--- module: 093-03 language: en chapter: 93 title: "Mechanistic Immunology: Recognition, Activation, and Effector Systems" module_title: "Antibodies, complement, Fc receptors, cytotoxic effectors, and immune-complex clearance" source_sha256: bb29bbff5befbcc123767e40bfaefbf864419fd9094f82a71691be8c076c4370 --- # Antibodies, complement, Fc receptors, cytotoxic effectors ## Effector overview ### Neutralise, opsonise, complement, kill, protect ### Antibodies give soluble specificity ### Complement amplifies by proteolytic cascades ### Fc receptors interpret isotype and context ### Deposited or misdirected products injure host ## Antibody structure ### Two heavy and two light chains ### Variable domains form two binding sites #### Complementarity-determining regions contact antigen ### Fc region binds receptors and complement ### Hinge permits binding at different angles ### Fab and Fc separable by proteolysis ### Affinity: one interaction; avidity: combined #### Low-affinity IgM gains high avidity ## Isotypes ### Class switch keeps the variable region ### IgM: pentamer, early, intravascular #### Timing limited by persistence, cross-reaction ### IgG: neutralises, opsonises, crosses placenta #### Neonatal Fc receptor extends half-life #### Maternal autoantibodies can transfer ### Secretory IgA crosses epithelium #### Secretory component resists proteolysis #### Neutralises with little inflammation ### IgE arms mast cells and basophils #### Specific IgE shows sensitisation only ### IgD: mainly naive B-cell receptor ### Kappa or lambda; light-chain restriction ## Neutralisation and opsonisation ### Neutralisation blocks attachment, entry, toxins #### Needs epitope access, not Fc #### Viruses escape by epitope change ### Mucosal prevents establishment, systemic limits spread ### Fc gamma receptors bind clustered IgG ### Complement receptors bind deposited C3 fragments ### Activating and inhibitory receptors balance ### Soluble monomeric IgG triggers weakly ## B-cell diversification ### Switching needs CD40 signalling and cytokines ### Intervening DNA deleted: largely irreversible #### Defects cause hyper-IgM syndromes ### Somatic hypermutation in germinal centres #### Clones compete for antigen and help #### Risks autoreactivity and translocation ### Plasma cells: abundant rough ER ### Long-lived cells in marrow or mucosal niches ### Serum level reflects production and catabolism ## Complement activation ### Classical: C1 binds antibody ### Lectin: mannose-binding lectin, ficolins ### Alternative: spontaneous C3 activation ### All form C3 convertases ### C3b opsonises and forms C5 convertase ### C5b to C9 membrane-attack complex #### Key against Neisseria ### C3a and C5a are anaphylatoxins ### Fragments lower B-cell activation threshold ## Complement regulation and deficiency ### C1 inhibitor restrains early and contact proteases #### Deficiency: bradykinin angioedema #### Antihistamines may be insufficient ### Factors H and I inactivate C3b ### DAF and membrane-cofactor protein ### CD59 blocks terminal pore formation ### Paroxysmal nocturnal haemoglobinuria #### GPI regulator loss: cell injury, thrombosis ### Early classical deficiency: lupus-like disease ### C3 deficiency: recurrent pyogenic infection ### Terminal deficiency: Neisseria infection ### Functional assays before single components ## Immune complexes and cytotoxicity ### Size, ratio, charge, flow set deposition ### Erythrocyte receptors carry them to liver, spleen ### Persistent complexes deposit in glomeruli, vessels ### CD16 antibody-dependent cellular cytotoxicity ### Eosinophils attack helminths too large to engulf ### Fc engineering alters potency, half-life ### Cytotoxic T cells: perforin-granzyme and Fas #### Defects cause haemophagocytic lymphohistiocytosis ## Access and amplification ### IgG in blood, IgA at mucosa, IgE in tissue ### Cytotoxic cells require contact ### Abundant defence fails without access ### Regulators protect host, clearance ends response ### Node failure: infection, allergy, autoimmunity