The immune response affects many aspects of human health. It cures us when we are infected with viruses and bacteria and protects us against attacks by toxins. On the other hand, when the immune response goes awry it can cause autoimmune diseases like rheumatoid arthritis, juvenile diabetes and lupus, or too-exuberant reactions such as those that drive asthma and allergies. During the last 60 years scientists have learned a tremendous amount about how the immune system works and these discoveries have had a tremendous impact on our ability to understand, diagnose and treat diseases . Some of the most important discoveries have been made here in Colorado, by members of the University of Colorado and National Jewish Health. Below we describe some of these discoveries and how they have affected our ability to treat diseases caused by the immune system.
Asthma and allergies
Many years ago Swedish scientists began to separate the proteins in blood and found that a certain set of these proteins, called antibodies, were produced after their hosts had been infected or immunized. It was found that antibodies bound the infection and, by binding, caused the inactivation and elimination of the invading organism. Separation of the blood also showed that there were several different kinds of antibody, called classes. Even though they may recognize the same invader, the different classes have different functions. For example, one kind of antibody can cross the placenta from mother to baby, thus human babies acquire the ability, while they are still in utero, to deal, to some extent, with invaders that their mothers can also resist. Another class of antibody is secreted into colostrum, the milk made immediately after babies are born, and transfer of these antibodies from mother to baby in milk again protects the baby against infections.
One type of antibody, the kind that causes rapid allergic reactions, remained relatively invisible to these analyses of the contents of serum. It wasn’t until Kimi Ishizaka and his wife, and a young postdoc called Tomio Tada who, working at the National Asthma Center in Denver, were studying the properties of serum antibodies after they were injected under the skin that the antibody that causes these allergic reactions, IgE, was discovered. Now we know that IgE is a very important in all allergic reactions and in asthma. In fact one of the new drugs being used to treat asthmatic patients targets IgE itself.
The Immune Response, Vaccines and Immunodeficiency Diseases
When we encounter a new infection our B cells make antibodies against that infection, but not others. For example, children infected with chicken pox virus make antibodies to chicken pox but not polio. Scientists struggled with this phenomenon for years, how to explain it. It was David Talmage , a long time member of the faculty at the University of Colorado, who first put forward an explanation, now called the clonal selection theory. David suggested that each B cell might be able to make only one antibody sequence, and that each B cell synthesized its personal antibody and placed the antibody on its surface. When chicken pox entered the body, the virus would bind to antibodies of the surface of the B cells that could synthesize that antibody. This binding would make the engaged B cells divide and secrete their characteristic antibody. Thus the serum of the host would soon contain high levels of antibodies that could bind chicken pox. Meanwhile, the B cells that could bind other invaders, such as polio, would be left untouched, awaiting the arrival of their target invader. David’s clonal selection theory turned out to be correct and is now the absolute foundation for everything we understand about how the specific immune response works.
Binding to antigen alone is not enough to make B cells divide, they have to receive an activating signal that gets them off the ground. John Cambier’s lab was the first to find out how this signal is delivered, via two proteins, called Igalpha and Igbeta, that bind to the antibody, detect when it has contacted antigen and tell the B cell bearing them to divide.
The immune system includes T cells as well as B cells. T cells are well known in the general public because the destruction of a certain kind of T cell, the CD4 cell, by HIV is what causes the symptoms and consequences of infection with this virus. On the whole T cells behave very much like B cells, they bear receptors that can react with material from invaders, and in response to these invaders they divide rapidly, giving rise to an army of cells all dedicated to the elimination of just that infection.
There are differences however. T cells don’t use antibodies as their receptors, in fact for many years the discovery of T cell receptors for antigen was a long sort prize, a sought of scientific holy grail. Two scientists at National Jewish, John Kappler and Philippa Marrack, were the first to understand the nature of T cell receptors and their team, together with Kathryn Haskins, now a faculty member at the University, were one of the first to actually identify the chemical nature of these receptors.
T cell receptors do not bind invaders directly, instead they react with small fragments of the invader carried by a one of a collection of proteins called the major histocompatibility complex. This fact created immense confusion in the field of immunology for many years, but was eventually unraveled by the experiments of Howard Grey, at National Jewish. Dr. Grey demonstrated that fragments of proteins from pathogens can bind to MHC molecules and create a composite epitope recognized by T cell receptors.
