Cell biology of leukocyte abnormalities--membrane and cytoskeletal function in normal and defective cells. A review.

Abstract

In this review I have attempted to explain the processes of chemotaxis, phagocytosis, oxidant generation, and lysosomal degranulation in normal and genetically abnormal human PMN. In my view these leukocyte functions are most importantly dependent on the integrity of three cellular components: the plasma membrane, the submembranous microfilaments, and the cytoplasmic microtubules. These components are often discussed in isolation, and the biochemical and pharmacological aspects of their function are analyzed separately here. However, PMN motile and bactericidal activities require the interdependent functioning of membranes, microtubules, and microfilaments. I have therefore tried to provide an integrated view of cytoskeleton-membrane organization and function in human PMN. I have particularly emphasized dynamic aspects of the cytoskeleton and membranes, eg, the induction of microtubule assembly and membrane enzyme activation by surface ligands and the reorganization of microfilaments in response to the same ligands. With this background established, I have selected for discussion a series of diseases in which abnormalities of chemotaxis, phagocytosis, lysosomal degranulation, and/or oxidant generation can be explained directly or indirectly by abnormalities in dynamic properties of PMN membranes, microtubules, or microfilaments. I emphasize that even preliminary insight into the basis of these disorders has sometimes been sufficient to suggest useful clinical approaches to the management of patients. In several of these neutrophil abnormalities, ie, neutrophil actin dysfunction, Chédiak-Higashi syndrome, and its "antithesis" described by Gallin and co-workers, the cellular dysfunctions were well documented but the molecular basis was completely obscure prior to cell biologic analysis. Snyderman and Pike 159 and Chusid and co-workers 160 emphasized the existence of a large number of other neutrophil bactericidal abnormalities resulting from as yet unexplained cellular defects. Further analyses of the functional interactions between membranes and cytoskeletal components in neutrophils may not only clarify the molecular bases of the disorders described here but also may provide insight into the origins and proper therapeutic approach to other granulocyte dysfunctions.

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