Immunology: Key Terms and Glossary

The 12/23 rule is the recombination principle that a signal sequence with a 12-base-pair spacer can be joined only to one with a 23-base-pair spacer. That constraint blocks joining of like segments to each other and forces a heavy-chain gene to assemble in the order V, then D, then J.

The acute-phase response is a cytokine-driven resetting of hepatic protein synthesis, led by IL-6, in which C-reactive protein, serum amyloid A, fibrinogen, and mannose-binding lectin rise while albumin falls. The change shows that the liver has sensed those cytokines; it does not identify a single disease.

Adaptive immunity builds antigen receptors by rearranging gene segments in each lymphocyte, so it can recognise structures never encoded in the germline, but a first response waits while the rare fitting clone expands. Clones that were selected are then retained as memory.

Antibody-dependent cellular cytotoxicity is killing of an IgG-coated cell by an NK cell that has engaged the antibody through CD16, the antibody contributing the specificity the NK cell does not have on its own.

An adjuvant is a substance included with a vaccine antigen to supply an innate pattern cue that a purified protein lacks, so that dendritic cells upregulate costimulatory B7 molecules. Alum is the classical example, and part of its action is through the inflammasome.

Affinity is the strength with which one antigen-binding site holds one epitope, and it is a different measurement from the multivalent grip of the whole antibody molecule.

Activation-induced deaminase converts cytosine to uracil in single-stranded DNA at the immunoglobulin locus during a T-dependent response. Repair of that damage as a point mutation alters affinity, whereas repair as a break in a switch region replaces the isotype.

AIDS is the acquired state in which loss of CD4 cells has withdrawn help from macrophages, germinal centres, and CD8 memory, so organisms that were already contained can escape control. By the conventional definition, that state is a CD4 count below 200 cells per microlitre or a specified opportunistic disease.

AIRE switches on tissue-restricted genes, insulin among them, in medullary thymic epithelium, so peptides from organs the thymus does not build can still be used in negative selection. Its loss causes APS-1, with autoimmunity directed at several endocrine organs.

Allelic exclusion is the halt in rearrangement of the other allele once a productive immunoglobulin chain has been formed, first at the heavy chain and then at the light chain. Each B cell therefore commits to a single receptor specificity.

An anaphylatoxin is a small complement fragment, C3a or C5a, released when C3 or C5 is cleaved; both increase vascular permeability and act on mast cells, and C5a also draws in neutrophils.

Anaphylaxis is type I hypersensitivity affecting several organs together, produced when antigen cross-links IgE on mast cells and the mediators that are released cause generalised vascular leak and constriction of bronchial smooth muscle.

Anergy is antigen-specific unresponsiveness in which a lymphocyte that met its antigen without the accompanying signals needed for activation survives, but responds poorly if that antigen returns. For a naive T cell the missing signal is B7 costimulation.

An anti-CD20 antibody is a therapeutic monoclonal that opsonises B cells for complement or antibody-dependent killing, the teaching example being rituximab. Plasma cells have lost CD20, so they are spared and immunoglobulin already made can persist while new B-cell responses stop.

An anti-TNF antibody is a therapeutic monoclonal that neutralises TNF, the teaching example being the chimeric antibody infliximab. TNF also helps keep granulomas intact, so removing it can let latent tuberculosis reactivate.

Avidity is the binding strength of an intact antibody when several of its sites are occupied at once, as distinct from the affinity of any single site. That multivalency is why IgM can cling to a bacterial surface even though each site binds weakly.

A B cell displays membrane immunoglobulin of one specificity and, after it receives help, secretes antibody of that same specificity. It can also present peptides from antigen that its own receptor has captured.

B7 is the pair of costimulatory proteins CD80 and CD86, which rise on a dendritic cell that has sensed microbial products or damage, bind CD28 to deliver signal 2, and are bound still more tightly by the inhibitor CTLA-4.

C3b is the principal opsonic fragment of complement: the convertase that cleaves C3 leaves C3b covalently attached to the nearest surface, where phagocytes recognise it.

C3bBb is the alternative-pathway C3 convertase, produced when factor D cleaves factor B on surface C3b and stabilised by properdin. Amplification continues on surfaces that lack the regulators which inactivate C3b.

C4b2a is the C3 convertase shared by the classical and lectin pathways, assembled from cleaved C4 and C2 on a surface where antibody, or a lectin bound to microbial carbohydrate, has started the cascade.

