A splinter goes in on Monday. By Tuesday the skin around it is red, warm and a little swollen, and by the weekend it is fine. You did nothing, but an army fought. Months later, a nurse gives you an injection of something that cannot make you ill, and you feel a sore arm for a day. Years after that, you meet the real germ and never notice. Somewhere in between, your body learned a face and kept the memory.
Immunology is the study of that army: how it tells friend from foe, how it learns, why it sometimes fires at pollen or at its own joints, and how medicine now borrows it to fight cancer. This explains how medicine works and is not medical advice. For a health question, see a clinician; in an emergency, call your local emergency number.
Your body runs two defence systems. The innate system is old (animals, plants and even bacteria have versions) and works within minutes. Skin and mucus are barriers. Cells such as neutrophils and macrophages carry receptors that recognise patterns no healthy body part has: bacterial wall sugars, the double-stranded RNA of many viruses. When they sense one they swallow the intruder and release chemical alarms. Those alarms cause the red, hot, swollen skin: blood vessels widen and leak, and more cells flood in. Innate defence is quick but has no memory, and it responds about the same way each time.
The adaptive system is the invention of jawed vertebrates. It takes days to start, but it is exquisitely specific and it remembers. Its two main players are B cells, which make antibodies (Y-shaped proteins that stick to a target), and T cells, which come in killer and helper forms and recognise fragments of proteins displayed on the surface of other cells. The two layers talk: innate cells that have swallowed a germ carry pieces of it to T cells, and without that introduction the adaptive system stays asleep.
Whatever an antibody or T cell recognises is called an antigen. The big question of the subject is how a body that has never met a given germ can possibly have a cell ready to recognise it.
You cannot have one gene per possible germ; there are not enough genes, and new germs keep evolving. The answer, worked out by Susumu Tonegawa in the 1970s (Nobel Prize 1987), is a lottery run inside each developing cell. The antibody gene is built from pieces: a heavy chain from one V, one D and one J segment chosen from a menu, a light chain from V and J, and then the joints between the pieces are sloppily trimmed and padded with random letters. Every B cell shuffles its own deck once, and keeps the result for life. T cell receptors are made by the same trick.
Round, illustrative segment counts (real counts are of this order but differ by person, gene and species, and not every combination is functional). A body has about 3×1013 human cells (the 2016 estimate quoted in 35/50).
With 40 × 25 × 6 = 6,000 heavy-chain combinations and 150 light-chain ones, the segments alone give 900,000 receptors. Add a thousand junction variants and it is 9×108. Push the junction slider to 9 and the possible repertoire is about 9×1014, some thirty times the cells in a body, so each of us carries only a sample. Most of the sample will never meet its target; the system works because it is huge, cheap and held in reserve.
Having a million random receptors raises a new problem: how do you use the right one? Frank Macfarlane Burnet's answer, proposed in 1957, is clonal selection. Each B cell carries one receptor. When a germ's antigen fits it, that one cell is triggered, and with help from a T cell it multiplies into a clone. Some clone members become plasma cells, antibody factories; others become memory cells. The antigen does not instruct the cell; it picks from what was already there. It is natural selection, run inside you in days.
Then it improves. In lymph-node structures called germinal centres, dividing B cells copy their antibody gene at a high error rate (somatic hypermutation). Most mutations make the antibody worse, a few make it grip tighter. Cells that grip better capture more antigen and get more help, so they win. The process is affinity maturation, and it explains why antibodies late in an immune response bind far more tightly than those made early.
A toy: 11 affinity classes with Kd from 1,000 down to about 1 (arbitrary units); each round, cells survive in proportion to the fraction bound; then 30% of cells mutate, of which 15% get tighter, 45% looser and 40% stay the same (invented split, but mostly-harmful is realistic). Expected values, no chance.
Start with weak binders (mean Kd about 707). After 8 rounds with little antigen around (the default), selection is strict and the mean Kd falls to about 32, more than twenty-fold tighter. With a flood of antigen (103) nearly everyone binds and survives, so mean Kd only reaches about 363. Selection needs scarcity, which is why a response that clears a germ keeps sharpening for a while and then stops.
