--- module: 093-01 language: en chapter: 93 title: "Mechanistic Immunology: Recognition, Activation, and Effector Systems" module_title: "Innate barriers, pattern recognition, inflammation, phagocytes, and antiviral defence" source_sha256: 5d069bcbc796bf731d977a3b4768f4a8bcbb2df4fb036e0bbdccd99dcdb7e129 --- # Innate barriers, recognition, phagocytes, antiviral defence ## Barriers and epithelium ### Goals: contain, remove damage, recruit, restore #### Without inflammation becoming the injury ### Skin: keratin, junctions, lipids, acidity, peptides ### Mucosa: mucus, cilia, flow, acid, secretory antibody ### Commensals occupy niches and educate immunity #### Defence is chemical and ecological ### Epithelia sense and release alarmins, peptides #### Paneth defensins, mucociliary defence, urinary flow ### Disruption exposes matrix and permits invasion ### Excessive repair causes fibrosis ## Pattern recognition ### Pathogen and damage patterns detected ### Toll-like receptors on membrane or endosomes ### Cytosolic NOD, RIG-I, cGAS-STING sensors #### Misplaced nucleic acid signals danger ### Adaptors link to NF-kappa B, AP-1, IRFs #### TNF, chemokines, type-one interferons ### Convergence with distinct timing and cells ### Repeat stimulation: tolerance or priming ## Inflammation and recruitment ### Mediators dilate vessels, open endothelium #### Histamine, nitric oxide, prostaglandins ### Exudate delivers antibody, complement, clotting #### But causes swelling ### Fever: hypothalamic prostaglandin signalling ### Selectins mediate transient rolling ### Chemokines activate leukocyte integrins #### Firm adhesion to immunoglobulin-family molecules ### Defects: high blood neutrophils, little pus ## Neutrophils and macrophages ### Neutrophils: rapid, short-lived, bacteria, fungi ### Phagosome fuses with granules #### NADPH oxidase generates superoxide #### Myeloperoxidase forms hypochlorous chemistry ### Extracellular granules damage host tissue ### Extracellular traps immobilise microbes #### Excess: thrombosis and autoantigen exposure ### Persistent inflammation: protease destruction ### From monocytes or embryonic precursors ### Present antigen, regulate iron, coordinate repair ### M1 versus M2 captures only extremes ## Phagocytosis and its disorders ### Opsonins: IgG, complement, lectins, pentraxins ### Receptor clustering drives actin engulfment ### Killing: acid, enzymes, oxidants, nutrient limits ### Chronic granulomatous disease: no respiratory burst #### Recurrent bacterial, fungal infection, granulomas ### Myeloperoxidase deficiency often mild ### Localise: arrive, engulf, oxidise, activate ## Inflammasomes ### Cytosolic platforms activate caspase one ### NLRP3 senses ion flux, crystals, lysosomal damage ### Caspase one matures interleukin-1 beta and 18 ### Gasdermin D pores drive pyroptosis ### Urate or cholesterol crystals activate NLRP3 ### Gain-of-function variants: periodic fevers #### Respond to interleukin-1 blockade ## Antiviral defence and sentinel cells ### Type-one interferons induced by viral nucleic acid #### JAK-STAT induces hundreds of antiviral genes #### Excess causes interferonopathies ### Natural killer balance: stress ligands, class one #### Lost class one removes inhibition #### Perforin, granzymes, interferon gamma ### CD16 enables antibody-dependent cytotoxicity ### Innate lymphoid cells mirror helper cytokines #### No rearranged antigen receptors ### Dendritic cells link sensing to naive T cells #### Maturation favours migration, costimulation ## Systemic response and sepsis ### Interleukins 6 and 1, TNF drive acute phase ### Liver raises CRP, fibrinogen, hepcidin #### Hepcidin degrades ferroportin #### Contributes to anaemia of inflammation ### Markers sensitive but not cause-specific ### Sepsis: dysregulated response, organ dysfunction #### Leak, coagulation, immune suppression ### Treat both trigger and physiology ## Resolution, memory, and sterile damage ### Resolution is an active programme ### Efferocytosis suppresses inflammation #### Failure: secondary necrosis, autoantigens ### Trained immunity: epigenetic, metabolic change ### Endotoxin tolerance dampens repeat responses ### Sterile necrosis releases DNA, ATP, urate ### Fever and neutrophils do not prove infection #### Microbiology, anatomy, timing, response