It comes in a variety of shades, continually regenerates itself and is the largest organ of the body. Yet most people rarely give it a second thought unless they notice a wrinkle or a blemish or decide to soak up a few rays.
Skin -- the living, breathing wrapper that literally packages the body and keeps it intact -- is a rich source of protective cells. This deceptively simple-looking tissue produces hair, nails and eyelashes. And while it often is dismissed as a kind of passive human armor, today it is gaining new respect as a powerful, active organ.
"The skin is dynamically interacting with the rest of the body," says Dr. Richard Edelson, chairman of the dermatology department at Yale University Medical School. Among its most remarkable -- and recently discovered -- roles is as "an integral and active part of the immune system," Edelson says.
Increasing evidence shows that, at times, skin cells also direct the immune system, marshaling the body's defensive forces against foreign invaders -- be they toxins from poison ivy, a bacterial infection around a wound or a small malignant cell that seems to develop periodically in almost everyone throughout life.
Skin is "an active organ which participates in various types of immunological reactions," says Dr. Stephen Katz, chief of the National Cancer Institute's (NCI) dermatology branch. "We are just now finding out about the role of skin in various diseases."
Most of this important activity occurs in the top portion of skin, called the epidermis -- a 0.2 millimeter layer about the thickness of plastic wrap. The epidermis coats the outside of the body, from the scalp to the soles of the feet. It also covers interior surfaces such as the mouth, the upper two-thirds of the esophagus, the vagina in women and the inside of the eyelid.
It is the epidermis that takes the toughest beating from the sun's ultraviolet rays. A glowing tan or a painful, lobster-red sunburn both come from changes in the cells of the epidermis, which in turn affects the dermis, the middle layer of skin. Researchers have long suspected that these alterations lay the foundation for skin cancer -- the most common form of cancer in the United States today. One in seven Americans will get skin cancer at some time in their life, according to the National Cancer Institute.
And now scientists are beginning to understand why. "When you go down to the beach and you wear a bikini, you are exposing the vast majority of skin" to ultraviolet rays, says Edelson. This causes two major actions.
First, "in the process of tanning you have to damage the skin," he says. "Tanning is largely the result of the skin's attempt to protect itself further from the harmful rays of the sun."
Second, tanning alters cells in the epidermis. Only recently have researchers learned of the extent of these changes. Ultraviolet light kills many Langerhans cells, which are skin cells that serve as gatekeepers between two parts of the body's immune system. The first part marshals forces for the body's defense, the other regulates those forces and keeps them from going out of control.
For example, Langerhans cells call some white blood cells to fight an infection and signal others, the T-suppressors, not to come into action. The T-suppressor cells are not needed until the invader has been conquered, because they would interfere with the immune response.
Without Langerhans cells, white blood cells aren't discharged to fight infection. To make matters worse, T-suppressor cells go into action, curbing the immune system.
Even more important, new studies indicate that the immune system is affected throughout the body, not just at the site of sun exposure. Experiments by immunologist Margaret Kripke at the University of Texas System Cancer Center at Houston and others show how this may happen. Kripke and her colleagues exposed just one side of mice to very strong ultraviolet rays. Then on the unexposed side of the mice, they painted a chemical that usually produces a rash. The rash -- which results from the immune system's attempt to protect the skin from the chemical -- never appeared in mice exposed to UV rays. It was as if the immune cells no longer recognized the chemical as dangerous.
Studies of people who bask under the sun or in tanning parlors show that ultraviolet rays have similar effects on the human immune system: a temporary, but significant, decrease in the number of white blood cells circulating in the body, again leading researchers to speculate that sunlight depresses the immune system at least briefly.
"It certainly raises questions about what you might be doing to your immune system by putting things on your skin and exposing it to ultraviolet radiation," says Kripke, chairman of the immunology department at the University of Texas.
But these findings also suggest new treatment options for a variety of conditions, from aging to the spread of tumors, such as breast cancer, throughout the body. By understanding the skin's role as an immune organ, Katz says, "it may be that we will develop techniques that we can modulate or alter the immune system to work to our benefit."
As dermatologists and immunologists have collaborated over the last decade to uncover the immunological properties of skin, Kripke says, "We keep finding new kind of cells -- particularly immunological cells -- in the skin that we had no idea existed before."
With a closer look, and the benefit of high-tech tools, researchers have learned that:
Keratinocytes, skin cells that manufacture the skin protein keratin, also produce powerful chemicals called cytokines. These substances are like tiny amounts of hormones, and can exert diverse effects on other cells.
Among the cytokines produced is interferon, which fights viral infections. Another cytokine is interleukin-1, which activates white blood cells and causes skin cells known as fibroblasts to reproduce and divide, resulting in healthier skin. Leukotriene and prostaglandin are cytokines which produce inflammation.
Keratinocytes also produce enzymes that metabolize drugs. These skin cells account for more than 90 percent of cells in the epidermis.
