beauhilton.com">git</a> 28 <a href="/contact">contact</a> 29 <a href="/atom.xml">rss</a> 30 </nav> 31 </div> 32 <main> 33 <h1> 34 Cold agglutinin disease: fish out of water? 35 </h1> 36 <p> 37 <time id="post-date">2024-03-22</time> 38 </p> 39 <p id="post-excerpt"> 40 Cold agglutinin disease is a fascinating and strange phenomenon, and might happen because we're fish. 41 </p> 42 <h2> 43 CAD: a matter of degree 44 </h2> 45 <p> 46 CAD is a disease of the cells that make the immune system, in which 47 they overproduce a protein called cold agglutinin, resulting in a 48 cascade of unfortunate events that are typically triggered by the blood 49 getting slightly too cold (going outside in the winter, getting ice 50 cream out of the freezer, drinking a Slurpie, etc.). Red blood cells 51 clump together and cause painful, blue fingers/toes/etc., sometimes so 52 severe the affected bits die and fall off, and an autoimmune attack on 53 the red blood cells begins, resulting in some of them being eaten alive 54 by the liver and spleen and others being (literally) exploded while 55 still in the blood vessels. 56 </p> 57 <p> 58 Everybody has cold agglutinins, these proteins that cause the 59 clumping (“agglutination”), at some low level. They’re a type of IgM, a 60 class of large proteins that are a key part of the immune system. IgM is 61 really good at sticking things together, which is exactly what you want 62 to happen in certain infections, etc., but which happens aberrantly, and 63 sometimes dramatically, with red blood cells in CAD. 64 </p> 65 <p> 66 All red blood will agglutinate at 0-5C. This has been known since, at 67 the latest, 1903. Karl Landsteiner figured it out. He’s the guy who won 68 the Nobel Prize for discovering blood types, which was based on 69 experiments with “iso-agglutination.” With blood typing came the ability 70 to cross-match blood for safe transfusion, which resulted in a huge leap 71 forward in our ability to help people who lose a lot of it, as in 72 surgery and trauma. We think of Landsteiner as the blood typing dude, 73 but it’s probably more accurate and expansive to think of him as the 74 dude who first exhaustively characterized the different situations in 75 which blood agglutinates. 76 </p> 77 <p> 78 Landsteiner’s discoveries came just in time for the World Wars, and 79 folks got to collecting blood in earnest, on a massive scale. We went 80 from a few laboratory fridges with dozens or hundreds of blood samples 81 for experiments, to blood banks worldwide, collectively full of hundreds 82 of thousands of units of blood for use in the operating room and 83 battlefield. Some oddities about human existence are only found when the 84 numbers grow to this size: blood bank technicians found that some blood 85 agglutinates all the way up to 25C (~77F, “room temperature”). This 86 resulted in difficulty with accurately typing blood, which led to a 87 number of deaths. 88 </p> 89 <p> 90 In 1946 Lubinski and Goldbloom at Johns Hopkins published a paper 91 describing seven patients with blood that would agglutinate all the way 92 up to 37C (98.6F). All of these patients had brisk hemolysis (red blood 93 cell explosion). 94 </p> 95 <p> 96 Putting it together, we have three categories of blood agglutination 97 in response to temperature: everyone’s blood will agglutinate in a 98 freezer, a small but significant portion of people have blood that 99 agglutinates at room temperature, and there are an unfortunate few who 100 have blood that agglutinates while still (relatively) warm in their 101 bodies. In all of these cases, it’s a cold agglutinin, a certain IgM 102 protein, that coordinates the clumping. 103 </p> 104 <p> 105 As a doctor I can accept that sometimes the body does horrible 106 things, about which the most that can be fairly said, despite all that 107 science can provide, is that they are random. A person’s blood deciding 108 to turn on them at the slightest cold provocation is well within the 109 realm of crazy things we deal with on a daily basis. I would love to 110 understand why everything horrible happens, but often have to move 111 forward only knowing that it does happen, and hope that there might be a 112 thing or two I can do to offset the horribleness. 