Immune recognition: innate and adaptive

All immune cells come from the same marrow stem cell, which splits into a myeloid line (neutrophils, eosinophils, basophils, monocytes and macrophages, mast cells, dendritic cells) and a lymphoid line (B cells, T cells, NK cells). The split matters because the two lines recognize danger differently.

Innate immunity uses receptors encoded unchanged in the germline. Every macrophage carries the same set, tuned to molecular patterns that many microbes share or that dying cells release. It answers in minutes to hours, it is not specific to one microbe, and the second encounter looks like the first: no memory. Adaptive immunity uses B- and T-cell receptors that each lymphocyte assembles for itself by V(D)J recombination, so every clone sees a different antigen. A first response takes days while the rare matching clone expands; afterwards, memory cells make the next response faster and stronger.

Innate defense is more than cells. Skin and mucosa are barriers; tears, saliva, sweat, mucus and breast milk wash, trap and kill; gastric acid kills; fever slows microbial growth; resident colonic bacteria occupy space and nutrients that pathogens would need. Epithelial cells secrete β-defensins, constitutively or when TNF induces them, which kill microbes and attract neutrophils. The liver releases acute-phase reactants: CRP and C3b coat microbes for phagocytes (opsonins), and IL-6 drives hepcidin, which locks iron inside macrophages and liver cells so bacteria cannot use it. That same hepcidin is why chronic inflammation causes anemia.

Lymphocytes are made and educated in the primary lymphoid organs. The bone marrow produces all lymphocyte precursors and is where B cells mature. T-cell precursors leave the marrow for the thymus, where they learn to recognize self-MHC and are purged of strongly self-reactive clones (see Building a repertoire, below). Mature naive cells then circulate through the secondary lymphoid organs, lymph nodes, spleen and mucosal tissue such as Peyer patches, where they meet antigen carried in by dendritic cells.

Innate receptors recognize two kinds of signal. PAMPs (pathogen-associated molecular patterns) are structures microbes need and we lack: lipopolysaccharide (endotoxin) of gram-negative bacteria, peptidoglycan of gram-positive bacteria, flagellin, unmethylated CpG DNA, viral double-stranded RNA. DAMPs (damage-associated molecular patterns) come from our own injured cells: ATP, uric acid, DNA, heat-shock proteins. Because DAMPs exist, sterile injury such as an infarct or a gout crystal also triggers inflammation.

Toll-like receptors sit on the plasma membrane (TLR4 binds LPS; TLR2 binds lipoteichoic acid and peptidoglycan; TLR5 binds flagellin) or in endosomes (TLR3, 7, 8 and 9 bind viral and bacterial nucleic acids). Their signal reaches the transcription factor NF-κB, which enters the nucleus and switches on TNF, IL-6, chemokines, adhesion molecules, costimulators and pro-IL-1β. Endosomal TLRs also switch on type I interferons against viruses.

NOD-like receptors work in the cytosol, mainly in macrophages, dendritic cells and monocytes. Sensing microbial products (the lecture lists Salmonella, Shigella, Pseudomonas, Legionella, Candida and several viruses), urate or cholesterol crystals, ATP or potassium leak, the NLR NLRP3 assembles with an adaptor and pro-caspase-1 into a large complex, the inflammasome. Active caspase-1 cleaves pro-IL-1β and pro-IL-18 into their active forms. IL-1β causes fever and recruits neutrophils; IL-18 drives IFN-γ. Caspase-1 can also punch pores in the cell's own membrane, a lytic, inflammatory death called pyroptosis.

A few sites, the eye, brain, testis and placenta, would be damaged badly by ordinary inflammation, so they limit immune responses. They use barriers (the blood–brain barrier; Sertoli-cell tight junctions in the testis), few lymphatics and low MHC expression, and they secrete suppressive cytokines such as TGF-β; some cells express Fas ligand, which kills activated T cells that enter. Trophoblast avoids the classical HLA-A and -B molecules that maternal T cells would attack.

Adaptive protection can be made by the person (active) or borrowed as ready-made antibody (passive), and either can happen in nature or by medical intervention. Active immunity needs time but leaves memory; passive immunity works at once but fades as the borrowed antibody is catabolized, because no memory cells were made.

Each developing lymphocyte cuts and joins gene segments to build its receptor: V, D and J segments for the immunoglobulin heavy chain and TCR β chain, V and J for light chains and TCR α. The recombinase enzymes RAG1 and RAG2 make the cuts; random nucleotides added at the joints multiply the variety. The result is a repertoire of millions of specificities, including, inevitably, receptors that recognize self. RAG mutations prevent receptor assembly, so neither T nor B cells mature: one form of SCID (3.6).

After a first response, some lymphocytes persist as memory cells: more numerous than the original clone, quicker to activate and, for B cells, already switched to IgG and refined in affinity. A second exposure therefore gives a faster, larger, higher-affinity response. That is the basis of booster vaccines and also why a second exposure to an allergen or drug is the one that causes trouble.