The immune system and its properties

The notes say the immune system is a network of cells, tissues and organs, and that each of the two systems has both cellular and humoral components, but they never say where any of it happens. That geography explains most of the vocabulary you will meet later. All the cells of both systems begin as haematopoietic stem cells in the red bone marrow. From there the pathways separate. Neutrophils, monocytes, eosinophils, basophils, mast cells and dendritic cells mature in the marrow and are released into the blood ready to act; they are the cellular effectors of innate immunity. Lymphocytes follow a different route. Those that mature in the bone marrow become B lymphocytes; those that travel as immature cells to the thymus, a gland behind the sternum, and are educated there become T lymphocytes. Marrow and thymus are therefore called primary lymphoid organs, because they are the sites where lymphocytes are produced and become functional.

Where lymphocytes meet antigen. The secondary lymphoid organs are the lymph nodes stationed along lymphatic vessels, the spleen filtering blood, and the mucosa-associated lymphoid tissue of the tonsils, the intestinal wall and the airways. This is why a sore, swollen lymph node during an infection is a sign of activity rather than a new disease: lymphocytes are proliferating there in response to antigen delivered from the tissues.

Cellular and humoral: two ways of delivering protection. Humoral immunity means the protective factors dissolved in blood and other body fluids — antibody made by B lymphocytes that have become plasma cells, and the complement proteins. Cellular immunity means protection delivered by cells themselves: T lymphocytes that kill an infected cell on contact, and phagocytes that engulf. The innate system has its own versions of both: the cellular side is the phagocyte and the natural killer cell — a lymphocyte that kills infected cells without recognising one specific antigen — and the humoral side is complement, lysozyme in tears and saliva, interferons and antimicrobial peptides such as defensins.

Four ways immunity is acquired, and nurses explain them to families every day. Active immunity means the person’s own system did the work; it appears after about one to two weeks and lasts years or a lifetime. Passive immunity means ready-made antibody was transferred; it works immediately but fades within weeks or months because no memory was made. Natural active immunity follows an infection, natural passive immunity is the mother’s IgG crossing the placenta or IgA in breast milk, artificial active immunity is vaccination, and artificial passive immunity is an injection of antibody or antitoxin, given after a snakebite or a tetanus-prone wound. This distinction is the reason a newborn is protected against measles for the first months of life and then becomes susceptible, and the reason a post-exposure injection can protect today without protecting next year.

The labels first line and second line suggest two relays handing over a baton, and the notes themselves warn that the innate and adaptive systems have separate functions but a relationship, and that they differ in a number of ways. The relationship is closer than a handover. Innate cells do not merely hold an infection until the adaptive system arrives; they decide whether an adaptive response happens at all, what kind it will be, and where. The mechanism has four named steps. First, recognition. Innate cells carry pattern-recognition receptors, such as the Toll-like receptors, which bind molecular motifs shared by whole classes of microbes rather than one species: lipopolysaccharide from Gram-negative outer membranes, peptidoglycan fragments, flagellin, and unmethylated CpG DNA. Because these patterns are conserved and essential to the microbe, the innate system recognises a broad category immediately, in minutes to hours, and the same receptor works against many different bacteria. The price of that breadth is that the receptor cannot distinguish one species from another with precision. Second, signalling. Engagement of those receptors makes the innate cell secrete cytokines, small soluble messengers, and chemokines that recruit more cells to the site. Interferons are cytokines made in response to viruses; they make neighbouring cells resistant to infection and activate natural killer cells. Interleukin-1, interleukin-6 and tumour necrosis factor produce fever and the local signs of inflammation, which is why fever appears before any specific antibody exists. Third, antigen presentation. This is the hinge between the two systems. A dendritic cell that has captured antigen migrates to a lymph node and displays fragments of it on its major histocompatibility complex molecules to T lymphocytes, while also delivering the cytokine signals that came with the encounter. A T lymphocyte whose receptor happens to fit that peptide–MHC combination is selected and expands. Without this presentation step the adaptive system has no way of knowing that an invasion is under way; antigen alone, in the absence of innate signals, tends to produce tolerance rather than attack. Fourth, arming the response and the effector phase. Activated helper T lymphocytes in turn license B lymphocytes to become plasma cells and to switch the class of antibody they make, and they license cytotoxic T lymphocytes to kill infected cells. Meanwhile complement proteins opsonise microbes with C3b so phagocytes engulf them more efficiently, and antibody does the same through its Fc portion. The two systems also converge on the same target: an antibody-coated bacterium is destroyed by an innate phagocyte, and a virally infected cell marked by antibody is killed by an innate natural killer cell. The clinical consequence of this cooperation is that damage to one system disables the other. A patient with advanced HIV loses helper T lymphocytes, so the adaptive response cannot be organised and the innate system cannot be armed against organisms it could otherwise clear; this is why opportunistic infections such as pneumocystis pneumonia and tuberculosis appear. Conversely, a congenital defect of innate signalling leaves the adaptive system uninformed, so vaccination may fail to produce protective memory. Nursing practice touches the same junction from the other direction: a live vaccine cannot be given to a patient whose adaptive system is suppressed, and an inflammatory reaction at an injection site is the innate system reporting that the antigen was noticed.

