How Does the Immune System Work? Two Systems, One Problem
By the BrainSnail editorial team. How these articles are written and checked, and how to tell us when one is wrong.
The body has to destroy anything foreign while leaving its own tissues alone, and it has to do this against threats that evolve far faster than we do. The solution is two systems working together: one fast, general and ready immediately, and one slow, specific and capable of learning. Almost everything about infection, vaccination, allergy and autoimmune disease follows from how those two interact.
The fast system
Innate immunity responds within minutes and does not need to have met the threat before. It begins with barriers: skin, mucus, stomach acid, enzymes in tears and the resident bacteria that occupy space a pathogen would otherwise take. Past those, cells including macrophages and neutrophils recognise molecular patterns shared by broad classes of microbes, such as components of bacterial cell walls, using pattern recognition receptors that are encoded directly in the genome and are the same in everyone. Recognition triggers engulfment and destruction, and the release of signalling molecules that produce the familiar signs of inflammation: blood vessels widen and leak, bringing more cells and fluid to the site, which causes the redness, heat, swelling and pain. The complement system, a cascade of blood proteins, punches holes in bacterial membranes and tags targets for destruction. Fever is deliberate, raising temperature to a range that impairs many pathogens and speeds immune responses. This system has no memory and responds identically to a second exposure.
The slow system
Adaptive immunity takes days to mount the first time and can then respond within hours for decades. Its central trick is that lymphocytes each carry a receptor generated by randomly rearranging gene segments during development, which produces an enormous repertoire of different receptors before any pathogen has been encountered. When one happens to fit an antigen, that cell is selected and multiplies, which is clonal selection. Two arms follow. B cells produce antibodies, proteins that bind a specific target and neutralise it, clump it together or mark it for destruction, and they refine their fit over the course of a response through further mutation and selection. T cells come in kinds: helper T cells coordinate the whole response by signalling to B cells and others, and cytotoxic T cells kill the body's own cells that have been infected, recognising them because every cell displays fragments of its internal proteins on its surface for inspection. Memory cells of both types persist afterwards, which is why a second exposure is met far faster, and is exactly what vaccination exploits.
Telling self from non-self
The most demanding requirement is not attacking the body, and the mechanisms are layered because the consequences of failure are severe:
- •Central tolerance, in which developing T cells in the thymus are tested against the body's own proteins and those reacting strongly are destroyed, with a specialised process that displays proteins from all over the body inside the thymus for this purpose
- •A comparable process for B cells in the bone marrow
- •Peripheral tolerance, since not every self protein can be shown during development, which suppresses self-reactive cells that escape
- •Regulatory T cells, which actively dampen responses and prevent them running on after a threat is cleared
- •A requirement for two signals, so that recognising an antigen is not enough to activate a lymphocyte without a second confirming signal from the innate system indicating genuine danger
- •When these fail the result is autoimmune disease, where the body attacks its own tissue, and the same brakes are exploited by tumours, which is what modern checkpoint inhibitor cancer drugs are designed to release
Where it goes wrong and how it is helped
Immune failures fall into recognisable categories. Underactivity gives immunodeficiency, inherited or acquired, with HIV being the defining acquired case because it destroys helper T cells and therefore disables the coordination of the whole adaptive response. Overactivity against harmless substances gives allergy. Overactivity against self gives autoimmune disease. Overactivity in general can kill directly, as in sepsis, where a systemic inflammatory response causes organ failure, and in the cytokine storms seen in severe infections. Medicine intervenes in both directions: vaccines induce memory without the disease; antibodies are now manufactured as drugs targeting specific molecules; immunosuppressants make transplantation possible by preventing rejection, which is the immune system working correctly against foreign tissue; and cancer immunotherapy tries to restore recognition of tumour cells. A recurring theme is the trade-off, since every suppression of unwanted immunity increases vulnerability to infection, and every enhancement risks autoimmunity.
The takeaway
Innate immunity acts within minutes using receptors encoded in the genome that recognise molecular patterns common to whole classes of microbes, and it has no memory. Adaptive immunity generates an enormous repertoire of randomly assembled receptors in advance, selects whichever fits, and leaves memory cells that respond far faster on a second encounter, which is what vaccination uses. Distinguishing self from non-self relies on destroying self-reactive cells during development, regulatory cells and a two-signal requirement.