San Francisco Chronicle - Monday, October 16, 2000
Sabin Russell, Chronicle Staff Writer

He has watched his friends die of AIDS for more than a decade, yet he hardly ever has been sick. He hikes and bicycles and takes long trips abroad. Cody does not take antiviral drugs.

"I've been asking myself why I have been picked," he said. "For whatever reason, I'm still here."

To his physician, University of California at San Francisco virologist Jay Levy, Cody may be living proof of the power of the "innate" immune system, an ancient and inherited arsenal of biological defenses that human beings share to some degree with all living things.

The idea that the human immune system is really two systems -- the innate and the adaptive -- is not new. But for years, researchers have concentrated on the sophisticated workings of the adaptive system, a cadre of elite warrior cells that has an extraordinary ability to recognize and attack invading bacteria and viruses.

Knuckle-Dragging Grunts

The innate system seemed less alluring. Compared to the smart weapons of the adaptive system, the innate immune system is a rabble of primitive, knuckle-dragging grunts --indiscriminate foot-soldiers that kill by eating their enemies or squirting them with poison.

Now researchers are beginning to conclude that they have underestimated this peasant army of disease-fighting cells. There is mounting evidence that innate immunity is vitally important, and that a better understanding of how it works may spur development of new treatments for AIDS and other immune diseases.

"There has been a real explosion of interest in identifying the players in this first line of defense," said Lewis Lanier, a UCSF immunologist. "People are realizing that, in trying to combat disease, don't put your money just on the adaptive immune system."

The two immune systems have fundamental differences. Innate immunity is a frontline system of defense, hard-wired into the genes, that kicks into action within minutes of detecting a threat. The skin itself is considered a part of the innate immune system. Also included on the roster of innate immunity is saliva and the anti-bacterial action of enzymes in tears.

Ground Troops

Of more interest to researchers are what comes next: an array of specialized blood cells lodged in the skin and floating in the bloodstream that recognize common traits of bacteria and viruses. These ground troops of the innate immune army include "natural killer" cells, which poison infected cells, and macrophages, cells that eat the invaders.

The attack is immediate and fierce. But these innate immune cells cannot recognize the highly specific features that, for example, distinguish one strain of flu virus from another.

Adaptive immunity, on the other hand, takes over when the frontline defense is outflanked or overwhelmed. Two types of white blood cells do the killing: B-cells that overwhelm the enemy with lethal proteins known as antibodies, and T-cells that track down the interlopers, then deliver a deadly chemical kiss. The adaptive system has the unique ability to take the chemical fingerprints of microbes, and then manufacture hordes of B-cells and T-cells programmed like a computer guidance system to attack anything in the body bearing those prints. It is this ability to adapt to new, never-before-seen threats that gives the adaptive immune system its name.

The body's lymph nodes serve as mustering sites for these newly programmed defenders. It can take a week or more to build up an effective immune response. But once a successful defense is mounted, the cells of adaptive immunity can store that chemical fingerprint of the invader -- and mount a speedier assault should the microbe ever appear again.

Indeed, all vaccines work using this principle. They are designed to program the adaptive immune system to attack microbes like the polio virus or influenza, as if it had already vanquished the invader in an earlier battle. But there is evidence that the innate immune system may be playing an equally vital role. What has intrigued scientists about AIDS survivors like Cody (who for privacy reasons asked that his surname not be disclosed) is that while his adaptive immune system appears to be in shambles, there are hints that his innate immunity is still hard at work, keeping him healthy.

Unlike most HIV-infected patients, Cody has normal levels of interferon-producing cells. These specialized blood cells churn out copious amounts of interferon, a protein that blocks viral replication and modifies the behavior of other cells. They are considered elements of the innate immune system.

Dr. Yong-Jun Liu, a scientist at DNAX Research Institute in Palo Alto, co-wrote a report last year in the journal Science that announced the discovery of interferon-producing cells. While most cells will produce interferon when attacked by a virus, these specialized blood cells crank out 1,000 times as much. "The speed of the interferon production is amazing," Liu said.

Equally important, the cells that produce interferon also play a role in the adaptive immune system. When they have completed their work producing interferon, they convert to a highly specialized form of T-cell. "They are a bridge between the innate and adaptive immune systems," Liu said.

Two Systems Interact

This finding suggests another important idea -- that in addition to their roles as a frontline defense, the innate immune system interacts closely with the more sophisticated elements of the adaptive immune system. "There is a connection between the innate and adaptive immune systems," said Dr. Anthony Fauci, director of National Institute of Allergies and Infectious Diseases.

