Сергей Пузанов – Multiple Sclerosis. Everything you need to know (страница 8)
The Perfect Storm: How Multiple Sclerosis Begins
I have no doubt that shortly after your diagnosis, you scoured the entire internet looking for an answer—why did this happen to you? What exactly did you do wrong, where did you take a wrong turn? Why did multiple sclerosis strike you instead of your neighbor or coworker? I’m sure you found dozens of answers online: either you drank and smoked too much, or you didn't get enough sleep, or your genes are garbage, or you shouldn't have gone to the sauna—it’s enough to make your head spin. Many patients are convinced they know exactly what triggered it in their specific case—for instance, over the last few years, people love to blame the coronavirus. Unfortunately, these people overlook a critical factor: multiple sclerosis begins 5 to 10 years before the first symptoms ever show up.
The truth is, for MS to develop, a whole series of consecutive errors must line up perfectly. It all starts at birth with a bad genetic foundation: without a flawed genetic bedrock, an autoimmune mistake is mathematically impossible. To comprehend this, you have to understand how evolution works. Its two primary mechanics are heredity and variation. If DNA from sperm and egg were assembled by rigid, unyielding rules, children of the same parents would be as identical as thermometers, and they would fail to drive any development of the species. The principle is simple: whoever reproduces most effectively wins the evolutionary race, while holders of bad genes are weeded out. It’s brutal, but staggeringly effective—all you need to do is create the right conditions and pack an infinite amount of patience: it’s believed that about four billion years passed from the first living organism, LUCA, to Homo Sapiens.
Which specific genes are responsible for the development of multiple sclerosis? Answering this precisely is tough—our DNA consists of roughly 3 billion nucleotides and 20,000 genes. Still, humanity has managed to narrow down the lineup of suspects. First and foremost, these are the genes of the HLA complex, Human Leukocyte Antigen: there are dozens of suspects, but the chief villain is the aforementioned HLA-DRB1*15:01. Beyond the leukocyte antigen, the risk of developing MS is shaped by cytokine receptors on the surface of naive T-cells, "communication and transit" genes that govern the activation cascades of immune cells, and vitamin D metabolism genes. If the latter carry structural variations, the body cannot properly absorb vitamin D, and the T-regulatory cells—which were supposed to contain the budding autoimmune mutiny—become sluggish and lethargic. There is no definitive answer yet—humanity is still a long way from fully mapping out the DNA blueprint.
The next stage of the catastrophe is the collision of this genetic powder keg with a detonator: the immunity must spot a viral fragment that resembles a myelin peptide a bit too closely. The prime suspect is EBV, the Epstein-Barr virus; without it, multiple sclerosis kicks off in exceptionally rare cases. Scientists even managed to isolate the viral protein EBNA1—it features an amino acid sequence that mirror-copies a peptide of the myelin basic protein, MBP. In an effort to purge the invader, dendritic cells cover themselves in viral wreckage, and if a person was dealt the unfortunate DRB1*15:01 gene, the display stands hold EBNA1 in a configuration that makes it completely indistinguishable from an MBP fragment. This critical error in reading context is genetically predetermined, but it isn't the only script for launching MS: this gene is present in 60% of MS patients and only 10% of the general population. In short—there appears to be no single, standalone genetic culprit.
Next comes the meeting between a T-helper and a dendritic cell covered in unfortunate viral wreckage. If this meeting happens in peacetime, when at least one of the participants lacks the necessary co-stimulatory signals, it won't lead to a thing. Actually, scratch that: if the meeting occurs in peacetime, it can cause the T-helper to decide to re-verify itself as a T-regulatory cell—a cell that will guard the body against autoimmune threats. Thus, the naive lymphocyte finds itself at a fork in the road: either it will attempt to launch an autoimmune rebellion, or it will dedicate the rest of its life to fighting anyone who wants to pull off something similar. The factor that decides the patient's fate at this exact moment is the external inflammatory background—the one that activates the co-stimulation receptors: CD28 on the lymphocyte and CD80/CD86 on the dendritic cell.
What reshapes the co-stimulation receptors? Virtually any negative shift in the external background: a viral or bacterial infection, physical trauma, food poisoning, systemic stress, and so on. The trigger that activates dendritic cells and lymphocytes can be the flu, a common cold, coronavirus, chickenpox—any nasty bug that generates a powerful inflammatory background will do. If the infection leads to a cytokine storm, tissues begin venting panic signals—interleukins and tumor necrosis factor. This chemical shower blinds the participants of the fatal meeting, priming them for aggressive actions. Thus, one of the frequent root causes of multiple sclerosis development is indeed this or that infection—solely because it sets up an inflammatory background in the organism that can drive the fatal activation of an auto-aggressive T-helper lymphocyte.
Once the clone army marches out into the blood, the T-regulatory cells retain a window to fix the error. Normally, they spot the autoimmune revolutionaries, strip away their fuel (interleukin-2), and force them to commit suicide, but their activity is governed by three primary variables. First and foremost, vitamin D: when the active form of vitamin D3 binds to the VDR receptor on a T-reg, it literally pumps it with horsepower—forcing it to release calming cytokines more actively. Second, genetic defects: errors in the Foxp3 and CTLA-4 genes render the military police incapable of binding the autoimmune mutiny. Finally, EBV again: at its worst moments, it generates such a high concentration of inflammatory interleukins around dendritic cells that the T-regs get disoriented and freeze in a stupor. Naturally, nothing here is discrete: all three variables can operate with varying intensity—either together or completely separate from one another. Anywhere from 0% to 100% of auto-aggressive cells can breach the T-regulatory blockades.
The lymphocytes that break through the regulatory barriers drift along the bloodstream and sail into any organs displaying invitation molecules on their vessel walls—in the case of the brain, these are the adhesion molecules ICAM-1 and VCAM-1. Why on earth would the brain display these molecules? It does so in response to any local or systemic alarm bell—this happens due to sleep deprivation, stress, blood pressure drops, general inflammation in the body, or local overheating after a sauna or even a hot bath. Furthermore, physical injuries—even minor ones from an accidental fall or a bar fight—can lead to the appearance of "velcro" on the vessels. To make things more chaotic, this must occur shortly after the primary activation of the lymphocyte, because after 2 to 3 weeks of aimless drifting, the activated clones burn out and trigger their own suicide sequence. Here is a funny fact: lymphocytes never commit suicide in the bloodstream; they prefer to die at home—in one of the organs of the immune system.
There are so many debates about the causes of multiple sclerosis precisely because, in many cases, these causes are entirely different. Or rather, the core cause is identical—an autoimmune error resulting from the activation and breakthrough of a myelin-aggressive lymphocyte—but this error could be triggered by vastly different events. The situation is complicated by the fact that a single error isn't enough; a whole combination of events must line up, and in recent years, illnesses like multiple sclerosis are termed "multifactorial." No matter how badly we want to single out a concrete cause for MS, doing so is, unfortunately, impossible: the bloodstream operates on tangled organizational structures, cascades of chemical interactions, complex backup safety mechanisms, and massive numbers—hundreds of billions and even trillions.
Chapter 2. Diagnosing and Assessing MS Progression
How Many Patients Are There in the World?
It seems astonishing, but there is no official, unified statistic on the number of multiple sclerosis patients worldwide. Different registries and studies use vastly different criteria, tracking scopes, and methodologies, making final estimates diverge. The explanation is logical and simple: multiple sclerosis has no standalone diagnostic marker. Sclerosis isn’t caused by an identifiable virus, fungus, or bacteria, which makes routine blood tests practically useless. Tests that can explicitly confirm or definitively rule out multiple sclerosis simply do not exist.