Immunology made easy: what every trial advocate should know.

• Author: Parker, Bruce R.
• Position: Coping with Science

THE science of immunology is the study of how the immune system is capable of differentiating between what is part of the host and what is foreign, and "all the rest is technical detail."(1) Understanding the "technical detail" of immunology is nevertheless challenging because it includes the study of all of the mechanisms used by the body to protect itself against agents that are foreign to the body.

THE CONCEPTS

Conceptually, it is helpful to divide the immune system into innate (non-specific) and acquired (specific) immunities. In reality, however, it is difficult to differentiate the innate and acquired immune responses to a foreign body. Many cells and soluble protein molecules participate in both types of immune responses.

Components of innate and acquired immunity generally are capable of recognizing the molecular differences between the host and foreign bodies and then eliminating the foreign bodies. Although the mechanisms by which immune cells recognize and respond to foreign agents has been fairly well described in the immunological literature, it still remains relatively conjectural as to how, during fetal development, the body is able selectively to destroy immune cells that lack the capacity to differentiate self from non-self.

In general, both innate and acquired immune responses involve striking a balance between the immune system aggressively attacking foreign bodies and minimizing damage to healthy host cells during the attack. The balance is achieved by cells of the immune system which turn off the immune attack at the appropriate times so that damage to healthy host tissue from the immune "friendly fire" is minimized.

A major difference between innate and acquired immunities is the lack of specificity and immunologic memory in cells that mediate innate immunity.

"Specificity" refers to the ability of white blood cells (leukocytes) and molecular components of the immune response (i.e., antibody) to discriminate between different molecular species presented to it and respond only to those molecular species against which the immune component has been designed to attack. A non-specific immune response (innate) is one in which the immune components respond randomly to foreign bodies.

"Immunologic memory" is the ability of specific types of leukocytes to remember having seen a foreign body (antigen) on re-exposure. Immunologic memory allows immune cells (i.e., lymphocytes) to respond to subsequent encounters with a "learned" response (i.e., quicker and stronger).

The chart on page 346 lists some of the key features of both types of immunity and their important differences.

1. Innate (Non-Specific) Immune Response

   Innate or natural immunity comprises all of those components of the host that are immediately available to protect the host from foreign bodies. Some of the defenses provide physical barriers (skin, mucosal membranes) to the entry of pathogens. Others provide an environment in which some pathogens cannot live--for instance, the ph balance of the digestive system. Others--phagocytic cells and soluble molecules, such as enzymes, complement and cytokines--attack foreign bodies that successfully bypass the physical and chemical barriers.

   The immunological response to the implantation of a medical device is a good example of how the innate immune system functions. Placing a medical device in the body damages tissue adjacent to the implant. Almost immediately, components of the innate immune system begin to remove damaged cells and attack the foreign body-the implant. The initial stage of this response is called acute inflammation. Additional white cells (leukocytes) circulating in the microvasculature are recruited to the site by chemical messages (cytokines) released by cells at the site. One type of cytokine binds to receptors on cells lining the microvasculature. This causes the microvasculature walls to become more permeable. The increased permeability permits blood plasma to flow from the microvasculature into the extravascular spaces around the injured cells. This fluid migration produces the swelling experienced in acute inflammation. The loss of plasma from the microvasculature slows the leukocytes circulating in the vasculature and allows them to migrate through the walls of the microvasculature into the tissue.

   White blood cells (leukocytes) are responsible for directing the innate and acquired immune response. The diagram below depicts the relationship of various types of leukocytes.

   The first type of leukocyte that migrates to the damaged area are polymorphonuclear leukocytes (PMN). Neutrophils are the primary PMN that respond during acute inflammation. Neutrophils are phagocytic cells that ingest cellular debris and/or foreign material. Once material is ingested, the neutrophil releases enzymes and superoxide radicals to digest the material. During this process, some of the degradative products are released from the phagocytic cells. When this occurs, adjacent healthy cells are damaged. The pain and redness experienced during acute inflammation is largely due to the cellular injury caused by phagocytic cells releasing degradative enzymes.

   Neutrophils live only a few days. During the acute inflammatory stage, which generally lasts two to three days, neutrophils release cytokines, which recruit longer-lived phagocytic mononuclear cells. Macrophages are the primary phagocytic mononuclear cells involved in acute and chronic inflammation. The predominance of macrophages over neutrophils signifies the transition from acute to chronic inflammation.

   Once they arrive at the site of inflammation, macrophages continue the process of ingesting and digesting cellular debris and foreign bodies. They are very efficient phagocytic cells and are capable of releasing more than 40 different cytokines. The cytokines released by macrophages help regulate the inflammatory response. Fever is one characteristic of an inflammatory response caused by some of the cytokines released by pyrogenic (fever-producing) macrophages. Such cytokines bind to receptors in the hypothalamus, which controls the set point for body temperature.

   Macrophages responding to...