Even the Immune System works with Pincers

Max-Planck-Scientists decipher central protein complex in the human immune system / Relevance for future therapies in allergies, autoimmune diseases and transplantation medicine

A key building block of the human immune system was identified up to the atomic detail using the method of x-ray crystallography by scientists of the Max-Planck-Institute for Biochemistry in Martinsried/Germany (Nature, 20. July 2000, S. 267-273). The protein complex, a mediator between the soluble and cellular compounds of the immune components in the blood, consists of an antibody and its respective receptor. Their dialogue in the immune system ensures that pathogenic germs which were previously labeled with antibodies are removed by receptor-equipped immune cells, eg macrophages. The identification of the structure and of the exact location of the interaction site between both proteins opens new possibilities not only for the therapy of diseases like allergies or autoimmune diseases, but also in the field of transplantation medicine.

Figure 1: Crystallized complex consisting of an IgG Fc fragment and an Fc receptor Upper left: Amino acid chains of the Fc fragment depicted in red and blue, Fc receptor in green. The Fab fragments as well as the "linker" by which the receptor is connected with the membrane are modeled into the figure and depicted semi-transparently. Upper right: Structure of the complex rotated by 90°. Lower left: Schematic view of the crystallized complex. The colour scheme is identical to the upper part of the figure. Lower right: Schematic view of the interaction between a pathogen and immune cell. Full size image available through contact

The most important weapon in the defense of diseases in the human organism are Y-shaped antibodies, the so-called immunoglobulins (Ig). Many quintillions of antibodies with more than a trillion different specificities are found in the blood of the human body. These subdivide themselves - as within all mammals - into five different antibody types: IgM, IgG, IgA, IgD and IgE. Every class has its own particular characteristics that makes it possible to adopt a certain defense function. IgA for example, can be transported through the uppermost layer of the skin and is found in saliva, sweat and tears.

The well investigated immunoglobulin IgG is, with 80 percent, the most abundant antibody class in the circulation. It easily passes through walls of blood vessels or the placental barrier and confers, by this, passive immunity from the mother to the embryo. IgG protects from bacteria, viruses and toxins in the lymphatic system and in the blood. In this case, the pathogen is marked on its surface through antibodies, which recognize their distinct structures with both "arms" of their Y-shaped structure. These arms are called Fab fragments (Fab=fragment antigen binding). Via Fc receptors (Fc=Fragment crystalline), which recognize a distinct structure in the "stem" region of the Y-shaped structure (Fc fragment), immune cells (leukocytes and lymphocytes) are bound. Only now the pathogen is removed when a macrophage engulfs and neutralizes it.

As the scientists from Martinsried found out, antibody and receptor contact each other like a pincer encloses a nail (Nature, 20 July 2000, S. 267-273). The horseshoe shaped Fc fragment of the antibody opens a little bit and picks up the receptor between its blocks. Both proteins (receptor and antibody) recognize each other by the "lock-&-key principle": The receptor only binds to antibodies of the IgG class and not to those of the IgE class.

Figure 2: Formation of an immune complex between a pathogen and an immunological active cell Simplified illustration of the defense against a pathogen (cyan-blue) by an immunologically active cell in the blood. The pathogen is labeled with antibodies. The two heavy chains of the antibody are depicted in red and blue, the light chains in the respective lighter colours. In the core of the antibodies is a carbohydrate (yellow). On the surface of the immunological active cell (magenta-red) are Fc receptors (green), of which two have already bound the antibodies attached to the pathogen (center). Full size image available through contact

To determine the X-ray structure of this protein complex the German Max-Planck scientists around Robert Huber had to overcome a series of obstacles. Since although the Fc fragment structure of an IgG antibody was solved by Huber 25 years ago, the crystallization of the whole IgG/Fc receptor complex was a difficult task. It took almost three years until the scientists could produce the first crystals of this IgG/Fc receptor complex, an indispensable prerequisite for the determination of its structure. The researchers used a strategy to overcome this: They did not crystallize the whole (and very flexible) antibody but only its quite rigid Fc fragment by which biochemical investigations had already shown that it is sufficient in its isolated form to bind the Fc receptor. On the other hand the Fc receptor was modified by genetic engineering techniques in such a way that it lacked the anchor peptide which is used for the membrane attachment on the immunological active cells.

As all antibodies of the immunoglobulin IgG and of the allergy triggering IgE consist of similar amino acid sequences and also have similar Fc receptors, the scientists from Martinsried/Germany conclude that also in these cases the respective antibody/receptor complexes resemble the described one. With this knowledge based on the X-ray structure it is now possible to develop tailor-made drugs which block the interaction between antibody and the Fc receptor on the immune cell and therefore are able to down-regulate the immune system. Peter Sondermann, the scientist responsible for this project, explained: "In the case of an infection this is of course undesirable, but in cases where the immune system has lost the right path. This is what happens in the case of allergies, where basically harmless substances cause a vehement and in some cases a life threatening immune response to occur. Examples also include transplantations, where the immune system fights the new organ or autoimmune diseases where the immune system attacks its own tissue." The German researchers are convinced that their discovery will make it possible to develop more directed therapies which can put the immune system back on a healthy course.

Contact:
Dr. Peter Sondermann
Max-Planck-Institut für Biochemie, Martinsried
Am Klopferspitz 18 a
D-82152 Martinsried, Germany
E-Mail: sonderma@biochem.mpg.de
Telefon::(+49 89) 85 78 - 27 01
Fax: (+49 89) 85 78 - 35 16