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Cell Biology of Leukocyte Abnormalities--Membrane and Cytoskeletal Function in Normal and Defective Cells. a Review

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Cell Biology of Leukocyte Abnormalities--Membrane and Cytoskeletal Function in Normal and Defective Cells. a Review REVIEW ARTICLE CELL BIOLOGY OF LEUKOCYTE ABNORMALITIES Cell Biology of Leukocyte Abnormalities-Membrane and Cytoskeletal Function in Normal and Defective Cells Ultratructure of the Human Neubtpl 22:3 Basic _bmisty of ke keon 22 Basic Pharmacology of the Cyoseton 226b Leukwyte Functo That Depen on CyosMkta Integrt 22-7 The Regulation of Miofdlament Disrbuon 232 The Regulto of Micobule Assaemb 2;34 Ligand-Membrane Interaction and Oidative Met :237 Membrane and Cytoskeletal Abrmnaties of Human Neutrophis 241 Neutrophil Dysfunction Linked to Structural Abnormalities of the Cytoskeleton 241 Neutrophil Dysfunction Linked to Regulatory Abnormalities of the Cvtoskeleton 242 Neutrophil Membrane and Cytoskeletal Dvsfunction Secondarv to Abnormal Oxidative Metabolism 246 Disorders of Oxidant Generation 246 Disorders of Oxidant Removal 249 Concluding Remarks 51 Cell Biology of Leukocyte Abnormalities-Membrane and Cytoskeletal Function in Normal and Defective Cells A Review Janet M. Oliver, PhD ALTHOUGH THE POLY\1ORPHONUCLEAR LEUKOCYTE (PMN, neu- trophil) has been studied since the days of Ehrlich, the precise mechanisms by which it functions to seek out and inactivate foreign microorganisms are not totally clear. Analvses performed over the past 2 decades have greatlv advanced our understanding of the biochemistry of bacterial killing by neutrophils and have provided important insight into the molecular basis of inherited diseases associated with specific enzvme deficiencies. Simi- larlv, immunologic studies have illuminated the role of complement and antibodies in the generation of chemotactic factors and in the opsoniza- tion of bacteria. In parallel, the high susceptibility of certain patients to infection has been explained in terms of defects in the serum opsonic or chemotatic activity. Recentlv it has become clear that PMN function is importantly influ- enced not onlv bv the immune svstem and the availabilitv of cytoplasmic and granule enzvmes but also by dvnamic properties of the cell mem- brane and the cvtoplasniic microtubules and microfilaments, known col- lectivelI as the cvtoskeleton. The processes of chemotaxis, phagocytosis, oxidant generation, and Iysosomal degranulation (Text-figure 1, Steps 5 through 8) are central to neutrophil function. Their initiation depends on the existence on the plasma membrane of receptors that recognize and bind surface ligands (Text-figure 1, Steps 1 through 4), setting in motion a variety of events, including the activation of membrane enzyme systems and the specific assembly or mobilization of microtubules and micro- filaments. The motile and bactericidal functions of the neutrophil are subsequently expressed. From the lepartments of Pathology and Physiology. University of Connecticut Health Center, lFarmington. COnnecticuit. Slupp)rted b-bGrants FS-01 106 and CA-15364 from the National Institutes of Health and bN- Grant BC-179 from the American Cancer Society. Dr. Oliver is an American Cancer Societv Facults R(esarch Aw5 ardee. A\ccepte(l for puibli.ation April 17. 1978. ..%ddrt-ss reprint requests to Janlet S1. Oliser, PhD, Department of Physiology, University of Con- oceticiat lealth (;enter Stho)ol of Medicine, IFarmington, CT 06032. 0002-9440/78/1010-0219$01.00 221 222 OLIVER American Journal of Pathology PMN Bacterial invasion Chemotactic factor (CF) generation - CF binding to surface receptors CHEMOTAXIS to site of infection Opsonization of bacteria _ Binding of bacteria to surface receptors 0 PHAGOCYTOSIS OXIDANT GENERATION LYSOSOMAL DEGRANULATION BACTERIAL KILLING _ Digestion TEXr-FIGURE 1-The role of the neutrophil in defense against infection. The proper initiation of bacterial surveillance by PMN requires a competent immune system for generation (Steps 1 and 2) and recognition (Steps 3 and 4) of chemotactic and opsonic factors. The proper resolution of inactivated bacteria depends on the presence of a correct biochemical complement of granule enzymes (Step 9). The intermediate processes of chemotaxis, phagocytosis, oxidant generation, and lvsosomal degranulation (capital letters, Steps 5 through 8), depend most importantly on the integrit of the plasma membrane and of the cytoplasmic microtubules and microfilaments. It has been recognized that the failure of bacterial surveillance in specific diseases is associated directly or indirectly with defects in mem- brane or cytoskeletal organization and function. In perhaps the most dramatic of disorders associated with cytoskeletal dysfunction, the Chediak-Higashi syndrome, it has also been possible to substantially improve the progress of patients by application of laboratory data