The first meeting with an antigen is slow: about a week before antibodies are measurable, a peak after one to three weeks, then decline. Memory B and T cells change the second meeting. There are many more cells already tuned to the target, they need less coaxing, and the best of them have already been through affinity maturation. So the antibody level rises in days instead of weeks and climbs far higher. A vaccine is a way to stage the first meeting safely, with a harmless version or fragment of a germ (or the instructions for one), so that the real one is the second. Edward Jenner's cowpox experiment of 1796 was the first deliberate version of this idea (see 35/50 for what it means for populations).
Why then is a booster ever needed? Two reasons, both visible in the model below. First, antibody levels from a single exposure fall over months as short-lived plasma cells die; a small pool of long-lived plasma cells and the memory cells remain, but the level may sink below what blocks infection quickly. A second exposure restarts the same rise with a bigger starting stock, and each round through the germinal centre improves affinity again. Second, some germs change (influenza drifts every year, which is why that vaccine is updated) so a new shot also teaches the army a new face. Waiting longer between exposures tends to give a stronger boost, because the response has time to mature: that is why vaccine schedules specify minimum gaps.
A teaching toy in arbitrary units, log scale. Peaks of 3, 24 and 60; lags of 7, 3 and 3 days; part of each response persists as a plateau; the dashed line at 2 is an invented "protective" level. Boost size shrinks if the gap is under six weeks. Not a vaccine schedule and nothing here is advice about any vaccine.
With one exposure the level crosses the invented threshold of 2 for only about 35 of 730 days. With two exposures 60 days apart the second rise is faster (3-day lag instead of 7), peaks at about 25 (eight times the first) and stays above threshold for about 705 days. Shorten the gap to 14 days and the peak is lower (about 17); lengthen it to 180 and the first response has decayed, but the second peak is still about 25. That is the heart of every real schedule: a prime, a gap long enough for memory to form, then a boost.
A lottery that makes random receptors also makes receptors that fit your own proteins. The body runs two safeguards. In the thymus, developing T cells are tested against self-fragments: those that bind too weakly to work are discarded, and those that bind self too strongly are mostly deleted (central tolerance). Out in the body, regulatory T cells and other checks restrain leakers (peripheral tolerance). The great majority of cells that start in the thymus never leave it. Burnet and Peter Medawar shared the 1960 Nobel Prize for the discovery of acquired immunological tolerance.
Both safeguards trade one error for another. Delete too much of the repertoire and you have fewer cells to recognise foreign things; delete too little and some cells that attack self get out. When they do, the result is autoimmune disease: the immune system attacking the body's own tissue. Type 1 diabetes (insulin-making cells), multiple sclerosis (the insulation of nerves), rheumatoid arthritis (joint lining) and lupus (many tissues) are examples. Causes involve inherited risk, environmental triggers and chance together, are only partly understood, and many of these diseases are more common in women. Treatment is not self-treatment and is not covered here.
Tolerance also explains transplant rejection. T cells read the surface proteins called HLA (human leucocyte antigens, the human version of the MHC) to know what is self. A donor organ with different HLA looks foreign, and a large share of the recipient's T cells react to it. The first successful organ transplant, a kidney between identical twins by Joseph Murray in Boston in 1954 (Nobel Prize 1990, shared with E. Donnall Thomas), avoided that problem; for everyone else, tissue matching and drugs that suppress the immune system (at the price of more infections) made transplants routine. The immune system does not know it is being unkind to a kidney that is saving a life.
A cartoon: self-reactivity is a bell curve (mean 0, spread 1, arbitrary units); cells above the threshold are deleted; cells above 2 are "dangerous" if they escape. Real thymic selection is far harsher and more complicated. Illustrative, not data.
At a threshold of 1.5, about 6.7% of the toy repertoire is deleted and no dangerous cell escapes. Raise it to 2.5 and only 0.6% is deleted, but 1.65% of cells are dangerous escapees, and with half caught by regulatory cells 0.83% still get out. Lower it to 0.5 and nearly a third of the repertoire is thrown away. No setting is free, which is the honest picture of tolerance: there is no threshold at which autoimmunity and weak defence both vanish.
