Cell-Glue Found Instrumental in Reversing Immune Response

Researchers headed by Dr. Daniel Krappmann of GSF - National Research Center for Environment and Health in Neuherber, Germany, report an exciting new finding regarding ubiquitin's role in the activation and reversibility of immune response.

Ubiquitin, first identified in 1975, is a protein that is found universally (ubiquitously) in all living organisms. Its function ranges from that of removing cellular waste to repairing DNA structures. After the discovery of ubiquitin in 1975, the subsequent research that delineated its function was important enough to receive the award of the Nobel Prize in Chemistry in 2004.

Dr. Krappmann and his co-researchers have added to the knowledge about the role of ubiquitin by describing its function in acquired immune response, which is the mechanism by which immune defense responders recognize the presence of an antigen that has precipitated an immune response on a previous occasion. In acquired immune response, an amino-acid peptide antigen engages with receptor molecules on white blood cell lymphocytes, which then respond with immune defense to the antigen stimulation. The acquired immune response system is integral to such things as food allergies, anaphylactic allergic reactions, autoimmune diseases and lymph diseases.

Chemical reactions cause cellular signaling pathways to activate the lymphocytes to respond in defense to the antigen. The CBM, or Carma1-Bcl10-Malt1, pathway is a crucial cellular signaling stitch in lymphocyte activation of immune defense in the acquired immune response system: antigen irritates receptor molecule on lymphocyte; CBM signals lymphocyte; immune defense response is activated; allergic or allergy-like reaction results.

Krappmann and his team have proved that in the lymphocyte sub-group T cells, which are critical to stimulating immune response, ubiquitin (one function of which is to code cellular metabolic waste) attaches to Malt1 in the CBM cellular signaling complex that is crucial in precipitating response to antigen irritation. Krappmann's team has proved that Malt1 ubiquitination (the process of ubiquitin attaching) is a fundamentally important step in releasing T cell defense responses: ubiquitin attached to Malt1 is fundamental to triggering an allergic reaction.

This is an important breakthrough that can potentially lead to development of therapeutic remedies for autoimmune diseases, like Lupus and arthritis, and to other chronic illnesses that involve the acquired immune response system. As Dr. Krappmann explains, ubiquitin acts like a cellular glue that links various protein components within the cell. This adhesive behavior of ubiquitin is unique because it is reversible. As he says, reversibility of adhesion means that the reaction causing "associations can be reversed."

As the researchers clarify, the process of reversing the associations, or attachments, of ubiquitin, which is called de-ubiquitination, is occurring naturally in cells all the time, probably to prevent an over-activation in the body of lymphocyte T cells that are thrown into immune defense mode by ubiquitin. What the researches call unopposed lymphocyte activity (lymphocyte immune response activity run wild) is responsible for many chronic diseases and autoimmune diseases.

If ubiquitin is instrumental in activating lymphocyte T cells, and if over-activation of T cells is instrumental in some serious diseases, and if ubiquitination is reversible, then ubiquitin may lead to much needed therapeutic remedies for some of our hardest to control health problems.

The research team is Dr. Krappmann's Junior Group and comprises Dr. Jürgen Ruland of TU, Munich and Dr. Claus Scheidereit of Max-Delbrück-Center, Berlin.

"Glue inside the cell: Ubiquitin builds up an immune response," GSF National Research Center for Environment and Health