A carrier is a protein to which a hapten must be covalently coupled so that a hapten-specific B cell can display a peptide from that same particle and thereby receive T-cell help.

Caspase-1 is the protease switched on inside an inflammasome; it cuts the precursors of IL-1β and IL-18 to their active forms and also cuts gasdermin D, freeing the fragment that pores the membrane.

CCR5 is a chemokine receptor that, together with CD4, allows many transmitted strains of HIV to enter memory CD4 cells and macrophages. Variants that arise later in some people use CXCR4 instead.

CCR7 is the receptor for the chemokines CCL19 and CCL21, and it retains naive T cells and mature dendritic cells in the paracortex of a lymph node.

A CD marker is a cell-surface molecule defined by a monoclonal antibody and assigned a number so that different laboratories name the same structure. One marker seldom identifies a lineage; the reading comes from a panel.

CD16, or FcγRIII, is the receptor through which an NK cell binds IgG-coated targets and kills them, the antibody supplying a specificity that the NK cell did not make by gene rearrangement.

CD28 is the costimulatory receptor on T cells that binds B7 and supplies signal 2, which a naive T cell needs together with peptide–MHC before it proliferates and makes IL-2.

CD4 is the co-receptor that binds MHC class II and, when it is found together with CD3, marks helper T cells. It is also present at lower density on monocytes, so CD4 by itself does not prove a helper T cell.

CD59 is a membrane regulator on host cells that prevents C9 from finishing the complement pore, so the membrane-attack complex is not completed on healthy self surfaces.

CD8 is the co-receptor that binds the α3 domain of MHC class I and, together with CD3, marks cytotoxic T cells. Some NK cells also express it, so CD8 alone does not establish that a cell is a T cell.

A complementarity-determining region is one of the loops, three from each variable domain, that make most of the contact between an antibody and its antigen. The loop called CDR3 crosses the recombined gene junction and is the most variable.

Cell-mediated immunity is adaptive defence carried out by T cells: CD4 cells activate macrophages and help B cells, while CD8 cells kill cells that display a foreign peptide on MHC class I.

Central memory T cells keep CCR7 and L-selectin, patrol lymphoid organs, and proliferate strongly when they are restimulated. Effector memory cells lack CCR7, enter peripheral tissues, and act quickly.

cGAS is the enzyme that detects DNA loose in the cytosol and synthesises 2′3′-cyclic GMP–AMP, the second messenger that STING then reads.

Chronic granulomatous disease is loss of a subunit of NADPH oxidase, most often X-linked gp91phox, so phagocytes ingest microbes and degranulate but cannot generate superoxide. Organisms that the burst would have killed persist and are walled off as granulomas.

Class-switch recombination places an existing VDJ exon beside a downstream constant-region gene and deletes the DNA in between, so the Fc changes and the antigen-binding site does not. Unlike the splicing that co-expresses IgM and IgD, the deletion cannot be undone.

CLIP is the fragment of invariant chain left sitting in the MHC class II groove after the rest of the chain has been degraded, and it stays there until HLA-DM exchanges it for a peptide from the endosome.

Clonal selection is the working account of adaptive specificity: each lymphocyte is generated already carrying receptors of one specificity, and antigen merely expands the clone whose receptor fits, provided the necessary extra signals are present.

Codominance, applied to MHC, means that protein products of both inherited haplotypes are displayed at once, so a heterozygote can present a broader collection of peptides than either haplotype alone.

The common γ chain is the shared signalling subunit of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, and the IL-13 receptor does not use it. X-linked loss of the chain abolishes IL-7-driven T-cell development and IL-15-driven NK cells, while B cells may be present but function poorly.

A competitive ELISA is a format in which labelled antigen and unlabelled analyte compete for a limited amount of antibody, so the signal falls as the amount of analyte rises.

A conjugate is a capsular polysaccharide covalently linked to a protein carrier, allowing a B cell that binds the sugar to present carrier peptides and receive T-cell help. The helper never sees the sugar, and mixing free polysaccharide with free protein does not replace the covalent link.

Cross-presentation is the display, on a dendritic cell's own MHC class I, of antigen that the cell took up from outside rather than synthesised. Type 1 conventional dendritic cells do this best, which lets them prime naive CD8 cells against a virus they never allowed to replicate, or against tumour debris.

CTLA-4 is an inhibitory receptor induced after T-cell activation; it binds B7 more tightly than CD28 does and strips B7 from the dendritic cell, braking costimulation at the priming step in the lymph node. Regulatory T cells express it all the time, and blocking it can damage healthy organs because the same brake restrains autoimmunity.

