A severe neutropenia was found. Bone marrow studies showed normal numbers of mature, morphologically normal neutrophils. A poor neutrophil response was obtained upon stimulation with both epinephrine and endotoxin, as well as upon induced inflammation by the Rebuck skin window technique. Leukocyte phagocytosis and bactericidal activity were normal. Both random mobility and chemotactic function were defective. Miller knew of 4 other cases.
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A A normal neutrophil polarized after exposure to a chemoattractant placed in the top right corner. The lamellipodia to the right is filled with dendritic branched networks of actin filaments.
The actin filaments are magnified to the right. In step 1, cofilin binds to the actin filaments and breaks apart the dendritic networks, leaving long actin filaments. In step 2, activation by Aip1 results in efficient severing and complete disassembly of actin filaments. B A mutant Aip1 neutrophil. A dense network of actin filaments is found throughout the cell, preventing effective polarization or directional amoeboid movement. The nuclei are pushed to the periphery of the cell.
Note in the magnified view that the actin filaments remain intact. The amount of mutant Aip1 protein is decreased and the reduced amounts of mutant protein fail to activate cofilin. Professional illustration by Somersault To fully understand the implications of their findings, the reader needs to understand a few fundamental facts about actin. Great progress has been made in understanding how actin regulatory proteins and specific signal transduction pathways induce actin assembly.
However, in order to change shape and produce amoeboid movement, actin filaments must also be quickly disassembled, and at the present time, our understanding of these mechanisms is more rudimentary. Actin depolymerizing protein ADF; also called cofilin has been isolated and shown to bind to the sides of actin filaments and to destabilize monomer—monomer interactions within the filament, causing actin filaments to break apart or undergo severing.
The 3 families with genetic mutations described by Kuhns et al now help to address this important question. Family members and patients all had mutations in the WDR1 gene that encodes for Aip1. The marked increase in neutrophil actin filament content, failure of these cells to form a normal polar structures with lamellipodia at the front, and the marked slowing of cell motility in response to chemoattractants all emphasize the central role of Aip1 in potentiating actin filament recycling and emphasize the vital role of Aip1 in supporting neutrophil motility see figure panel B.
These exciting findings emphasize that the study of genetic diseases, combined with basic cell biology and biochemistry, can provide the fullest understanding of structure—function relationships and promises to provide future targets for controlling inflammation and improving host defense. Conflict-of-interest disclosure: The author declares no competing financial interests.
Lazy leukocyte syndrome.
Lazy leukocyte syndrome