T cells are not loners. They have many tasks, amongst these, is their ability to stimulate B cells to make more and better antibodies. This helper activity of T cells was first discovered by Henry Claman in the 1960s who was then, as now, at the University of Colorado Health Sciences Center. When T cells help B cells the receptors and other proteins on T cells bind molecules on B cells. The contact between the two cells is quite a large area, and is very highly organized with some molecules at its center, the bulls-eye, and other molecules surrounding it, so that the whole structure looks like a shooting target. The organization of this target allows the T cells to deliver its helpful signals to the B cells as efficiently as possible. The target structure and its importance was discovered by another scientist at National Jewish, Avi Kupfer.
All these findings have led to our understanding of how the immune response works. The discoveries of the separate roles of T cells B cells have helped in the treatment of immunodeficiency diseases, diseases that occur because one arm or other of the immune system fails. Knowing that failures can be due to deficiencies in either or both, B and T cells has helped proper treatment. For example, HIV infection causes lack of helper T cells. Proper treatment tries to restore the response of these cells. On the other hand many immnodeficiencies are diagnosed in infancy. In this case, often both T and B cells are involved, and the proper treatment is to replace both kinds of cells, by bone marrow transplants.
The discovery that T cell receptors recognize antigenic peptides bound to major histocompatibility complex proteins was also of immense importance because it has helped to explain why autoimmune diseases run in families. Autoimmunity-prone individuals have often inherited MHC proteins with unique ability to bind autoantigens. Because of this, T cells in these people are stimulated to attack self tissues, such as pancreatic beta cells that make insulin, and this leads to autoimmunity such as diabetes.
This problem would be much more widespread amongst all of us if it were not for the fact that most T and B cells that can attack us are silenced before they can mount an effective response. This silencing phenomenon, called tolerance, was discovered for T cells, by Kappler and Marrack. In spite of the fact that many autoreactive cells are destroyed early in their lives, some sneak through and survive to begin their attack against self. Experiments by John Cohen and Rick Duke, at the University, showed that many of these survivors die even as they begin their attack, by a special kind of death, called apoptosis.
Dead cells are not always a good thing, their debris can itself cause autoimmunity when T and B cells contact the debris of mortality and recognize and respond to this. Therefore it is very important that dead cells are cleared away, disposed of before they can lead to any more damage. The body has many ways of dealing with these corpses. Peter Henson at National Jewish Health is one of the best recognized experts on this subject and the first to show that one of the routes to the mortuary not only clears out dead cells but also simultaneously suppresses any untoward inflammation and response.
B cells, whose daughters make antibodies that protect us against disease, recognize and are activated by intact antigen molecules. Each of us produce about 10 billion B cells each day, and about 60% of these are autoreactive, and therefore must be silenced by tolerance mechanisms to prevent production antibodies against our own tissues. For example, in individuals with lupus, some B cells make antibody against the genetic material of the host. These antibodies, bound to their targets accumulate in the kidneys and cause inflammation and blockages in these organs. Our immune system has developed ways to prevent these problems and reduce the inflammation. Many of the protective devices have been discovered by National Jewish investigators. David Nemazee showed that some autoreactive B cells are silenced by a process of receptor editing in which cells change, at the genetic level, the specificity of their antigen receptors. Roberta Pelanda later showed that when cells fail to do this successfully, they are induced to die. John Cambier discovered that most autoreactive B cells actually stay around in the animal, but are unresponsive to antigen stimulation. This mechanism is called anergy.
In spite of all these safeguards some people do become autoimmune. To some degree autoimmunity runs in families, hence our genes affect whether or not we will get diseases such as juvenile diabetes and rheumatoid arthritis. In the belief that prevention is much better than treatment or cure, researchers around the world have tried to find out which genes are involved. For lupus, Brian Kotzin, a former research at both the University and National Jewish, and George Eisenbarth, at the Barbara Davis Center, have been leaders in identifying these genes and then driving attempts to intervene before disease begins.
These are just some of the people and discoveries which have made Denver a world-recognized center for research in Immunology and one of the jewels in the crown of our national effort to reduce human disease and suffering.