Langerhans cells originate in the bone marrow but end up living near the surface of the skin. Named for Paul Langerhans, the medical researcher who first described them 100 years ago, these skin cells seem to be closely related to the immune system. Langerhans cells are very rare; they make up just 1 to 7 percent of total cells in the epidermis, but also produce cytokines, including interleukin.
These cells may play a role in acquired immune deficiency syndrome (AIDS), according to studies presented recently at a meeting of the Society for Investigative Dermatology by Dr. George Stingl of the University of Vienna and his colleagues at the National Cancer Institute. Stingl reported finding the HTLV-3 virus, which causes AIDS, in Langerhans cells, and showed one slide of the virus budding off -- a reproduction process that kills the host cell.
One theory is that AIDS virus may hide in the Langerhans cells. "Langerhans cells are critical in terms of generating immune responses," says NCI's Katz.
Merkel cells, a newly discovered, mysterious skin cell, appear in "minuscule amounts," says NCI's Katz. "We don't know what they do yet. But the speculation is that they may be related to nerve cells."
Thy-1 cells, recently discovered in mouse epidermis, are thought to provide an important link between the skin and the immune system. Researchers are now searching for a human counterpart, so far without success. The suggestion is that Thy-1 cells, which are also derived from bone marrow, are related to T lymphocytes, the white blood cells of the immune system that engage in direct combat with foreign invaders.
Most of these special skin cells are found in the epidermis. A middle layer of skin, called the dermis, contains hair follicles, sweat and sebaceous glands and blood vessels. Cells known as melanocytes, which secrete the melanin that produces a tan, are found in the dermis. Nerves also reside here, as do the touch and temperature receptors that warn about a hot iron or send signals to the brain about the smooth, appealing feel of satin sheets.
A third, deeper layer called subcutaneous tissue is where the protective fatty layers of skin are found.
Although the concept of skin as "an immunologic organ was hatched around 1975," according to Yale's Edelson, the field has exploded during the past decade.
"This whole area is changing month to month," Edelson says. The newest research shows further evidence of the wide-reaching effects skin cells have on the rest of the body. One example: The ability of keratinocytes to affect the rate of bone growth and bone loss, reported by Dr. Daniel Sauder of Canada's McMaster University at the Society for Investigative Dermatology annual meeting in April.
The growing insight into skin's varied roles comes at a time when skin diseases, particularly skin cancer, is increasing at an alarming rate. NCI estimates that approximately 23,000 new cases of melanoma will be diagnosed this year, and that 5,500 Americans will die from this form of cancer in 1986. Melanoma is the most rapidly increasing malignancy in white men, and the second most rapidly increasing malignancy -- after lung cancer -- in white women.
Less serious forms of skin cancer -- basal and squamous cell carcinoma -- are the most common malignant cancerous growths occurring in the white population of the United States, says NCI's Katz.
"In geographic areas of high ultraviolet radiation exposure," he says, "skin cancer exceeds all other forms of cancer combined. And skin cancer incidence increases strikingly with age, and appears to be increasing over time."
*About 500,000 Americans develop these skin cancers each year. Vice President Bush last month joined the list of skin cancer victims, which includes President Reagan, First Lady Nancy Reagan and former president Richard Nixon. They are usually removed with minor surgery and, if caught early, the cure rate is virtually 100 percent.
The complete story of skin and its complex relationship with the rest of the body continues to unfold.
"The bottom line of all of this is that skin is the most accessible solid tissue in the human body," Edelson says. "And the epidermis appears clearly as a factory for numerous biologically important factors. The skin doesn't just sit there passively on the surface."
Already medical science is taking advantage of this active connection by administering some drugs via the skin. Nitroglycerin, the powerful drug used for heart patients, is now given by a Band-Aid-like patch affixed to the chest. Sailors, pilots and astronauts avoid motion sickness by wearing patches of anti-nausea medicine behind the ear on the wrist, to be absorbed through the skin and circulated throughout the body.
Future skin research will be geared toward better ways of manipulating the body via the skin. For instance, some drugs might be activated in the skin by light, but then would "turn off" when they went to other darker parts of the body. One class of drugs, the psoralens, "bind to DNA in the presence of light," reports Dr. D. Martin Carter of the Rockefeller University, and might be used to repair aging DNA, or deoxyribonucleic acid, which is the chemical blueprint of the cell. This process could become a tool for getting into damaged DNA and repairing it, a possible approach to treating cancer and genetic disorders.
Other questions under study include:
What causes a cell to age and die?
What prompts the skin changes associated with old age?
Could aging's affect on the skin be associated with the decreased functioning of the immune system in advanced years?
Researchers don't know yet, although they have important clues to suggest that much of the wrinkling seen in older skin is caused by sun damage -- not by aging.
"We do not expect to make cells immortal," says Carter. "It is likely that there are a number of genetic controls that limit the life of individuals and of cells."
But one goal, he says, "is to reduce the deterioration that sometimes accompanies aging. We'd like to enable the functioning of the cells to be maintained at a high level until the end of life."