CXCL13 is the chemokine read by CXCR5 that draws B cells into the follicle and also brings T follicular helpers into that same B-cell area.

CXCL8 is the chemokine that attracts neutrophils and, when presented on endothelium, switches on their integrins so that cells which were rolling come to a stop and can leave the vessel.

A cytokine storm is inflammatory and T-cell cytokines, including TNF, IL-1, IL-6, and IFN-γ, rising in the blood and driving one another in a positive loop. Vessels then leak, pressure falls, and coagulation is disordered, whereas the same mediators confined to a focus of infection are ordinary defence.

A damage-associated molecular pattern is a host molecule displaced by injury, such as extracellular ATP, crystals of uric acid, HMGB1, or DNA that has left the nucleus. Innate receptors read that misplacement as a cue to inflame, which is how sterile tissue damage causes inflammation.

A dendritic cell is the antigen-presenting cell that activates naive T cells, because exposure to a microbial pattern or to damage makes it display peptide together with B7 and travel, via CCR7, into the paracortex.

Direct allorecognition is binding of intact donor MHC on a donor cell, often a donor dendritic cell, by a recipient T cell. Foreign MHC is read much as self MHC plus a foreign peptide would be, at a frequency often around one T cell in a hundred and sometimes higher, which is why a first response against the graft is rapid.

The direct Coombs test asks whether immunoglobulin or complement is already coating the patient's own red cells, the situation in autoimmune haemolysis and in haemolytic disease of the newborn.

An epitope is the part of an antigen that an adaptive receptor actually touches, either a continuous run of residues or a surface assembled only in the folded protein. Unfolding can destroy an antibody epitope and, at the same time, uncover peptides that T cells can see.

Equivalence is the proportion of soluble antigen to antibody at which the two form a cross-linked lattice and come out of solution. Too much of either partner leaves only small complexes, which stay dissolved.

An Fab fragment is one arm of an antibody, still able to bind antigen through a paired heavy and light variable domain, but lacking the Fc region that calls in complement, Fc receptors, or transport.

Factor H is a soluble regulator that binds surfaces rich in sialic acid and, with factor I, cuts C3b so that those host surfaces cannot seed a C3 convertase.

Fas ligand is the membrane protein on a cytotoxic lymphocyte that engages Fas on a target and thereby starts extrinsic apoptosis through caspase-8, killing the cell without rupturing it.

The Fc region is the portion of an antibody formed by the heavy-chain constant domains, and it is what recruits complement, Fc receptors, or a transport receptor after the binding sites have engaged antigen.

FcRn is the receptor that binds IgG inside acidic endosomes and returns it to the circulation instead of sending it for degradation, which gives IgG its long serum life and carries it across the placenta.

FcεRI is the high-affinity receptor for IgE carried by mast cells and basophils, and it holds IgE so that a later encounter with antigen cross-links the receptor and releases histamine within minutes.

A follicle is the B-cell region of the lymph-node cortex, or of splenic white pulp, where CXCL13 acting on CXCR5 keeps B cells gathered and where an activated focus may become a germinal centre.

A follicular dendritic cell is a stromal cell of the follicle, not a haematopoietic dendritic cell, and it holds antigen in the form of immune complexes for B cells to test their receptors against.

Foxp3 is the transcription factor that specifies the regulatory T-cell programme. People who lack it develop IPEX, early autoimmunity in many organs, which shows that deleting clones in the thymus is not a sufficient brake.

Gasdermin D is cut by caspase-1, and its N-terminal fragment forms pores that release IL-1β, which has no signal peptide of its own; the same pores can kill the cell by pyroptosis.

A germinal centre is a site inside a follicle where B cells proliferate and mutate, then compete for antigen displayed on follicular dendritic cells and for help from T follicular helpers. Cells that win leave as memory B cells or as long-lived plasma cells, which a short-lived extrafollicular plasmablast response does not supply.

Graft-versus-host reaction is ordinary allorecognition pointed the other way: mature donor T cells inside a haematopoietic graft attack recipient tissues that present antigen well, classically skin, liver, and gut, because the recipient cannot reject those T cells.

A granzyme is a protease stored in cytotoxic granules and delivered into the target through pores made by perforin; granzyme B starts apoptosis both by cutting caspases and by engaging BID and the mitochondrion.

Graves disease is organ-specific autoimmunity in which IgG stimulates the TSH receptor, so the thyroid makes too much hormone rather than being destroyed. The destructive T-cell disease of the same gland is Hashimoto thyroiditis.