An allergy is an immune response to something harmless, such as pollen, a food protein or a venom. The common type is built on an antibody class called IgE. In a sensitised person IgE sticks to mast cells in skin, airways and gut; when the allergen binds two neighbouring IgE molecules the mast cell releases histamine and other chemicals within minutes: itch, swelling, sneezing, wheeze. Rarely the response is body-wide and dangerous (anaphylaxis), which is an emergency: call the local emergency number. IgE evolved, in the usual account, for defence against parasites such as worms; in places with few of them it is aimed at peanuts and pollen. Why allergy has become more common in many countries is still debated.
What changed practice is a trial. The old advice was to keep babies away from peanuts. In the LEAP trial (Du Toit and colleagues, New England Journal of Medicine, 2015) 640 infants at high risk because of severe eczema or egg allergy were randomised to eat peanut or avoid it until age five. Among those with a negative skin test at the start, 13.7% of the avoidance group were allergic at 60 months against 1.9% of the peanut group; among those with a positive test, 35.3% against 10.6%. Early exposure helped, which fits the idea that the gut teaches tolerance. That advice depends on the child and a clinician, not on a general experiment at home.
Cancer cells are your own cells, so they are mostly tolerated. But some carry changed proteins that T cells can see, and tumours use the same brakes that protect healthy tissue. A T cell has built-in switches: signal 1 (the target), signal 2 (a "go" confirmation) and checkpoints, such as CTLA-4 and PD-1, that dampen an attack. Tumours can display PD-L1, which presses PD-1 and tells a T cell to stand down. Checkpoint inhibitors are antibody drugs that block the brake. James Allison (CTLA-4) and Tasuku Honjo (PD-1) shared the 2018 Nobel Prize in Physiology or Medicine; the first one, ipilimumab, was approved by the US FDA for melanoma in 2011. Older roots: William Coley injected bacteria into tumours in the 1890s, with erratic results. A second route, CAR-T cells, takes a patient's own T cells, equips them with an engineered receptor and returns them; the first was approved in 2017.
The same brake guards healthy tissue, so removing it can cause autoimmune-type side effects (inflammation of the bowel, thyroid or lungs are well known). The tumour gains; some healthy tissue is also at risk.
A cartoon: net signal = target signal + 2 (go signal) − 0.8 × PD-L1 × (1 − blockade). Attack when net is above 3. Healthy tissue: weak target signal 1.5 and PD-L1 3. All numbers invented to show the logic, not real patients or doses.
With a target signal of 4 and a brake of 7, the tumour's net is 0.4, far under the threshold of 3: the T cell stands down. With full blockade it is 6.0. At 50% blockade it is 3.2, just over, while healthy tissue is at 2.3, still below. Pushed to 80%, healthy tissue creeps to 3.02. A real drug has a window, and no single threshold fits every patient or every tumour, which is why some cancers respond well and others hardly at all.
The immune system is a learning army built on a lottery and a filter: random receptors, selection by the enemy, memory afterwards, and a set of brakes that stop it hitting you. Vaccines borrow the memory, allergy and autoimmunity are the filter misfiring, and modern cancer drugs borrow the brakes.
Try this: next time a cut turns red and warm, name what you are seeing: innate alarm signals, not infection by itself. Check your own vaccination record with your clinic or health service; do not decide about shots on a web page.
Sources. Clonal selection (Burnet 1957, Nobel 1960 with Medawar), V(D)J recombination (Tonegawa, Nobel 1987), HLA, tolerance, IgE and mast cells are standard immunology (Abbas; Janeway). Murray's 1954 kidney transplant and the 1990 Nobel, and Jenner's 1796 experiment, are standard history. Checkpoint inhibitors: Nobel Prize 2018; ipilimumab FDA 2011; first CAR-T FDA 2017 (Wikipedia, Cancer immunotherapy). LEAP: Du Toit et al., N Engl J Med 2015;372:803–813. All interactive numbers were computed in node. This describes how medicine works; it is not medical advice.