Nonspecific Defenses

Epithelia that cover surfaces exposed to the external environment function as protective barriers to prevent entry of injurious agents, such as microbes and chemicals. This barrier function can be enhanced by epithelial secre­tions, such as hydrochloric acid in the stomach and nonspecific antimicrobial agents in saliva (e.g., lysozyme).

When microbes or injurious agents pene­trate an epithelial barrier, their presence and any tissue damage that they produce initiate a response, inflammation. The initial phases of this response are immediate and similar regard­less of the type or identity of the microbe or agent. Thus, these are nonspecific responses, or innate responses. The terms nonspecific immune response and innate immune response have also been used. A specific or acquired immune response entails identification of the specific microbe or agent and development of a response directed at that specific agent.

Local tissue phagocytes (macrophages) are among the first cells to respond during a non­specific response; they attempt to engulf and destroy any foreign microbe or substance. The primary mode of destruction is by intracellular fusion of phagocytic vesicles with enzyme­containing lysosomes. An accumulation of neu­trophils in the area is another component of the rapid nonspecific response. Recall that neutro­phils are attracted to an area of injury and inflammation by chemotactic factors and those chemotactic factors may include substances released from damaged cells and by the invad­ing microbes. Chemotactic factors are also released by tissue macrophages as part of their response to foreign microbes.

The release of chemotactic factors by respond­ing macrophages is one example of a general scheme by which nonspecific and specific immune responses are regulated.

Cytokine is the general term applied to all chemical messengers (primarily proteins) that regulate cells involved in any immune response. Responding cells produce many of the cyto­kines, but other cell types also secrete them. More than 100 compounds have been classified as cytokines, which provides some insight to the complexity of these responses. The various cytokines that function as chemotactic factors are collectively termed chemokines. Interleu­kin-1 is a specific cytokine that also functions as a pyrogen (an agent that produces fever). The pyrogen effect of interleukin-1 is but one example of a systemic effect of a cytokine that is unrelated to cells of the immune system. Many of the systemic changes characteristic of a diseased animal are produced by cytokines leaving a site of inflammation and entering the general circulation.

specific chemokines also attract more mac­rophages to areas of inflammation. since mac­rophages are derived from circulating monocytes, part of this effect requires that monocytes migrate from vessels and develop into tissue macrophages. The monocyte response is slower than that of neutrophils, so an accumulation of inflammatory cells that is primarily neutrophils is characteristic of an acute inflammatory response. An accumulation of macrophages is more characteristic of a chronic inflammatory response.

Another characteristic of an acute inflamma­tory response is an increase in local blood flow and in movement of fluid and plasma protein into the interstitial space. Agents that affect blood vessels in the local area of inflammation bring about these changes.

Plasma proteins delivered to a site of inflam­mation include complement (also known as complement proteins'). These are a group of plasma proteins that are normally inactive in circulation (similar to the clotting factors), but some can be activated by the presence of certain polysaccharide components of the outer cover­ings of bacteria. The activated complement pro­teins can activate other complement proteins (similar to the clotting cascades). The activated complement proteins have a number of effects that contribute to the local nonspecific response. These include (1) leukocyte chemotaxis, (2) direct attack on bacteria by increasing the per­meability of their cell walls, (3) stimulation of histamine release from mast cells, and (4) opso­nization. Opsonization is the facilitation of engulfment by phagocytes, and any agent that can perform this facilitation is termed an opsonin. The local release of histamine causes a further increase in blood flow and accumula­tion of interstitial fluid and plasma proteins by its actions on blood vessels.

One unique aspect of viral infections is that viruses can replicate only within cells. Viruses must enter cells of the animal’s body and use the cell’s own synthetic processes to form new viruses to infect other cells. Two types of non­specific defense mechanisms function to prevent viral infection and replication. Interferons are polypeptides produced and secreted by cells containing viruses, and almost all types of cells produce interferons after being infected by viruses. Interferons are a means by which an infected cell can prevent further spread of the viral infection because they act on other cells in the area to prevent viruses from using the syn­thetic pathways of newly infected cells to produce new viruses. Viruses may enter cells protected by interferons, but they cannot replicate within protected cells. Interferons are not specific for individual viruses, so interferons produced in response to infection by one virus will protect against infection by a different virus.

Natural killer (NK) cells are a specific type of lymphocyte that can recognize and destroy cells infected with viruses. This recognition does not appear to be based on viral antigens, so it is not specific for any given virus. The NK cells destroy the infected cell by the secretion of substances known as perforins and granzymes while in direct contact with the infected cell. These secretions act on the cell membrane and enter the infected cell to destroy it. While NK cells act in a nonspecific manner, their numbers are normally relatively low and are only increased during a specific immune response.