The haematopoietic stem cell of adult bone marrow renews itself and also gives rise to the common myeloid progenitor and the common lymphoid progenitor.

Haemolytic disease of the newborn is type II hypersensitivity in which IgG against RhD, made by an RhD-negative mother after an earlier sensitising pregnancy, crosses the placenta on FcRn. Foetal red cells that carry RhD are destroyed; the mother's cells, which lack the antigen, are not.

A haplotype is the set of linked MHC alleles inherited together on one chromosome. Because each parent transmits one haplotype, full siblings have a one-in-four chance of receiving the same pair.

A hapten is a small molecule that antibody can bind but that does not, on its own, provoke an immune response. A response follows only when the hapten is covalently attached to a carrier protein that can furnish peptides for helper T cells.

Herd immunity is indirect protection of people who are not themselves immune, arising when immune contacts are common enough that chains of person-to-person spread fail. The immune fraction required is not a single figure for every infection: it is higher when each case infects more people, it depends on how the population mixes, and it does not apply in the same way when infection comes from the environment or an animal reservoir.

A high endothelial venule is the specialised post-capillary vessel through which naive lymphocytes enter a lymph node from the blood, using L-selectin to begin that exit from the circulation.

HLA-A is a classical human MHC class I gene whose heavy chain, paired with β2-microglobulin, presents short peptides to CD8 T cells.

HLA-B is a classical MHC class I gene that presents short cytosolic peptides to CD8 T cells, and groups of its alleles are also ligands for inhibitory killer immunoglobulin-like receptors.

HLA-C is a classical MHC class I gene presenting short peptides to CD8 T cells, and groups of its products are recognised by killer immunoglobulin-like receptors on NK cells.

HLA-DM is the MHC-encoded catalyst that releases CLIP from the class II groove and loads a peptide which binds stably, a peptide-exchange step that invariant chain does not itself perform.

HLA-DP is a classical MHC class II locus whose αβ heterodimer presents longer peptides, generated in endosomes, to CD4 T cells.

HLA-DQ is a classical MHC class II locus that presents endosomal peptides to CD4 T cells. HLA-DQ2 and HLA-DQ8 are the alleles that present peptides linked with coeliac disease.

HLA-DR is a classical MHC class II locus presenting endosomal peptides to CD4 T cells, and a single haplotype often encodes an additional β chain, so two different DR molecules are displayed.

Humoral immunity is adaptive defence mediated by antibody, which acts on microbes and toxins in extracellular fluid by neutralising them, coating them for phagocytosis, and turning on complement. Antibody does not survey peptides produced in the cytosol of an intact cell.

A hybridoma is a continuously propagating clone that secretes the antibody of one B cell, obtained in principle by fusing that B cell with a myeloma so that a single specificity and the ability to grow indefinitely are combined.

Hyper-IgM, in its X-linked form, is deficiency of CD40 ligand, so IgM can still be secreted but class switching, germinal centres, and CD40-dependent activation of macrophages fail. Infections that depend on that macrophage activation therefore appear alongside the failure to switch isotype.

Hyperacute rejection is destruction of a graft within minutes to hours by pre-formed antibody and complement, classically when IgM against an A or B blood-group structure the recipient lacks binds donor endothelium.

IL-1 is an inflammatory cytokine of activated macrophages and dendritic cells that activates endothelium and promotes fever, and that contributes to shock when it circulates in large amounts. The active β form is produced only after caspase-1 cleavage and leaves the cell through gasdermin pores.

IL-2 is the growth factor T cells secrete once antigen receptor and costimulus have both fired, and it acts through a high-affinity receptor that includes CD25. Regulatory T cells display CD25 from the start and rely on IL-2 made by other cells.

IL-6 is an inflammatory cytokine with several jobs at once: it pushes the liver towards the acute-phase pattern, contributes to fever, supports antibody responses, and, with further signals, favours differentiation of Th17 cells.

IL-7 is the cytokine required to develop and maintain lymphocytes, and T-cell development fails when the signal from IL-7 cannot be received.

Immunoediting is the description of tumour control as three successive phases: elimination of a new transformed clone, an equilibrium that contains and shapes variants, and escape of a variant that lymphocytes no longer restrain.

Indirect allorecognition is processing of donor MHC proteins as ordinary foreign antigens by the recipient's own dendritic cells, which then present peptides from them on recipient MHC class II. Responding T cells are present at ordinary frequencies, antibody to donor HLA is readily driven, and chronic injury of the graft depends heavily on this route.