The cells of the innate immune system act as an early warning system that can send chemical signals to rouse the elite fighters of the adaptive immune system. Adaptive immune cells, in turn, produce chemical signals that spur a more vigorous assault on the frontline. Biologists refer to this battlefield communication between innate and adaptive immune cells as chemical "cross talk."

Part of the renewed interest in innate immunity is driven by the progress made in identifying genes through the human genome project, which is attempting to map the genetic blueprints shared by all beings. Researchers have found that both humans and fruit flies have similar abilities to detect proteins called "toll receptors" that line the outer membranes of bacteria.

When scientists redesign a fruit fly blood cell so that it no longer recognizes the toll protein, "the flies become covered in bacteria," said UCSF pathologist Dr. Abul Abbas, who has written a textbook on immunology. New discoveries already have forced a rewriting of those texts. "In the first edition of our book, we didn't even have a chapter on innate immunity," he said. "We used to think that innate immunity was nonspecific, and weak. Now we know that it is extraordinarily specific: It evolved over millions of years to recognize bacteria and viruses. And far from weak, it is extraordinarily strong."

For AIDS researchers like Levy, the examination of innate immunity has opened a new chapter in his search for a cure. Much of Levy's work since the early days of the epidemic has involved the mysterious actions of a type of T-cell called CD8, which seems to protect many HIV-infected patients from progressing to AIDS.

For years he has been on the trail of an elusive chemical signal that triggers the protective action of these cells. It came as a revelation to Levy that the CD8 cells were behaving much like soldiers of the innate immune system: they respond early, but show no signs of remembering what they are attacking. Their function appears to be to hold off a variety of microbial invaders -- not just HIV -- to give the adaptive immune system time to respond. Recent research has linked activity of CD8 cells to signals from the interferon-producing cells.

"I'd been studying a function of the innate immune system, without realizing it," Levy said.

Special Brand of Luck

What this means for HIV-infected people like Cody remains to be seen. In the short term it means he will gladly take his healthy body for regular checkups, to be poked and prodded and bled like a laboratory rat.

He'd like to think that his special brand of luck will help others, and his hope takes on spiritual overtones. When Cody was born 37 years ago, he was an unexpected twin to his slightly older brother. The umbilical cord was wrapped around Cody's neck, and he barely survived. He thinks of that story, and ponders the performance of his own miraculous immune system. "I feel like I'm here for a reason," he said.

PARTNERS IN THE FIGHT AGAINST DISEASE

Renewed interest among medical researchers is focusing on the differences between the body's "innate" and "adaptive" immune systems.

INNATE IMMUNE SYSTEM

The body's first line of defense, the cells of the innate immune system, are primitive foot soldiers that kill by eating invaders or squirting them with poison. Origins: Versions of the innate system are found in most primitive organisms. Cell types: neutrophils, macrophages, natural killer cells and interferon-producing cells.

Macrophage Destroys pathogens by engulfing them whole. Neutrophil Also engulfs and destroys pathogens Natural Killer cell Seeks out pathogens and kills them with release of toxins

ADAPTIVE IMMUNE SYSTEM

A more sophisticated, second line of defense, the cells of the adaptive immune system are elite, specialized warriors that can pinpoint and destroy the craftiest invading microbes. Origins: The adaptive system first appears about 100 million years ago with the emergence of jawed fish. Cell types: antibody-producing cells, B-cells and killer T-cells.

B-cells Produce Y-shaped protiens called antibodies that kill or block the activity of invading microbes.

Activated T-cells Link up to specific sites on the surface of pathogens and infected cells, killing them.

CROSS TALK

The innate and the adaptive immune system cells engage in battlefield communication biologists refer to as "cross talk." 1. Innate immune system cells send chemical signals to rouse the elite fighters of the adaptive immune system. 2. Adaptive immune system cells, in turn, produce signals that recruit more natural killer cells and macrophages into action.

SITES OF THE IMMUNE SYSTEM

THYMUS: The gland where T-cells develop from stem cells that originate in the bone marrow.

SPLEEN: Largest lymph organ.

BONE MARROW: Source of stem cells and antibody-producing white blood cells.

LYMPH NODES: Sites throughout the body where B-cells and T-cells make multiple copies that target specific sites on pathogens.

Sources: Chronicle research; Immuno Biology by Chas. A. Janeway, P. Travers, M. Walport, J. D. Capra

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E-mail Sabin Russell at srussell@sfchronicle.com.

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