, Keynote Address: Learning the Rules of Antigen Presentation, by Emil R. Unanue, M.D.
...The award for Scientific Leadership in Immunology was presented to Dr. Emil R. Unanue, the Mallinckrodt Professor and Chairman of the Department of Pathology and Immunology at the Washington University School of Medicine.He
is currently engaged in the analysis and presentation of the antigen responsible for autoimmune diabetes.
..., Keynote Address: Learning the Rules of Antigen Presentation, by Emil R. Unanue, M.D.
Keynote Address, Learning the rules of antigen presentationA Report on the Keynote Address by Emil R. Unanue, M.D.,
...Emil R. Unanue, M.D.
...Emil R. Unanue, M.D. Emil R. Unanue, M.D. is the Mallinckrodt Professor and Chairman of the Department of Pathology and Immunology of Washington University School of Medicine in St. Louis, MO.He
has carried out seminal studies of the cellular and biochemical basis of immunogenicity, the property of being able to evoke an immune response within an organism.His
laboratory defined the requirements for intracellular processing of proteins, showing that protein antigens are recognized as linear peptides by T cells.He
was the first to prove biochemically that histocompatibility molecules bind peptides, establishing the biological role of these molecules.
A current focus of his
work is the analysis of processing and presentation of the antigen responsible for autoimmune diabetes.
described briefly the history of the field, then summarized his
own recent work on the molecular interactions between the MHC antigen-presenting proteins and antigen peptides.He
lecture by describing an MHC mutation that can lead to spontaneous autoimmune diabetes.Dr. Unanue
was the recipient of the 2003 Irvington Institute Scientific Leadership Award.He is a member of National Academy of Sciences and of Alpha Omega Alpha; a fellow of the American Academy of Arts and Sciences; a recipient of the William B. Coley Award, Cancer Research Institute, the Albert Lasker Basic Medical Research Award (co-recipient), the Rous-Whipple Award, American Society for Investigative Pathology and the Gardiner Foundation International Award (co-recipient), among others.
However, that theory took a long time to reconcile and assemble, Unanue
...The roles of phagocytes in interactions with lymphocytes was still unclear, however, when Unanue started his work at the National Institute for Medical Research, at Mill Hill in London.
It remained controversial whether phagocytes have anything to do with the activation of lymphocytes.To address this question, he
isolated macrophages from mice, exposed the cells to a protein antigen, and then transferred the cells to a normal mouse.
"Lo' and behold," said Unanue
, "the mouse made an exquisite immune response to the protein that the cells had ingested.
Both the adaptive and innate systems are truly dependent on each other, continues Unanue
The glue, MHC proteins
The MHC proteins serve as the glue between the two systems, said Unanue
.These molecules take the peptides from the catabolic system of the phagocytes and plant them on the surface of the cell, bringing them to the attention of the lymphocytes.In fact, when Unanue's
group adds T-cells to a plate of bacteria, the lymphocytes fail to detect the presence of the microbes and do not stick to them.If, however, the team first adds phagocytes, allows them to ingest the bacteria, and then adds the T-cells, the lymphocytes recognize the presence of the bacteria and stick to the phagocytic cells.
The catch to this experiment though, Unanue
added, is that although the T-cells bind to the exterior of the phagocytes, the microbes are inside.In other words, how can the T-cells bind to the exterior if the invader is internalized?It turns out that some of the microbial proteins are first catabolized by the phagocytic cell, then presented to the T-cell receptors by the MHC molecules on the outside of the phagocytes.If, however, the phagocytes are treated with a chemical that raises the internal pH of the cell, then the protein antigens are not broken down, and the T-cells have nothing to bind.
That work took many years to complete, says Unanue
To learn the rules that guide protein catabolism and antigen presentation, Unanue
colleagues have focused recently on the chicken lysozyme protein.
Here, said Unanue
, peptide exchange occurs with one peptide displacing another on the MHC binding site.
Although most of the protein antigens bound by MHC class II molecules are from vesicular compartments, some come from the cytosol."We don't yet know how this happens," says Unanue
Each mass spectrometry peak alone contains thousands of peptides, noted Unanue
, and one of the major problems his
group and others are facing is identifying the individual peptides.They have now started using a modified mass spectrometry protocol that puts two mass spectrometry machines in tandem.The first machine separates the isolated peptides into peaks, and the second one reanalyzes the peptides within a single peak.This approach, known as mass spectrometry-mass spectrometry, allows the group to identify the individual peptides in any given peak. Unanue
works jointly on this approach with the mass spectrometry group of Michael Gross.
Despite their absence in the proteins, these neoantigens appear to play an active role in the antigenic response, says Unanue
.Finally, the researchers find a high degree of specificity between the peptides and the MHC molecules, with 40, of the peptides being strong binders.These peptides are expressed at 100 or more copies per antigen presenting cell.
Crystallographic analysis of the peptide binding siteUnanue's group, in collaboration with David Fremont, a crystallographer in the department, has recently deciphered the details of peptide-MHC combining site.
As the peptides unfolds, there are usually five sites in the core region that anchor it to the MHC binding site-called the 1, 4, 6, 7, and 9 sites."The structural work has poised the field to move forward because it has given us a way to examine how these examine how these interactions are taking place in a rational way," Unanue
With this information in hand, Unanue
suggested, it becomes possible to address more rationally two important issues surrounding the immune system-its ability to protect against microbial function and avoidance of autoimmunity. Unanue
is focusing on a mouse model of diabetes, called NOD, in which cells of the immune fail to distinguish between self and non-self peptides.
"That single amino acid change is the cause of this problem," said Unanue
"This one amino acid is responsible for the exquisite specificity of selection and, I am sure, for bringing in new beta cell peptides responsible for this autoimmune disease," Unanue