The indirect Coombs test asks whether serum contains antibody that can bind red cells offered as the test reagent, which is what a cross-match is asking, and anti-human IgG is what reveals a coat of IgG that did not clump the cells by itself.

An indirect ELISA reports antibody: antigen is fixed on the surface, the sample supplies unlabelled primary antibody, and a labelled reagent directed at that antibody's Fc produces the signal. A negative result early in infection means antibody is not yet detectable, not that the person is uninfected.

An inflammasome is a cytosolic assembly, of which NLRP3 with ASC and procaspase-1 is the example used here, that activates caspase-1 after a second danger signal. A Toll-like receptor must already have transcribed the cytokine precursors, because the inflammasome cuts them and does not itself induce them.

Innate immunity is defence that uses a limited, germline-encoded set of receptors for structures shared by many microbes, or for host molecules released by damage, and that acts within minutes to hours without forming antigen-specific clonal memory.

Instruction theory is the rejected alternative to clonal selection: it held that antigen is a template around which a generic antibody chain folds, so specificity would not already be written in the lymphocyte. Refolding without antigen, and the finding that one cell secretes one specificity, showed that the information sits in the sequence instead.

An integrin is an adhesion molecule, such as LFA-1 or Mac-1, that arrests a rolling leucocyte on endothelial ICAM-1 once a chemokine such as CXCL8 has activated it.

Invariant chain, or CD74, occupies the groove of newly assembled MHC class II so that peptides intended for class I cannot bind, and it routes the dimer to a late endosome.

JAK–STAT signalling is the pairing of a cytokine receptor with gene transcription through a JAK kinase and a STAT factor, different pairs serving different cytokines. Loss of STAT1, or of the receptor for IFN-γ or for IL-12, therefore removes defence against intracellular bacteria even though antibody can still be made.

Junctional diversity is sequence variation created while coding ends of antigen-receptor segments are joined, by palindromic nucleotides, by bases removed with nucleases, and by nucleotides added without a template. The altered stretch lies in CDR3, so two cells that chose the same segments can still differ there.

A killer immunoglobulin-like receptor is an inhibitory receptor on NK cells that recognises groups of HLA-B or HLA-C molecules and, while those ligands are present, restrains killing.

Linked recognition is the requirement that the epitope bound by a B cell and the peptide recognised by the helper T cell come from one and the same physical particle. A free hapten offered beside an unattached carrier protein does not meet that requirement.

Lysozyme is an enzyme of tears, saliva, and neutrophil granules that hydrolyses the bond in peptidoglycan between N-acetylmuramic acid and N-acetylglucosamine, after which turgor can burst a susceptible bacterium. An intact Gram-negative outer membrane conceals that bond until some other injury exposes it.

A macrophage is the tissue cell of the monocyte lineage, resident for example as a Kupffer cell, an alveolar macrophage, or microglia, and it clears debris, secretes inflammatory cytokines, and presents antigen to T cells that are already effectors or memory cells. Starting a naive clone is the job of a mature dendritic cell, which pairs peptide with costimulation.

The marginal zone is the region of splenic white pulp that captures antigen arriving in the blood, especially repetitive polysaccharides, and that supports the B-cell response to those antigens. Removing the spleen removes this filter and leaves the person susceptible to encapsulated bacteria.

A mast cell is a tissue-resident cell bearing FcεRI, and antigen that cross-links IgE already bound to that receptor releases histamine within minutes.

The membrane-attack complex is the pore C5b–C9, assembled when C5b recruits C6, C7, C8, and many copies of C9, whose polymer forms the channel. It lyses susceptible thin-walled Gram-negative bacteria; thick walls and capsules are controlled by opsonisation instead.

Memory is the antigen-specific persistence, after a primary response, of expanded lymphocyte clones and of long-lived plasma cells, so a later meeting with the same antigen is handled by cells that are already numerous and easier to trigger. It is clonal, unlike the non-specific heightening called trained immunity.

MHC restriction means that a T cell recognises a peptide only when that peptide is displayed in a self MHC molecule, because the receptor contacts the peptide and the MHC protein holding it as one combined ligand.

A minor histocompatibility antigen is a polymorphic peptide from an ordinary self protein, presented on an MHC molecule that donor and recipient share, and it can still provoke rejection, more slowly, when the MHC itself matches. Male-specific H-Y peptides are the classical illustration.

