1.1 Two systems, one defence #
1.1.1 Speed, specificity, and memory #
Innate immunity uses germline-encoded receptors for structures shared by many microbes, or for host molecules released by injury. Cells and pre-formed proteins act within minutes, and induced genes within hours. A receptor for lipopolysaccharide treats Gram-negative species as one class, and there is no antigen-specific clonal memory. Adaptive immunity assembles receptors by somatic gene rearrangement, so it can bind shapes never encountered in evolution. A primary response takes days, while the few fitting clones divide, and those clones are then remembered. Innate recognition supplies the costimulation a naive T cell needs before it starts. Antibody and T cells use complement, phagocytes, and macrophages as effectors. Trained immunity is only a non-specific heightening of innate cells for weeks or months, from epigenetic change, not from clonal selection.
| Property | Innate | Adaptive |
|---|---|---|
| Time to act | Minutes to hours | Days for a primary response |
| Receptors | Germline-encoded, limited set | Somatically rearranged; one specificity per clone |
| Targets | Shared microbial patterns; molecules released by damage | Any structure a lymphocyte receptor can bind |
| Memory | No antigen-specific clonal memory | Memory lymphocytes and long-lived plasma cells |
| Discrimination | Receptors were selected in evolution to spare healthy self | Clones are selected in each person; self-reactive ones must be controlled |
1.1.2 Humoral and cell-mediated immunity #
Metchnikoff showed that phagocytes engulf foreign material. Von Behring and Kitasato showed that serum from an animal immunised against diphtheria toxin protected another animal against that toxin. Humoral immunity is antibody: it neutralises extracellular microbes and toxins, opsonises them, and activates complement, and it does not see a peptide made in a living cell’s cytosol. Cell-mediated immunity is T cells. CD4 cells activate macrophages and help B cells. CD8 cells kill cells that display foreign peptides on MHC class I. Landsteiner and Chase transferred contact hypersensitivity with cells; serum did not carry it. Extracellular bacteria are largely a humoral and phagocyte problem. Viruses and microbes living inside macrophages are largely a T-cell problem.
Immunoglobulin Basic Unit
1.1.3 Primary and secondary responses #
On a first meeting with a protein antigen, specific antibody is usually detectable only after about a week. IgM appears first, and class-switched antibody, often IgG, follows if T-cell help is available. Amounts are modest and average affinity is low, because the responding cells used unmutated receptors. Memory B and T cells are already more numerous and easier to trigger, and many B cells have switched and improved their receptors, so a later response rises within a few days, peaks higher, lasts longer, and binds more tightly.
Immune Response Of Lymphocytes
1.2 Clonal selection and tolerance #
The study of Clonal selection and tolerance provides fundamental principles governing cellular architecture, molecular interactions, and physiological regulation.
Clonal Selection
1.2.1 Why instruction theories failed #
A body can make antibody against a synthetic chemical it has never seen. The instruction, or template, theory said antigen moulds a generic globulin. Pauling’s 1940 version had the chain fold around the antigen so that specificity need not sit in the amino-acid sequence. Haber denatured antibody fragments and let them refold without antigen; specificity returned, so the information is in the sequence. Nossal and Lederberg, in 1958, found that one cell from an immunised animal secreted antibody of only one specificity. A template rebuilt at every encounter leaves memory unexplained, and leaves unexplained the rise in binding strength. Self antigens are the most abundant templates, yet healthy people do not make antibody against them.
1.2.2 Clonal selection #
Burnet stated clonal selection in 1957 and set it out in 1959. Each lymphocyte displays receptors of one specificity, generated before antigen arrives by a genetic process that does not need the antigen. Antigen selects the clone whose receptor already fits and, with the right extra signals, that clone proliferates and differentiates. Daughter cells keep the specificity; some become effectors and some memory cells. A clone that recognises self is deleted, inactivated, or regulated rather than recruited.
1.2.3 Tolerance as the partner of recognition #
A random repertoire contains receptors for self, so recognition is safe only if particular clones can be spared. Tolerance is that specific silencing; the rest of the system stays available. Owen, in 1945, found that dizygotic cattle twins that had shared a placental circulation carried each other’s blood cells as adults and accepted them. Billingham, Brent, and Medawar showed in 1953 that foreign cells given to a newborn mouse, before its repertoire had matured, were later treated as self. The mechanisms in Chapters 6 and 8 are deletion, receptor editing, anergy, ignorance, and regulatory T cells. Their failure is a route into autoimmunity.
1.3 Key terms, summary, and self-check #
Key terms. Innate immunity; adaptive immunity; humoral immunity; cell-mediated immunity; primary response; secondary response; memory; clonal selection; instruction theory; tolerance; anergy; trained immunity.
Summary. Innate immunity is fast, germline-encoded, and broad; adaptive immunity is slow at first, clonally specific, and remembered. Antibody handles extracellular antigen and T cells handle infected cells. A secondary response is sooner, larger, and of higher affinity because clones have already been selected. Clonal selection says antigen chooses among pre-existing specificities, and a random repertoire is safe only because self-reactive clones are deleted, edited, anergised, or suppressed.
Self-check.
1. On what three properties do innate and adaptive immunity differ most sharply, and what does trained immunity add to that contrast?
2. What is transferred when protection moves with serum, and what did Landsteiner and Chase show could not be transferred that way?
3. Why does a secondary antibody response appear sooner and bind more tightly than a primary response?
4. What did Haber’s refolding experiment, and Nossal and Lederberg’s single-cell experiment, each do to the template theory?
5. Why is a random repertoire unsafe unless tolerance exists? Name one classical observation that tolerance can be acquired.
