ABSTRACT
The innate immune system is essential for defense of the host against pathogens during the initial phase of infection, before acquired immune responses are generated. Neutrophils are prominent participants in this early defense against bacterial disease agents. They are produced from stem cells in the bone marrow, and mature neutrophil cells are released into the circulation daily. These cells are called from the blood vasculature to areas of bacterial invasion by chemotactic factors, such as complement components. As described in Case 2, the neutrophils leave the circulation by binding their β2 integrins to adhesion molecules expressed on the endothelial cells that line the blood vessel. Next they undergo a process called diapedesis—that is, a crawling motion that results in the cell moving between the endothelial cells that line the blood vessel, and ultimately exiting the blood vessel into the surrounding tissue. The neutrophils are directed towards the pathogen by creation of a concentration gradient. Chemotactic factors such as C5a, IL-8, and leukotriene B4 are released at the site of pathogen accumulation in the tissue. Once the neutrophil reaches the site of bacterial infection, it attempts to engulf bacteria and kill them. This process, called phagocytosis ( Figure 4.1 ), involves the flowing of cytoplasm around the bacteria, ultimately forming an enclosed vesicle called a phagosome within the cytoplasm of the neutrophil. Most bacteria are easily engulfed and taken into a phagocytic vacuole, but those with heavy polysaccharide capsules may require substances called opsonins to help to bridge the gap between bacteria and the neutrophil membrane. The C3b molecules from complement and antibody are opsonins that can perform this function. The process of phagocytosis involves adhesion, engulfment, formation of a phagosome, and then fusion of lysosomes with the phagosome and killing by oxidative and non-oxidative mechanisms, followed by elimination of bacterial remnants. The engulfment phase involves initial binding of receptors on the phagocyte membrane to bacteria that are to be engulfed. These may be mannose receptors or integrins, but can also be CD32, an Fc receptor that binds antibody Fc which is serving as an opsonin for the bacteria. C3b receptors (CR1) will also bind bacteria that have C3b fixed to the bacterial surface. Once the receptors have bound, there is polymerization of F actin, and the actin-myosin forms a filamentous network of lamellipodia that engulfs the bacterium and draws it into the cell, where it is contained in a vacuole called a phagosome. The destruction of the bacterium is the goal of this process, and it is accomplished by the fusion of the lysosomal granules with the phagosome. With this fusion the cell membrane-associated NADPH oxidase is activated to create toxic oxygen radicals (H<sub>2</sub>O<sub>2</sub> and OC1<sup>−</sup>), which damage and kill the engulfed bacteria. The myeloperoxidase catalyzes the conversion of H<sub>2</sub>O<sub>2</sub> into toxic radicals. Other granule contents have additional bactericidal effects: lysozyme breaks up bacterial cell walls, elastase and cathepsin G degrade connective tissue, and antimicrobial peptides exert a bactericidal effect by creating pores in bacterial cell membranes and causing membrane disruption. (From Geha R & Notarangelo L [2016] Case Studies in Immunology, 7th ed. Garland Science.) https://s3-euw1-ap-pe-df-pch-content-public-u.s3.eu-west-1.amazonaws.com/9781315165462/60fbfcfb-355a-42ef-afe0-e83f73f326f8/content/fig4_1.tif"/>
