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With B-lymphocytes maturing in the bone marrow, evolution was slightly more merciful. The starting line is just as bleak: about 50% of B-cells fail to assemble a receptor at all, and of those that do, 75% build a weapon targeted directly at their own body. But unlike the brutal thymus, where a single mistake gets a T-cell executed on the spot, the bone marrow grants B-lymphocytes the right to retake the exam. This process is called receptor editing. Upon discovering that a cell has built a weapon against the host's own tissues, the bone marrow triggers a genetic conveyor belt, forcing the cell to rearrange the pieces of its construction set. If the receptor is fixed on the second or third attempt, the cell is saved. Only the unteachable dropouts who fail to reshape themselves are sent to the incinerator. In the end, only 10 to 20% of bone marrow students make it to graduation; the rest are recycled.
Where do the graduates go once they pass their exams? The bloodstream is merely a transit highway for them, holding only two or three percent of the total lymphocyte population at any given moment. Their actual deployment zones are the peripheral organs of the immune system: lymph nodes, the spleen, tonsils, and the Peyer's patches embedded in the intestines. In these outposts, young T- and B-cells receive "naive" status—meaning they have passed the test not to attack "themselves" and are armed with a functional receptor, but have never encountered a real enemy in their lives. They take up their posts in the lymph nodes and go on daily reconnaissance, ready to wake up and deploy at the first alarm.
Funnily enough, lymph nodes are called lymph nodes not just because lymphocytes congregate there, but because they collect lymph—a tissue fluid carrying the wreckage of viruses, bacteria, and other foreign proteins. Sometimes antigens drift into the lymph nodes on their own, and sometimes the body uses a courier service, typically crewed by dendritic cells. This makes lymph nodes the primary mixing ground where lymphocytes and antigens meet. Immune cells that aren't shown an antigen matching their receptor head back out to patrol the body every few hours, but they soon drift into other lymph nodes—because that is where the encounter with the enemy almost always takes place.
The ironic twist is that the vast majority of lymphocytes will live out their entire lives without ever encountering the exact amino acid sequence that matches their receptor. Only one out of roughly a million lymphocytes will ever be activated by a real enemy. The rest spend their days patrolling the body, socializing with comrades in the lymph nodes, growing old, and quietly dying, only to be replaced by a fresh batch. Here is a quick fact for those tracking their weight: every single one of us carries a few hundred grams of lymphocytes that will never be used.
It is precisely within this mass of unemployed, patrolling lymphocytes that the internal threat slumbers. The reality is that no filter is flawless. No matter how strictly the thymus and bone marrow audit their graduates, a tiny fraction of cells with receptors targeted against the body’s own tissues slips through into the periphery. In peacetime, these traitors remain dormant—their activation threshold is high, and regulatory systems deny them permission to attack. However, when the immune army goes to war against a real enemy, the balance of power shifts. Severe stress, a hormonal crash, or a cold endured on your feet can cripple internal security. Inflammatory signaling molecules wake the sleeping saboteur, its receptor locks onto a protein on the host's own cell surfaces—like a peptide of the nervous tissue's myelin sheath—and a cell built for defense begins a war against its own body.
This is roughly how multiple sclerosis takes off. A T-lymphocyte with a receptor matching myelin protein fragments slips past the filters of the thymus, drifts out to the periphery, and lives a boring, peaceful life. Then, one day, it crosses paths with a virus that forces it to wake up. Once that primarily activated T-lymphocyte penetrates the brain tissue, all it needs is to encounter its "real enemy," undergo secondary activation, and launch a full-scale war. The saddest part is that the cell isn't trying to do anything malicious or wrong—it is simply attacking what fits its receptor. If a lymphocyte were a sentient being, you could say it "continues to think" it is fighting off a dangerous predator.
Pathogenesis of Multiple Sclerosis
No matter how strict the thymic filter is, it isn't perfect. The mathematics here are brutal: every single day, this organ unleashes several million T-cells into the bloodstream. The probability of a cell engineered to destroy myelin proteins slipping past security is one in a million, or somewhere in that ballpark. Massive numbers cancel out tiny probabilities: this margin of error means that a few potential brain killers leak into your blood daily. However, catastrophe is still a long way off. These potential saboteurs enter the periphery "naive"—they are lazy, blind, and passive. After exiting the thymus, they settle in the lymph nodes, go for routine walks around the body, and quietly die without ever seeing battle—their lifespan ranges from a few months to a few years.
