Сергей Пузанов – Multiple Sclerosis. Everything you need to know (страница 6)
T- and B-lymphocytes, on the other hand, form the backbone of the adaptive immune system. On one hand, the architecture of this system shields us from virtually any virus or bacteria on earth. On the other, this exact design means that when things go sideways, lymphocytes can lose their minds and start tearing the body’s own tissues apart.
Lymphocytes and Their Receptors
So, lymphocytes mature in either the bone marrow or the thymus: the former become B-cells, the latter T-cells. Once they graduate from "school," they disperse to other organs of the immune system, but the defining choice of their life path happens right at the source. This is where lymphocyte receptors are built—and the blueprint of these receptors holds the root cause of all autoimmune diseases. Here is an absolutely counterintuitive, borderline bizarre fact: lymphocyte receptors are different. "Different" doesn't even do it justice: the human body can harbor one hundred million distinct T-lymphocyte receptors and one billion unique B-lymphocyte receptors.
Despite having less receptor diversity, T-cells outnumber B-cells in the body three to one. Many popular science texts frame T-lymphocytes as commanders and B-cells as raw privates, but frankly, that has nothing to do with reality. There is indeed a subset of T-lymphocytes that act as commanders, but that applies strictly to T-helpers—also known as CD4+ cells. If I were mapping out the military hierarchy of immunity, I would place B-lymphocytes right below them, since they rarely engage in hand-to-hand combat with pathogens. Only below them would I place T-killers (the frontline soldiers, CD8+) and T-regulatory cells (the military police). Why on earth do lymphocytes need so many receptor variants? The answer is simultaneously simple and complex: evolution is blind and incapable of thought. It ran prototypes of various immune systems, and the jackpot went to the one capable of defending the organism against literally anything.
The tip of a lymphocyte receptor is essentially a randomized sequence of amino acids. When a cell collides with a foreign fragment (an epitope) that fits this sequence, it triggers primary activation and readies itself for war—a war against anything matching that specific amino acid sequence. The process of randomly assembling a receptor is scientifically termed V(D)J recombination, where V stands for variable, D for diversity, and J for joining. Think of it as a modular construction set—some chains require V-D-J components, while others only need V-J, which is why the "D" sits in parentheses. To make things more chaotic, the splicing isn't always surgically precise, which jacks up the diversity of the finished receptors even further.
Why did evolution choose such a bizarre method to protect the body? First and foremost, because viruses evolve and constantly reshape their protein structures. If receptors were hardcoded to recognize a virus as a whole, a single mutation would instantly render it invisible, completely disarming the immune system. The evolutionary race was won by a blueprint that is brilliant in its simplicity: lymphocytes are prepped to destroy absolutely anything, but before they are deployed, they must pass a background check to ensure they won't attack the body's own cells. Science calls this pre-launch audit "central tolerance." If a newly assembled receptor reacts aggressively to the body's own tissues, the lymphocyte fails inspection and is ordered to commit cellular suicide. The scale of this purge is mind-boggling: no more than 5% of T-lymphocytes successfully graduate from the thymus.
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.