Missing self is the NK-cell rule that inhibitory receptors for MHC class I normally restrain killing, so a cell that has lost class I can be killed when activating stress ligands are also present.

MyD88 is the adaptor used by most Toll-like receptors to turn on NF-κB and, through it, the inflammatory cytokines TNF, IL-1, and IL-6 together with chemokines.

NADPH oxidase is the electron-transport complex assembled in the phagosome membrane, with gp91phox as the catalytic subunit, that reduces oxygen to superoxide and so creates the respiratory burst used to kill ingested microbes.

Negative selection deletes developing T cells that bind self peptide in self MHC too strongly, a test carried out especially by medullary epithelium and by dendritic cells. Some cells that bind strongly are diverted into the Foxp3-positive regulatory lineage instead of being killed.

A neoantigen is a peptide encoded by a mutation the thymus never displayed as self, and a viral protein in a virus-associated cancer is foreign for the same reason, so either can be a credible target for CD8 T cells.

Neutralisation is blockade, by bound antibody, of a toxin or virus before it can engage its cellular target, and it is the effector function that remains when only an Fab fragment is present.

A neutrophil is the most numerous circulating leucocyte and the phagocyte first called in large numbers to a bacterial infection; it lives briefly, can mount a respiratory burst, and does not prime naive T cells.

NF-κB is the transcription factor turned on by MyD88-dependent Toll-like receptors and by cytosolic NOD receptors, and it drives inflammatory cytokines together with the precursors of IL-1β.

An NK cell is a lymphoid cell of the innate system that does not rearrange an antigen-receptor gene and that kills targets which have lost MHC class I or which are coated with IgG.

NLRP3 is the sensor that assembles with ASC and procaspase-1 into an inflammasome after diverse insults, including ATP through P2X7, uric acid crystals, and alum, which often share a fall in cytosolic potassium.

Opsonisation is coating a particle with antibody, with C3b, or with both, so that phagocytes bind it through Fcγ receptors, especially FcγRI (CD64), and through complement receptors.

A pathogen-associated molecular pattern is a conserved microbial structure that healthy host cells lack, such as lipopolysaccharide, flagellin, double-stranded RNA, or unmethylated CpG DNA, and that germline-encoded receptors read as a sign of infection. Commensals manufacture many of the same structures.

The paracortex is the T-cell zone of a lymph node, lying deep to the B-cell follicles, where dendritic cells and naive T cells are held and where a T cell proliferates after it meets antigen.

PD-1 is an inhibitory receptor that is high on T cells exhausted by chronic stimulation: they stay specific but kill and divide poorly. Binding of PD-L1 recruits SHP-2 and dampens signalling from the T-cell receptor and from CD28 in the tissue, and blocking that pair releases cells that already recognise the target rather than creating a new specificity.

PD-L1 is the ligand of PD-1, induced by IFN-γ on inflamed tissue and on many tumours, and the pair inhibits effector T cells at the target site rather than during priming in the node.

Perforin is the pore-forming protein of cytotoxic granules, released only at the contact with the target so that granzymes enter that cell and spare its neighbours. Death is by apoptosis, so the cytoplasm is not spilled.

Pleiotropy is one cytokine having several jobs, as IL-6 does when it induces acute-phase proteins, contributes to fever, supports antibody, and favours Th17 differentiation.

MHC polymorphism is the extreme allelic variation of the peptide-binding pockets, such that a peptide accommodated by one person's HLA may find no groove in a neighbour. In a population that diversity slows escape by pathogens; between a transplant donor and recipient it is the chief reason for rejection.

Positive selection is the survival, in the thymic cortex, of a double-positive thymocyte whose receptor binds weakly to self peptide presented by self MHC on cortical epithelium. Cells that bind nothing die of neglect, and neglect accounts for most thymocytes that never emigrate.

The pre-B-cell receptor is a productively rearranged μ heavy chain paired with the surrogate light chain of VpreB and λ5. Assembly signals the cell to proliferate and to stop rearranging the other heavy-chain allele before a conventional light chain is tried.

A primary lymphoid organ is a site at which lymphocytes are generated and tested against self, with foreign antigen largely excluded: bone marrow for B cells and for T-cell precursors, and the thymus for completion of T-cell selection.

A primary response is the adaptive response at the first encounter with an antigen, slow because only a few clones fit and must divide, and the early antibody is mostly unmutated IgM of modest amount.