Even a first encounter with the enemy is no reason to panic. When a lymphocyte finds an epitope that fits its receptor, it doesn’t launch a war immediately. First, it looks around to see if there are signs of inflammation or any other indicators of general panic. If the surroundings are wrapped in an idyllic silence, the lymphocyte is forced to admit (likely with some sadness) that the problem lies within itself: "Since central headquarters hasn't declared a state of emergency, yet I am recognizing this peptide in peacetime, my receptor must be defective." Following this epiphany, the lymphocyte likely goes on a cellular bender and either shuts down ("anergy") or triggers its own execution program ("apoptosis"). This is precisely how the mechanism of "peripheral tolerance" works, and without it, autoimmune diseases would claim almost every single one of us. Both the lymphocyte and the dendritic cell must receive "co-stimulatory signals" from the external environment, otherwise the activation sequence fails to launch.
Thus, to trigger multiple sclerosis, the flawed lymphocyte must not only meet its matching epitope but must also find itself in the middle of a wartime environment. Usually, the onset of the disease is linked to a person catching a virus—specifically, the Epstein-Barr virus (EBV), which is considered one of the primary triggers for MS. By adulthood, 90 to 95% of the population is infected, and in most cases, it happens completely without symptoms. The virus multiplies in the lymphoid tissue of the throat, where dendritic cells ambush it. They chop the enemy into fragments (essentially stripping it down for parts) and head to the nearest lymph node. There, they display these pieces on their surface—on MHC molecules—so that passing T-cells can inspect them.
This is where the autoimmune trap springs shut: molecular mimicry. One of the viral fragments, named EBNA1, happens to be identical to a degree of confusion to a myelin peptide called MBP, and this resemblance is a primary trigger for multiple sclerosis. However, for the most part, the issue lies in how the dendritic cell showcases this wreckage: 2022 research proved that a prerequisite for MS is the presence of the DRB1*15:01 gene—which dictates exactly how the dendritic cell presents EBV antigens. Thus, while the fatal process kicks off with the activation of a T-helper cell, the cell itself is entirely blameless. The blame lies with the dendritic cell—it carelessly presented the antigen, botching its primary function. Then again, it didn't do it on purpose: it was born with a flawed MHC-II protein, and the viral fragment simply couldn't sit in it properly. Crucial note: once EBV triggers the primary activation of the T-helper, its role in the development of MS is completely finished. Trying to stop multiple sclerosis by hunting down the virus is entirely pointless.
When a naive T-lymphocyte, whose receptor by a twist of fatal convergence matches this distorted shape, collides with a dendritic cell, it sees a blood enemy on its display stand. Do not forget the massive numbers: a dendritic cell carries up to 200,000 display stands, and the viral wreckage occupies only a few hundred of them. To wake up, the T-cell needs to rack up 200 to 300 receptor hits, and a clever evolutionary trick takes over. An assembly line fires up in the contact zone: a few dozen stands displaying the virus sequentially activate hundreds of T-cell receptors, like a punch card in an old industrial loom. Having collected the magic sum of signals, the lymphocyte activates and begins to multiply: the cell divides every 6 to 8 hours, and in just 4 to 5 days, an army of 10,000 clones is manufactured. The virus retreats into latent standby mode inside the body, while the newborn army of now auto-aggressive T-cells marches out to hunt down enemy agents.
Still, unleashing thousands of militants into the blood is not an absolute death sentence; the body retains a window to correct the mistake. On their way out of the lymph node, the revolutionaries are ambushed by the military police—T-regulatory cells. Their receptors also recognize the body's own tissues, but instead of launching an attack, they deploy protection. The main objective of these "regulators" is to spot an autoimmune mutiny, bind the aggressors, and force them to commit suicide. Furthermore, without a steady feed of inflammatory signals, the militants quickly burn out and perish—the "contraction phase of the immune response" usually wraps up within a couple of weeks. In the vast majority of cases, this security grid works: the clone army is liquidated (or simply dies out) long before reaching the CNS. But if the process is hit by a bad genetic foundation, severe stress, or a profound vitamin D deficiency, the balance of power collapses. The military police fail to contain the uprising, and the surviving militants head down the home stretch—straight toward the border of the brain.
