The immune system protects against pathogens that penetrate the physical barriers of the skin and mucous membranes lining the digestive, respiratory, and reproductive tracts. It is subdivided into the innate and the adaptive immune systems. These two systems work differently, but collaboratively, to provide a powerful defense against microbial invaders. Increasing evidence suggests that the immune system also plays a role in detecting and eliminating tumor cells, and can be manipulated therapeutically against cancer.

Innate Immunity

Characteristics of the Innate Immune Response

The innate immune system provides a rapid but nonspecific response to the most common foreign pathogens.¹ This system, in some form, is present in all animals, and some elements of it have existed for more than 500 to 700 million years.² Cells of the innate immune system have specialized receptors (eg, Toll-like receptors) that recognize molecular structures or patterns that are characteristic of—and often indispensable parts of—common pathogens.³ As such, they recognize these pathogens immediately, even without having encountered them previously, and can react promptly. Disadvantages of the innate immune system are that it can recognize only a limited number of molecules, has limited ability to recognize viruses once they have entered normal cells, and has no "memory" and therefore cannot provide lasting protective immunity against these molecules.

The innate immune system is often sufficient to protect against the small quantities of common pathogens humans come into contact with on a day-to-day basis.² When additional "help" is needed, the innate immune system activates and modulates the adaptive immune system.^2,3

Cells of the Innate Immune Response

Macrophages. Macrophages are the "sentinels" of the immune system. Present in large quantities under the skin, in the lungs, and in the tissues surrounding the intestines, these cells are in key positions to detect microbes where they first enter the body.² The name macrophage means "large eater," and its primary responsibility is to rid the body of debris as well as pathogens, largely but not exclusively via phagocytosis.^2,3

In their usual resting state, macrophages sample their environment and serve as "housekeepers," scavenging dead cells, cellular debris, oxidized lipoproteins, and other normal cellular by-products.^2,3 When exposed to certain cytokines (eg, interferon gamma) released by other immune cells, such as helper T-cells and natural killer cells, macrophages become primed or activated. The activated macrophage engulfs a pathogen, containing it in a phagosome, which then fuses with a lysosome full of antimicrobial enzymes that destroy the pathogen. After digesting the pathogen, macrophages release various chemicals that increase the flow of blood to the area, trigger capillaries to allow extravasation of blood cells into the affected tissue, stimulate pain signals from nerves in the area, and release cytokines that facilitate communication with other cells in the immune system. As will be described in more detail later, activation also causes the macrophage to upregulate major histocompatibility complex (MHC) class II receptors on its cell surface, and protein fragments from the invading pathogen are transported to the MHC receptors and presented there for detection by helper T-cells and natural killer cells.²

Macrophages also have cell surface receptors (eg, the Toll-like receptors mentioned above) that enable them to detect molecules (eg, lipopolysaccharide, mannose) that are not normally found on human cells but are common cell wall components in typical pathogens.² When a macrophage detects such molecules, it becomes "hyperactivated." The macrophage stops proliferating and becomes a virtual killing machine, growing larger and increasing the number of lysosomes and its rate of phagocytosis. It also actively migrates toward a foreign invader, even extending out "feet" to grab it up.² In this state, macrophages also secrete tumor necrosis factor (TNF) alpha, interleukin (IL) 1, IL-6, and IL-8. These inflammatory cytokines help kill tumor cells and virus-infected cells and activate and summon other cells in the immune system.^2,3

Neutrophils. Neutrophils are highly phagocytic cells. Produced from myeloid precursors and with a lifespan of only 2 to 5 days, these cells circulate through the bloodstream, where they are within easy reach of all cells in the body until they are summoned.^2,3



Cytokines and chemokines released by macrophages and mast cells draw neutrophils to the area of infection.^2,3 It takes only about 30 minutes for neutrophils to exit the bloodstream and arrive fully activated at the site of an infection.² Once there, they not only perform phagocytosis, they secrete cytokines (eg, TNF) to summon other immune cells and release various antimicrobial products from granules into the extracellular space.^1-3

Mast cells and eosinophils. These cells lie beneath exposed surfaces of the body (ie, the skin and mucosal barriers) and can survive for years. Their best-known function is to provide a defense against parasites. Mast cells are phagocytic and also contain granules of chemicals, most notably histamine. Eosinophils are poor phagocytes but do carry granules. When a mast cell or eosinophil detects a parasite, it "degranulates," that is, it unloads the chemicals.



Unfortunately, this not only kills the parasite, but also induces an allergic reaction, and in severe cases, anaphylactic shock. It is now known that mast cells also phagocytize opsonized bacteria, secrete cytokines (eg, TNF alpha) that summon neutrophils and other immune cells,^2,3 and mediate immune system suppression by orchestrating tolerance among regulatory T-cells in the adaptive immune system.

Natural killer cells. After maturation in the bone marrow, natural killer cells await activation in the secondary lymphoid tissues and bloodstream.² Natural killer cells are activated by certain bacterial cell wall components and also by certain cytokines (eg, interferon [IFN] alpha and IFN beta) secreted by cells infected with viruses. Natural killer cells also can be activated by IL-2. Activated natural killer cells or lymphokine-activated killer cells lyse tumor cells, virus-containing cells, bacteria, parasites, and fungi.² Cell lysis is accomplished either by puncturing the cell membrane with perforin and then injecting enzymes into the cell or by binding of Fas ligand on the natural killer cell surface to Fas on the target cell surface, thereby triggering apoptosis.^2,4 Natural killer cells also release cytokines, including IFN gamma, TNF alpha, and granulocyte colony-stimulating factor.⁴

Natural killer cells have two basic types of receptors ^1,2,4,5:

• Activating receptors that detect unusual carbohydrates or proteins on the surface of an abnormal cell, which signal the natural killer cell to target that cell for killing
• Inhibitory receptors that recognize class I MHC molecules found in varying quantity on healthy human cells and prevent natural killer cells from targeting normal human cells for destruction

Natural killer cells interpret the balance of these two types of signals to determine whether to destroy a target cell.

Complement system. The innate immune system also includes the complement system, consisting of about 20 proteins produced mainly by the liver.² These proteins include proteolytic enzymes, inflammatory and regulatory proteins that summon or enhance the activity of phagocytic cells in both the innate and adaptive immune systems, and lytic proteins that attack cell surface membranes.^2,6 The complement system also opsonizes viruses that are outside of cells for phagocytosis and penetrates the membranes of enveloped viruses.² Normal human cells have defense mechanisms that counter these attacks, protecting them from the activities of the complement system.²