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History of the Integrated Department of Immunology

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 lot 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 faculty of the University of Colorado Denver School of Medicine and National Jewish Health.   The following is a brief description of  how some of these discoveries 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 of other animals (and Tomio Tada himself), that the antibody that causes these allergic reactions, IgE, was discovered.   Physicochemical properties of reaginic antibody. V. Correlation of reaginic activity wth gamma-E-globulin antibody.
(Ishizaka K, Ishizaka T, Hornbrook MM., J Immunol. 1966 Dec;97(6):840-53.)

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 how to explain this phenomenon for years.  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    Allergy and immunology. (TALMAGE DW., Annu Rev Med. 1957;8:239-56.)

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. (Campbell KS and Cambier JC. 1990. B lymphocyte antigen receptors (mIg) are non-covalently associated with a disulfide linked, inducibly phosphorylated glycoprotein complex. EMBO Journal. 9:441-448.)

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 sought prize, a sort 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 (Kappler, J., Skidmore, B., White, J. and Marrack, P.  Antigen-inducible, H-2-restricted, interleukin-2 producing T cell hybridomas: Lack of independent antigen and H-2 recognition.  J. Exp. Med. 153:1198, 1981, PMC2186156.) 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. (Haskins, K., Kubo, R., White, J., Pigeon, M., Kappler, J. and Marrack, P.  The major histocompatibility complex-restricted antigen receptor on T cells.  I.  Isolation with a monoclonal antibody.  J. Exp. Med. 157:1149, 1983.)

T cell receptors do not bind invaders directly, instead they react with small fragments of the invader borne 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. (Shimonkevitz, R., Kappler, J., Marrack, P. and Grey, H.  Antigen recognition by H-2 restricted T cells.  I.  Cell free antigen processing.  J. Exp. Med. 158:303, 1983.)

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 at the University of Colorado Health Sciences Center.   Immunocompetence of transferred thymus-marrow cell combinations. (Claman HN, Chaperon EA, Triplett RF., J Immunol. 1966 Dec;97(6):828-32.)

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.

Autoimmunity
The discovery that T cell receptors recognize fragments of invaders, bound to major histocompatibility complex proteins was of immense importance because in the end it has helped to explain, not only how T cells help get rid of infections, but also why autoimmune diseases run in families.  Major histocompatibility complex proteins can engage fragments of ourselves, as well as fragments of invaders.  Some of these proteins seem to be particularly good at doing this, binding, for example, products of the beta cells of the pancreas.  In individuals who have inherited MHC proteins with this property T cells are stimulated to divide and attack, in this case destroying not an invader, but rather pancreatic beta cells, the cells that make insulin, leading to 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 destroyed before they are mature enough to mount an effective response, a phenomenon that was discovered, for T cells, by Kappler and Marrack. ( Kappler, J., Roehm, N. and Marrack, P.  T cell tolerance by clonal elimination in the thymus.  Cell 49:273-280, 1987.)

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  Endogenous endonuclease-induced DNA fragmentation: an early event in cell-mediated cytolysis.
(Duke RC, Chervenak R, Cohen JJ., Proc Natl Acad Sci U S A. 1983 Oct;80(20):6361-5.)

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  Apoptosis: getting rid of the bodies. ( Fadok VA, Henson PM., Curr Biol. 1998 Sep 24;8(19):R693-5.)

Some B cells are not beneficial.  For various reasons the body can produce B cells which, instead of making helpful antibodies that protect us against disease, make 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 here in Denver, by David Nemazee, John Cambier, Larry Wysocki and Roberta Pelanda, at the University and National Jewish

BCR ligation induces receptor editing in IgM+IgD- bone marrow B cells in vitro. (Hertz M, Nemazee D., Immunity. 1997 Apr;6(4):429-36.)

Maintenance of B cell anergy requires constant antigen receptor occupancy and signaling. (Gauld SB, Benschop RJ, Merrell KT, Cambier JC., Nat Immunol. 2005 Nov;6(11):1160-7.)

Activation and tolerance in CD4(+) T cells reactive to an immunoglobulin variable region. (Snyder CM, Aviszus K, Heiser RA, Tonkin DR, Guth AM, Wysocki LJ., J Exp Med. 2004 Jul 5;200(1):1-11.)
Receptor editing is the main mechanism of B cell tolerance toward membrane antigens. (Halverson R, Torres RM, Pelanda R., Nat Immunol. 2004 Jun)


Other efforts try to understand and reduce the inflammation these antibodies generate, and people who work with Michael Holers at the University are deeply involved in these efforts  Innate autoimmunity. (Carroll MC, Holers VM., Adv Immunol. 2005;86:137-57.)