The prozone is the region of antibody excess in a precipitation or agglutination assay, in which complexes stay small and soluble, so a potent undiluted serum can appear negative until it is diluted towards equivalence.

A pattern-recognition receptor is a germline-encoded innate receptor for a pathogen-associated or damage-associated molecular pattern, displayed as a fixed set on a given cell, with no somatic rearrangement and no affinity maturation.

RAG1 and RAG2 are the endonucleases of developing B and T cells that cut beside recombination signals and thereby start assembly of one variable-region exon from V, D, and J segments. NK cells do not use RAG, so they remain when loss of RAG has removed T and B cells.

Receptor editing is a renewed attempt at light-chain gene rearrangement by an immature B cell that has bound multivalent self antigen in the marrow. Failure to produce a harmless receptor leads to death of the cell, whereas soluble self antigen more often anergises the cell than restarts recombination.

Redundancy is the sharing of one function by more than one cytokine, as when IL-1 and TNF can each activate endothelium and can each cause fever.

A sandwich ELISA reports antigen in a complex mixture: a capture antibody immobilises it and a second antibody, aimed at a different epitope, produces a signal only when the antigen has bridged the two. A hapten is usually too small to be bound by both at once.

Severe combined immunodeficiency is failure of adaptive immunity from infancy because T cells do not develop and useful antibody therefore fails as well. X-linked loss of the common γ chain removes T cells and NK cells but can leave B cells present; loss of RAG removes every antigen-receptor rearrangement, so T and B cells are absent and NK cells are spared.

A secondary response is the recall response of memory B and T cells, rising sooner, reaching a higher peak, and lasting longer than the primary response, with antibody that binds more tightly because many of the B cells have already switched and mutated.

Secretory component is the piece of the polymeric immunoglobulin receptor that stays attached to dimeric IgA after the antibody has crossed an epithelium, and it helps that IgA resist proteases in the gut.

A selectin is an adhesion molecule that mediates the initial rolling of leucocytes on endothelium by binding sialylated carbohydrates such as sialyl-Lewis X.

Serum sickness is the prototype of type III hypersensitivity, in which antibody appears while a soluble foreign antigen is still in the circulation and the resulting immune complexes deposit in vessels, joints, and glomeruli. Complement fixation and an influx of neutrophils produce the fever, urticaria, joint pain, and proteinuria.

Systemic lupus erythematosus is systemic autoimmunity to nuclear antigens found in every cell, such as double-stranded DNA, histones, and ribonucleoproteins, with tissue injury caused largely by deposition of immune complexes. Nucleic acid inside those complexes stimulates TLR7 and TLR9, which drives type I interferon and further activation of B cells.

Somatic hypermutation is the introduction, dependent on activation-induced deaminase, of point mutations into the variable regions of rearranged immunoglobulin genes inside a germinal centre, after which B cells whose mutated receptors bind better are selected. T-cell receptor genes are not mutated in this way.

STING is the endoplasmic-reticulum protein that binds the cyclic dinucleotide made by cGAS and, through TBK1 and the transcription factor IRF3, induces type I interferon, with NF-κB activated alongside.

A superantigen is a microbial protein, such as a staphylococcal toxin, that binds MHC class II outside the peptide groove and a Vβ domain shared by many T-cell receptors, so several per cent of T cells can be activated together and release a large burst of cytokine.

A T-independent antigen stimulates B cells without help from a peptide-specific CD4 cell, either by co-engaging an innate receptor or, in the classical capsular form, by cross-linking many B-cell receptors at once. The product is largely unmutated IgM with little memory, and lipopolysaccharide via TLR4, the usual mouse example of the first kind, does not transfer unchanged because human B cells express little TLR4.

TAP is the heterodimer of TAP1 and TAP2 that pumps peptides generated by the proteasome from the cytosol into the endoplasmic reticulum, where they can be loaded onto MHC class I.

Tapasin is part of the peptide-loading complex that retains empty MHC class I in the endoplasmic reticulum until a peptide suited to that allele completes folding with β2-microglobulin.

Terminal deoxynucleotidyl transferase adds non-templated N nucleotides to the coding joints of rearranging antigen-receptor genes, vigorously at the heavy chain and weakly at the light chain. It is scarce in foetal life, so foetal junctions carry less random sequence.

A T follicular helper is a CD4 subset, associated with the transcription factor Bcl6, that enters the B-cell follicle and provides IL-21 and CD40 ligand so that germinal-centre B cells can switch isotype and improve affinity.