How does a blind T-cell know that behind the blank wall of a blood vessel lies the myelin it's hunting for? It doesn't know a thing—it simply forces its way into any tissue emitting a universal distress signal. Hurtling through the bloodstream, the auto-aggressive clones audit every organ in sequence, and from time to time, they spot invitations to enter: when vessel walls display chemical "velcro"—adhesion molecules—the cell reads it as a plea for intervention. Instant lock-on occurs: the lymphocyte slams on its molecular brakes and begins squeezing through the vessel wall—for instance, into the nervous tissue. What's the funniest part? Even at this exact moment, the immune cell has no idea that the blood-brain barrier hides myelin on the other side. Had the lymphocyte ended up in some other organ, multiple sclerosis would never have started.
The cells of the brain's blood vessels are tightly stitched together, and under normal circumstances, immune cells cannot leak inside. But the surviving militants are activated, which means they are packed with burglary gear. To breach the brain barrier, they carry specialized proteins on their membranes called integrins. T-cells use these to glue themselves to the vessel wall, resisting the powerful torrent of blood flow. Once anchored to the vascular wall, they deploy their chemical weapons—matrix metalloproteinase enzymes. These enzymes dissolve the tight junction proteins between the vessel cells, burning open structural breaches in the BBB. The barrier springs a leak, and the aggressive clones squeeze into the holy of holies of the organism—the tissue of the brain and spinal cord.
Once inside the brain, the T-cells collide with myelin and see that everything around them is occupied by their enemy—the exact match for their receptor. The militants sound a chemical siren, releasing signaling proteins called cytokines. This rallying cry triggers a chain reaction: the brain's local security force, microglia, declares martial law, while heavy artillery—macrophages—pours through the breached barrier from the bloodstream. A ruthless scorched-earth clearance of the territory begins. Macrophages literally scrape the myelin sheath off the nerve fibers, stripping the brain's live electrical cables bare. The organs of the CNS transform into a full-scale combat zone, but the absolute worst unfolds slightly later, as the first wave of the assault winds down.
At this moment, a terrifying mechanism engages: epitope spreading. Myriads of shattered myelin fragments are salvaged by scout cells and put on display. A secondary antigen presentation occurs, completely independent of any virus. The fire rages so intensely that previously hidden layers of insulation are exposed, and the distress signals attract fresh factions of lymphocytes. Auto-reactive cells whose receptors target entirely different myelin peptides join the fray. If the initial breach was launched by clones of just one or two receptor variants, the immune system now recognizes a massive array of targets, drawing hundreds of weapon types into the hotspot. The war becomes entirely self-sustaining, and the shattered blood-brain barrier leaves the gates wide open for anyone to enter.
Uninvited guests rush through the breached doors of the barrier. Absolute chaos erupts: by this stage of the crossfire, the T-lymphocytes targeted specifically at myelin make up no more than 10% of the forces inside the brain. The other 90% are bystander cells that drifted into the hotspot completely by accident. Yet, they don’t just sit on their hands. Blinded by the overwhelming signals of inflammation, these "pedestrians" begin venting toxic enzymes and free radicals, obliterating healthy brain tissue purely by inertia—a phenomenon termed the bystander effect. The catastrophe intensifies with the arrival of B-lymphocytes, which account for 20 to 30% of the cells entering the brain at the height of the disease—many of them hijack the antigen-presenting function, driving completely neutral T-lymphocytes toward aggression. Furthermore, some of these B-lymphocytes, having mutated into plasma cells, set up autonomous factories inside the nervous tissue and stamp out billions of antibodies—which yield the oligoclonal bands that doctors find when analyzing cerebrospinal fluid. The most insane part is that only a handful of these antibodies are targeted at myelin; the other millions of copies are manufactured against completely random antigens. The oligoclonal bands in the CSF of MS patients consist mostly of antibodies against random background noise.
What does the destruction of myelin lead to? Nerve insulation is engineered like a multi-layered pastry, with the fiber wrapped in a membrane dozens of layers deep—and macrophages methodically gnaw away at this armor, layer by layer. As long as a fraction of the winding remains intact, the cable functions. But when the destruction hits a critical threshold—less than 3 layers of myelin—the body's electrical grid surrenders. Normally, a signal shoots down an axon at speeds up to 100 meters per second, but on a stripped section, this mechanism shatters, and the impulse speed drops 50- or even 100-fold. The signal no longer flies—it barely crawls, and frequently shorts out along the way, failing to reach its destination. To make matters worse, the bare wires begin to cross-talk, bleeding false impulses into neighboring fibers. It is these systemic wiring failures that translate hidden molecular chaos into the terrifying symptoms of multiple sclerosis.
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
«If you don’t know where you’re going, any path can take you there»
Lewis Carroll, Alice in Wonderland
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.