Cells of the Innate Immune System

The cellular components of innate immunity consist of macrophages, neutrophils, Mast cells, eosinophils, and natural killer (NK) cells. The primary phagocytic cells, macrophages and neutrophils, have receptors on their surface for carbohydrate moieties such as lipopolysaccharide and mannose receptor that are not usually expressed by vertebrate cells. Phagocytic cells also have CR1 receptors for C3b and Fc receptors for antibodies on their surface. These carbohydrate and complement receptors allow phagocytic cells to attack antigens without assistance from the acquired immune system. These receptors allow the phagocytic cell to bind an antigen when complementary carbohydrate moieties or C3b is near one of the receptors

Carbohydrate and complement receptors bind in a zipper-like fashion until the antigen is completely enclosed by a membrane-bound vesicle called a phagosome. The phagosome then fuses with another vesicle filled with degradative enzymes known as a lysosome. This fusion forms a phagolysosome. Within the phagolysosome, the antigen is destroyed by myeloperoxidase, NADPH oxidase, cathepsins, and lysozyme. Early in the immune response neutrophils are the predominant phagocyte and they provide the primary defense against pyogenic bacteria. If the infection persists and the immune response continues, macrophages derived from circulating monocytes become more numerous. In addition to their role as phagocytes, macrophages secrete cytokine mediators, that modify the immune response. Neutrophils also secrete inflammatory mediators but their ability to do this appears limited by comparison to macrophages.

When a pathogen is too large to be phagocytized as in the case of certain parasitic worms, another cell type, the eosinophil, mediates the attack on the pathogen. Eosinophils express CR1 receptors and FceRII, a receptor for IgE, on their surface. When the eosinophil encounters a pathogen opsonized by either C3b (Note: this can be mediated by innate immunity via the alternative pathway or acquired immunity via the classical pathway) or IgE its receptor for that particular opsonin is

Figure 2.4. T cell receptor; v= variable region; c= constant region.

engaged and when enough receptors aggregate for crosslinking to occur the cell degranulates. The eosinophilic granules contain major basic protein, cationic protein, histaminase, and phospholipase D. Production of reactive oxygen intermediates is also upregulated in eosinophils by receptor crosslinking. By releasing these compounds the eosinophil mounts an extracellular attack against those pathogens that are too large to be engulfed.

C3a, C4a, and C5a are anaphylatoxins each capable of triggering mast cell degranulation and mediator synthesis to varying degrees. Mast cell granules contain preformed molecules of histamine, platelet activating factor (PAF), and interleukins 3, 4, 5 and 6. When appropriately stimulated, mast cells are also capable of producing leukotrienes, prostaglandins, and thromboxanes, which are all products of arachi-donic acid metabolism. The result of mast cells releasing these mediators is vasodilation, increased vascular permeability, and recruitment of other inflammatory cells and proteins to the site of infection producing the cardinal signs of inflammation (rubor, calor, dolor, and tumor).

In addition to bacteria and parasites, the innate immune system is capable of defending against viral infection. Viruses lack the ability to reproduce independently. They must enter host cells and commandeer the replicative machinery to reproduce. When a virus infects a cell, the cell expresses certain high molecular weight glycoproteins on its surface distinguishing it from uninfected cells. Natural killer (NK) cells are large granular lymphocytes that possess receptors capable of recognizing these foreign glycoproteins and Fc receptors (FcR) for the Fc region of antibodies. When a NK cell binds to a cell by either of these receptors, it releases the contents of its granules into the extracellular space adjacent to the target cell. One of the proteins released, perforin, diffuses across the extracellular space and inserts into the target cell membrane. It then polymerizes with other perforin molecules to form a pore-like structure that allows water and solutes to pass freely between the intracel-lular and extracellular compartments. These porelike structures allow other granular contents such as endonucleases, granzymes, and TNF-p to enter the cell where they cause nuclear fragmentation and interfere with other vital functions resulting in apoptosis. When this process is initiated by binding of the Fc region to FcR, it is referred to as antibody dependent cell-mediated cytotoxicity (ADCC). Although perforin is capable of causing lysis under experimental conditions, its primary role physiologically seems to be providing a port of entry for these apoptosis-inducing proteins. After viruses enter a cell there is a lag phase before new viruses are produced; thus killing a few infected cells is beneficial to the host as a whole because the cell is destroyed before intact viruses capable of infecting neighboring cells are produced. NK cells act on cells infected with intracellular bacteria in a similar fashion and have also been demonstrated to have antitumor activity.

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