113 </p> 114 <p> 115 I can also accept that unnatural environments lead to unnatural 116 phenomena, such as blood clumping in a freezer. That’s a 117 physical/chemical situation that never happens in a living animal (at 118 least, in vertebrates. Don’t get me started on the Antarctic midge). 119 There doesn’t need to be an evolutionary justification for the clumping 120 in this case, just a biochemical one. 121 </p> 122 <p> 123 It’s the room temperature thing that bothers me. In physiologic 124 findings that are so clearly a matter of degree, with an obvious sliding 125 scale, I wonder: what in our deep past created the affordance for this 126 thing in the first place? Why do we have cold agglutinins at all? 127 </p> 128 <h2> 129 Whence cold agglutinins? Probably fish. And fish are us. 130 </h2> 131 <p> 132 Sigbjorn Berentsen is a Norwegian physician and researcher (CAD is, 133 as you might expect, much more common in colder climates), and is The 134 Man when it comes to understanding and treating CAD in the modern 135 era. 136 </p> 137 <p> 138 A recent paper from him had this to say about the most likely 139 possibility of the origin of cold agglutinins: 140 </p> 141 <blockquote> 142 <p> 143 …the physiological function of CAs has not been clarified. It is 144 difficult to envision a functional role of antibodies with a temperature 145 optimum way below body temperature. Comparative studies, however, have 146 strongly indicated that the evolution of the adaptive immune system 147 began with the jawed vertebrates. Cartilaginous fish, which are 148 phylogenetically ancient and considered closely related to the first 149 jawed vertebrates, have only one immunoglobulin class in common with 150 humans: IgM… [T]he temperature optimum of CAs is much closer to the 151 environmental and body temperature of non-mammal sea vertebrates. 152 Furthermore, CAs can react with antigens other than RBC surface 153 macromolecules, and structures closely related to the I antigen are 154 present on some microorganisms such as Streptococcus and Listeria 155 species. Thus, one might explain human CAs as remnants of a primitive 156 vertebrate immune system. 157 </p> 158 </blockquote> 159 <p> 160 <a href="https://doi.org/10.3389/fimmu.2020.00590">https://doi.org/10.3389/fimmu.2020.00590</a> 161 </p> 162 <p> 163 So, ancient fish, swimming in room temperature or colder water, had 164 to fight certain bacteria. The fish are us, if you go back far enough. 165 We happened to have held on to this ability, these proteins, an 166 immunologic vestigial tail. Certain proteins on our red blood cells look 167 an awful lot like the proteins on those bacteria, and, if you are 168 unlucky enough that your vestigial tail grows out more than the average 169 bear, friendly fire ensues. (That last sentence has a staggering number 170 of mixed metaphors. Smiling, tongue firmly in cheek, he turned to you 171 and said, “Humans <em>are</em> mixed metaphors.”) 172 </p> 173 <h2> 174 Conclusion, prefaced by an aside on Jaron Lanier 175 </h2> 176 <p> 177 Jaron Lanier is a computer scientist, ethnomusicologist, and 178 all-around wonderful weirdo who was behind a lot of the early virtual 179 reality experiments in the 70s-80s (and now works on VR with Microsoft 180 when he’s not putting on concerts showcasing Chinese mouth-organs). He 181 would do this thing where he would create VR avatars with many more 182 limbs than humans (lobster is a classic one) and attach sensors to the 183 participants to allow them to control all the limbs with various subtle 184 movements (hips, elbows, knees, etc.). They found that it didn’t take 185 long for the humans to achieve surprising proficiency acting as a 186 >4-limbed creature, and he would wax poetic about the ancient 187 phylogenetic compatibility still hidden in the motor centers of the 188 brain, and other related, delicious ideas (maybe it’s not four limbs and 189 20 digits that are mapped discretely and <em>a priori</em> into the 190 human brain, maybe it’s the capacity to map any number of prehensile 191 bits that is inherent, etc. The therapeutic and geeky possibilities 192 leading from this are way too much fun to contain in an aside). 193 </p> 194 <p> 195 Anyway, the point it this: I love it when the answer is, “idk, maybe 196 we’re fish. What’s a fish, anyway?” 197 </p> 198 </main> 199 <div id="footnotes"></div> 200 <footer></footer> 201 </div> 202 </body> 203 </html>