A Th1 cell is a CD4 subset driven by IL-12 and IFN-γ, under the transcription factor T-bet, whose signature cytokine IFN-γ, together with CD40 ligand, makes macrophages kill microbes living inside them.

A Th17 cell is a CD4 subset whose signature cytokines IL-17 and IL-22 recruit neutrophils and induce epithelial antimicrobial peptides against extracellular bacteria and fungi at barriers. Induction by IL-6 plus TGF-β is the mouse pattern; in humans, IL-1 and IL-23 weigh more.

A Th2 cell is a CD4 subset driven by IL-4 under the transcription factor GATA3, secreting IL-4, IL-5, and IL-13, and steering IgE, eosinophils, mucus, and mast cells towards helminths and allergic inflammation.

ThPOK is the transcription factor that fixes the CD4 fate of a thymocyte positively selected on MHC class II, as opposed to the CD8 fate that follows selection on MHC class I.

TLR3 is the endosomal Toll-like receptor for double-stranded RNA, and it signals through the adaptor TRIF rather than MyD88, biasing the response towards type I interferon.

TLR4, acting with MD-2 and CD14, is the surface receptor for lipopolysaccharide; it signals through MyD88 at the plasma membrane to activate NF-κB, and through TRIF after it has been internalised.

TLR7 is an endosomal Toll-like receptor for single-stranded RNA, richly expressed on plasmacytoid dendritic cells, which use it to secrete large amounts of type I interferon.

TLR9 is the endosomal Toll-like receptor that binds unmethylated CpG DNA. Cytosolic DNA is not its ligand; that compartment is surveyed by cGAS.

TNF is an inflammatory cytokine released by activated macrophages and dendritic cells that activates endothelium, causes fever, and helps to maintain granulomas. In a local focus it is part of defence; widespread in the blood it contributes to shock.

Tolerance is the antigen-specific silencing of lymphocytes whose receptors bind self, by deletion, receptor editing, anergy, ignorance, or regulatory cells, so that a random repertoire can be used without a standing attack on the host.

A toxoid is a toxin altered until it is no longer poisonous but is still antigenic, and what it shows the immune system is a target for neutralising antibody. That antibody need not prevent the organism from colonising.

Trained immunity is a heightened responsiveness of innate cells that lasts weeks or months because of epigenetic change, and it is not the antigen-specific clonal memory of adaptive immunity.

A regulatory T cell is a CD4 cell defined by Foxp3 that suppresses other lymphocytes, whether it left the thymus already committed or was induced from a naive cell by TGF-β and IL-2. The restraint uses IL-10 and TGF-β, consumption of IL-2 through CD25, and removal of B7 by CTLA-4.

TRIF is the adaptor engaged by TLR3, and by TLR4 after internalisation, that activates the transcription factor IRF3 and thereby type I interferon rather than only the MyD88-dependent inflammatory programme.

The tuberculin test is a type IV skin reaction in which mycobacterial protein recalls memory Th1 cells, and IFN-γ plus macrophages produce a palpable induration after about two to three days. A positive reaction reports memory of the antigen; by itself it reports neither active disease nor protection.

Type 1 diabetes is organ-specific autoimmunity in which CD4 and CD8 cells destroy the insulin-producing β cells of the pancreatic islets, and clinical disease appears only after most of those cells are already lost. Antibodies against islet antigens mark the process more than they mediate the killing.

Type I interferon is the family made up of many IFN-α species and one main IFN-β, secreted by infected cells and in large amounts by plasmacytoid dendritic cells. It places neighbouring cells in an antiviral state, increases MHC class I, and activates NK cells.

V(D)J recombination is the cutting and joining, in a developing lymphocyte, of separate variable, diversity, and joining gene segments to build one exon for the variable region of an antigen receptor before any antigen is encountered. Light-chain genes use V and J segments only; the heavy chain uses D segments as well.

A western blot reports antibody binding to a polypeptide of a known size after the proteins have been denatured and separated. Epitopes that exist only in the folded protein are often destroyed by that denaturation, so a serum can bind in an ELISA and still give no band on a blot of the same antigen.

X-linked agammaglobulinaemia is loss of Bruton tyrosine kinase, which signals from the pre-B-cell receptor, so development halts at that stage, mature B cells are almost absent, and every antibody isotype is profoundly low. T cells are spared.

β2-microglobulin is the invariant partner of the MHC class I heavy chain, encoded on chromosome 15 outside the MHC, and the heavy chain is unstable at the cell surface until it has folded with both this partner and a peptide.