The notes set antigen, immunogenicity, epitope, hapten, adjuvant and complement as an assignment without defining any of them, and the fourth property — any molecule capable of being recognised is considered an antigen — is only useful once you know what recognition physically involves. Recognition is shape and chemistry, not identity. An antibody binding site, called a paratope, is a pocket formed by a few loops of the immunoglobulin molecule, and it contacts roughly fifteen to twenty-two amino acid residues of the antigen in a space about the size of a small sugar. The contact is non-covalent: hydrogen bonds, ionic attraction, hydrophobic packing and van der Waals forces. Because each of these is weak, a useful bond requires many of them at once, which is exactly why binding depends on complementary shape over a small area and why a single amino acid change can abolish it. That small contacted area is the epitope. Epitopes come in two kinds. A linear epitope is a short run of consecutive residues, exposed when the protein is unfolded or digested; a conformational epitope is formed by residues brought together by the folded three-dimensional shape, and it disappears if the protein is denatured. This is not a technicality. It explains why antibody raised against a whole live virus may fail to bind that virus after it has been heat-killed or fixed in a test, and why some laboratory tests use intact organisms or native proteins rather than fragments. Chemically, the strongest antigens in nature are proteins, because they can present many different epitopes and can be processed into peptides for T lymphocytes; polysaccharides are also antigenic, which is how pneumococcal and meningococcal capsular vaccines work, and nucleic acids and lipids become antigenic mainly when bound to protein. Size and complexity matter: a molecule of about ten thousand daltons can be immunogenic under good conditions, and immunogenicity generally rises with molecular size, with the number of foreign epitopes, and with how different the molecule is from the host’s own proteins. Now the hapten problem follows directly. A molecule smaller than about a thousand daltons, such as penicillin, a nickel ion or a dinitrophenol group, simply cannot hold an antibody or a lymphocyte receptor with enough non-covalent contacts to trigger a response, and it also cannot be processed into peptides for T lymphocytes. On its own it is recognised weakly or not at all, so it is antigenic in principle but not immunogenic. If the same small molecule is covalently joined to a large protein, the carrier supplies what the hapten lacks: carrier epitopes that helper T lymphocytes can recognise, and the molecular bulk that makes the complex hold together long enough to be taken up by a dendritic cell. The result is antibody that binds the small molecule itself, because the paratope fits the hapten portion. Clinically this is the mechanism of drug allergy. Penicillin is too small to provoke a response, but it reacts with the amino groups of serum albumin and of cell-surface proteins, creating a hapten–carrier complex; some patients then make IgE against the penicillin epitope, and a subsequent dose triggers mast cell degranulation, urticaria and, in the worst case, anaphylaxis. Patch-test allergy to nickel works the same way, with skin proteins acting as carrier. Adjuvants exploit the other half of the same problem: even a large protein antigen given alone may fail to activate innate pattern-recognition receptors strongly enough to license a full adaptive response, so an adjuvant such as an aluminium salt or an oil-in-water emulsion supplies the danger signals, holds the antigen at the injection site so that dendritic cells can collect it, and recruits those cells. This is why the notes’ assignment matters beyond vocabulary: hapten and carrier explain drug allergy, adjuvant explains why vaccine formulations are not merely antigen in water, and epitope explains why immunity to one part of a microbe does not always protect against the whole of it.