to the therapy of the disease. I have tried in the following pages to present an integrated view of PMN functions that depend on the integrity of the cytoskeleton. This synthesis is preceded by a general overview of PMN ultrastructure and of the biochemistry and pharmacology of microtubules and microfilaments. I emphasize the role of the plasma membrane both as a transducer, signal- ling changes in cytoskeletal order, and as the generation site for oxidants required for bacterial killing. These basic data are applied to give insight Vol. 93, No. 1 LEUKOCYTE ABNORMAUTIES 223 October 1978 into a series of diseases associated with defects in neutrophil chemotaxis, phagocytosis, lysosomal degranulation, and oxidant generation or dis- posal. In specific cases, some possible therapeutic approaches are sug- gested. The analysis draws heavily from the concepts of modern cell biology. Alternative approaches to normal and pathologic leukocyte func- tion have been presented in several recent monographs 14 and sym- posiums.5'6 Ultrasbtucre of the Hwnan Neutophil The basic ultrastructure of human neutrophils is well known and has been especially finely illustrated by Bessis.7 Review of ultrastructure here will accordingly be brief and will emphasize features of the PMN that are not the major concem in textbook descriptions. As shown in Figure 1, PMN contain a multilobed, highly condensed, and metabolically inactive nucleus (N), an abundance of large, round granules (probably the azurophilic granules, AG), as well as smaller often elongated or dumbbell-shaped granules (probably specific granules, SG). The azurophilic granules are lysosomes; they are membrane-bounded and contain biochemically and cytochemically demonstable acid hydrolases as well as myeloperoxidase which is involved in bacterial killing via oxidative mechanisms. The specific granules are not strictly lysosomes; their mem- brane encloses alkaline phosphatase, lysozyme, a variety of bactericidal cationic proteins, and an iron-binding protein, lactoferrin.A13 In the present context the most important morphologic features of the PMN are its so-called cyoskeletal components (primarily the micro- tubules [MT] and microfilaments [MF]) and the plasma membrane. The origin and appearance of microtubules is illustrated in Figures 1 and 2. Examination at low magnification (Figure 1) reveals fibers approx- imately 240 R in diameter that radiate from the center of the cell in all directions toward the plasma membrane. At higher magnification (Figure 2) it is apparent that the central concentration of microtubules forms about the centrioles. These are paired cylindric structures 1500 R in diameter, some 3000 to 5000A long and made up of nine groups of three microtubules arranged in a spiral.7 A 600 to 900A diameter satellite (S) emerges from each of the microtubule groups, and cytoplasmic micro- tubules originate from the satellite region. The centrioles usually occupy the concavity of the horseshoe-shaped cell nucleus 7 (Figure 1). Micro- tubules were resistant to identification in PMN until recently,14 in part because their preservation for electron microscopy requires fixation of PMN in glutaraldehyde at room temperature or higher and in part be- cause their formation in cells from soluble tubulin dimer (see below) 224 OLIVER American Journal of Pathology requires the interaction of the PMN with a surface or with a ligand.15 Thus, the centriole in Figure 2A was photographed from a section through a PMN that had simply been isolated from buffy coat, fixed in suspension, and processed for electron microscopy. The satellites of this centriole are particularly well preserved, but only two microtubules are present. In contrast, the abundant microtubules in the PMN illustrated in Figure 1 and associated with the centriole in Figure 2B reflect their assembly during a 5-minute exposure of the leukocyte suspensions respectively to the plant lectin concanavalin A (Con A) or to phagocytic particles (oil emulsion). The microfilaments in Figure 1 occupy the region of the cytoplasm immediately below the plasma membrane. These fibers, approximately 60 A in diameter, are present under the membrane of the round cell, occu- pying protrusions and ruffled regions of the plasma membrane and pre- venting access of cytoplasmic granules to the membrane. Their major subunit component is the globular protein actin. Microfilaments become more prominent in PMN during motile or endocvtic processes due in large part to their concentration in regions of surface activity.",-- Thus, the cells in Figure 3 which are internalizing oil emulsion by phagocytosis show marked polarization of microfilaments in pseudopods. A similar recruit- ment of filaments is shown below to accompany other motile events, eg, chemotaxis and Con A cap formation. The reticular appearance of the microfilaments in Figures 1 and 3 is typical of neutrophils: organized filament
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