Overview of Immunology

In 430 BC, plague swept through Athens and killed perhaps a third of the city. Thucydides, living through it, noticed something that nobody could explain for another two thousand years: the people who had already had the disease and survived could nurse the dying without catching it again. Something in them had changed. They had not become generally hardier — they could still catch anything else. They had become resistant to one specific disease, permanently, because they had met it once.

That single observation contains almost the whole of immunology. Something in the body recognises a particular invader, remembers it specifically, and responds faster and harder the second time. The rest of this course is the mechanism behind Thucydides's note — which molecules do the recognising, which cells do the remembering, and what happens when the system misfires and attacks the wrong thing.

TMU teaches the immune system as having exactly three jobs, and this framing is examined directly — a fill-in-the-blank asking you to complete the list appears in both papers we hold. Learn the three names as a set, because the question gives you one and asks for the other two.

The elegant part is that each of the three functions has a matching disease for when it goes wrong, and the pairing is not arbitrary. Defence failing gives you infection; defence overshooting gives you allergy. Homeostasis failing means the body stops tolerating itself, which is autoimmunity. Surveillance failing means abnormal cells are no longer spotted, which is cancer. If you learn the three functions with their two failure modes, you have also learnt the map of the entire clinical half of this course.

The immune system is not an organ you can point to on a dissection table. It is a network distributed through the whole body, and TMU divides it three ways — organs, cells, and molecules. Nearly every later lecture in this course is one branch of that tree, so it is worth fixing the shape of it now: lecture 3 is the immunoglobulins, lecture 4 the complement, lecture 5 the cytokines, lecture 6 the CD and adhesion molecules, lecture 10 the MHC. Those are all sitting in the 'molecules' branch.

The lymphoid organs split cleanly by what happens to a lymphocyte there. In the central organs, lymphocytes are born and grow up — they develop, mature, and get tested for self-reactivity, all without ever meeting a real pathogen. In the peripheral organs they take up residence as finished cells and wait to meet antigen. Development happens in the centre; the actual immune response happens at the periphery.

The naming is worth a moment, because it trips people up. Central and primary mean the same thing here, as do peripheral and secondary. TMU's slides and both past papers use central/peripheral; Janeway's uses central and peripheral too, so for once the two sources agree exactly.

Think about what happens when you cut your finger on a dirty blade. Within seconds, before your body has any idea what species of bacterium it is dealing with, the response has already begun — the skin barrier is breached, complement proteins in the tissue fluid start landing on bacterial surfaces, and neutrophils are being pulled toward the site. None of that required prior exposure and none of it is tailored to that particular organism. That is innate immunity: pre-built, fast, and generic.

Meanwhile, something slower is starting. A dendritic cell picks up fragments of the bacterium, carries them to the draining lymph node, and shows them to lymphocytes. Days later — four or five, not minutes — T and B cells specific for that organism have multiplied into an army, antibodies are being made against it, and a population of memory cells is being laid down that will still be there years from now. That is adaptive immunity: slow to start, exquisitely specific, and permanent.

The six features of adaptive immunity are worth listing properly, because they are more than the two everyone remembers. Beyond specificity and memory there is diversity — the lymphocyte repertoire can discriminate somewhere between 10⁹ and 10¹¹ distinct antigenic determinants; specialisation, meaning the system responds in different ways to different classes of microbe rather than one way to all; self-limitation, meaning every normal response winds down after the antigen is cleared and returns the system to rest; and non-reactivity to self, which is tolerance, and whose failure is autoimmune disease.

• Specificity — responses are specific to distinct antigens, and even to distinct epitopes within one antigen
• Diversity — a repertoire able to discriminate 10⁹–10¹¹ determinants
• Immunological memory — the second exposure gives a faster, larger, more efficient response
• Specialisation — distinct kinds of response for distinct kinds of microbe
• Self-limitation — responses wane after antigen clearance, returning to homeostasis
• Non-reactivity to self — tolerance; its failure is autoimmunity

Here is the problem that puzzled immunology for fifty years. Your body can make a specific antibody against essentially any molecule — including molecules that have never existed in nature, synthesised in a laboratory last week. How can the body be prepared for something it cannot possibly have anticipated?

Burnet's answer in 1957 was to turn the question inside out. The body does not design a receptor to fit the antigen. It builds an enormous library of lymphocytes first — each one carrying a single type of receptor, of one unique specificity, generated at random before any antigen arrives. When an antigen enters, it does not instruct anything; it simply finds the few cells that already happen to fit it and switches them on. Those cells divide, and their daughters all carry the same receptor. The antigen selects; it does not instruct.

That last postulate is the one students skip, and it is the most consequential. Because receptors are generated at random, the library inevitably contains keys that fit you. Those self-reactive cells are purged from the repertoire early, before clonal expansion — which is where immunological tolerance comes from, and why its failure produces autoimmune disease. Tolerance is not an extra mechanism bolted on afterwards; it falls out of the same process that generates diversity in the first place.

Adaptive immunity splits into two arms, and the split is dictated by where the enemy is hiding. A bacterium multiplying in the tissue fluid, or a toxin diffusing through the blood, is out in the open — an antibody can reach it, bind it, and mark it for destruction. But a virus inside one of your own cells is untouchable by antibody; no soluble protein can cross the membrane to reach it. Something has to recognise the infected cell from the outside and kill it. Two hiding places, two arms.

One more distinction, and it is the one that matters most at the bedside. Immunity you make is called active; immunity you are given is called passive. A vaccine makes you build your own response — slow to appear, but it lays down memory and lasts for years. An injection of ready-made antibody protects you within hours, but you made none of it yourself, so there is no memory and it fades as the transferred protein is catabolised.

The exam map for this unit

Unit 1 is unusually profitable. Five separate parts of the paper draw on it, and because the 2019 and 2020 papers are near-identical, every item below has already been set twice.

History — the names worth knowing