Harpers

622 / CHAPTER 52Table 52–11. Examples of integrins that are important in the function of neutrophils, of other whiteblood cells, and of platelets. 1Integrin Cell Subunit Ligand FunctionVLA-1 (CD49a) WBCs, others α1β1 Collagen, laminin Cell-ECM adhesionVLA-5 (CD49e) WBCs, others α5β1 Fibronectin Cell-ECM adhesionVLA-6 (CD49f) WBCs, others α6β1 Laminin Cell-ECM adhesionLFA-1 (CD11a) WBCs αLβ2 ICAM-1 Adhesion of WBCsGlycoprotein llb/llla Platelets αllbβ3 ICAM-2 Platelet adhesion and aggregationFibrinogen, fibronectin, von Willebrandfactor1 LFA-1, lymphocyte function-associated antigen 1; VLA, very late antigen; CD, cluster of differentiation; ICAM, intercellular adhesion molecule;ECM, extracellular matrix. A deficiency of LFA-1 and related integrins is found in type I leukocyte adhesion deficiency (MIM 116290).A deficiency of platelet glycoprotein llb/llla complex is found in Glanzmann thrombasthenia (MIM 273800), a condition characterized by ahistory of bleeding, a normal platelet count, and abnormal clot retraction. These findings illustrate how fundamental knowledge of cellsurface adhesion proteins is shedding light on the causation of a number of diseases.bisphosphate of inositol triphosphate and diacylglycerol.These two second messengers result in an elevationof intracellular Ca 2+ and activation of protein kinaseC. In addition, activation of phospholipase A 2produces arachidonic acid that can be converted to avariety of biologically active eicosanoids.The process of activation of neutrophils is essentiallysimilar. They are activated, via specific receptors, by interactionwith bacteria, binding of chemotactic factors,or antibody-antigen complexes. The resultant rise in intracellularCa 2+ affects many processes in neutrophils,such as assembly of microtubules and the actin-myosinsystem. These processes are respectively involved in secretionof contents of granules and in motility, whichenables neutrophils to seek out the invaders. The activatedneutrophils are now ready to destroy the invadersby mechanisms that include production of active derivativesof oxygen.The Respiratory Burst of PhagocyticCells Involves NADPH Oxidase& Helps Kill BacteriaWhen neutrophils and other phagocytic cells engulfbacteria, they exhibit a rapid increase in oxygen consumptionknown as the respiratory burst. This phenomenonreflects the rapid utilization of oxygen (followinga lag of 15–60 seconds) and production from itof large amounts of reactive derivatives, such as O 2−⋅,H 2 O 2 , OH • , and OCl − (hypochlorite ion). Some ofthese products are potent microbicidal agents.The electron transport chain system responsiblefor the respiratory burst (named NADPH oxidase) iscomposed of several components. One is cytochromeb 558 , located in the plasma membrane; it is a heterodimer,containing two polypeptides of 91 kDa and22 kDa. When the system is activated (see below), twocytoplasmic polypeptides of 47 kDa and 67 kDa are recruitedto the plasma membrane and, together with cytochromeb 558 , form the NADPH oxidase responsiblefor the respiratory burst. The reaction catalyzed byNADPH oxidase, involving formation of superoxideanion, is shown in Table 52–4 (reaction 2). This systemcatalyzes the one-electron reduction of oxygen to superoxideanion. The NADPH is generated mainly by thepentose phosphate cycle, whose activity increases markedlyduring phagocytosis.The above reaction is followed by the spontaneousproduction (by spontaneous dismutation) of hydrogenperoxide from two molecules of superoxide:O −⋅ 2 + O −⋅ +2 + 2 H → H2O2 + O2The superoxide ion is discharged to the outside ofthe cell or into phagolysosomes, where it encounters ingestedbacteria. Killing of bacteria within phagolysosomesappears to depend on the combined action ofelevated pH, superoxide ion, or further oxygen derivatives(H 2 O 2 , OH • , and HOCl [hypochlorous acid; seebelow]) and on the action of certain bactericidal peptides(defensins) and other proteins (eg, cathepsin G andcertain cationic proteins) present in phagocytic cells.Any superoxide that enters the cytosol of the phagocyticcell is converted to H 2 O 2 by the action of superoxidedismutase, which catalyzes the same reaction as thespontaneous dismutation shown above. In turn, H 2 O 2 isused by myeloperoxidase (see below) or disposed of bythe action of glutathione peroxidase or catalase.NADPH oxidase is inactive in resting phagocyticcells and is activated upon contact with various ligands(complement fragment C5a, chemotactic peptides, etc)