Complement Initiation by Pentameric and Hexameric IgMs

Our human body is exposed to all kinds of potential hazards every day - often through mechanical injuries, but also through small, invisible substances, particles and foreign organisms. The invasion of tiny organisms, such as bacteria, viruses, or other pathogens is called infection. Fortunately, we have a defense system that inactivates such invaders which is essential for our survival. This excellent defense system is called the immune system and one part thereof is the complement system. Once the system gets started, a set of reactions run one after the other, like in a gradual waterfall, the subsequent reaction always being triggered or, as we say, initiated by the previous one. At the end, a protein-complex is formed that dissolves or enwraps the pathogen and thus eliminates it. Today, we already have a fairly precise idea of how these individual reactions take place, but in order to be able to develop better targeted drugs, there are still many important details to be explored. With this project, we will contribute to answering a central question: how is the first step of this cascade activated and what are the fine adjustments? To this end, we will investigate the link that transmits the information from the invader - immunologically this is called "antigen" - to the first building block in the complement cascade this protein is called C1q. These messengers are often antibodies that recognize the antigen precisely, dock to it and thereby pass on the signal for activation of the complement system to C1q. To do this, we will (i) produce different antibodies as well as C1q and different variants thereof in the lab, (ii) we will study how well the different variants can recognize each other, and (iii) we will then test how well our self-produced building blocks can trigger the complement cascade. From the analyses, we can draw conclusions about the important regions in the proteins and use this knowledge for better understanding of complement related diseases and the development of new drugs.

Humans on our planet are constantly exposed to dangers that often originate from small, invisible organisms and substances. When microorganisms enter the body, this is referred to as an infection; when toxic substances are ingested, it is referred to as intoxication. Fortunately, we have a defense system that renders such foreign bodies harmless-which, incidentally, can also be tumor cells formed by the body itself. This defense system is called the immune system. It is essential for the survival of higher animals and developed very early in evolution. Proteins are substances that perform many different tasks in the organism. They form the basis of most biochemical reactions, transmit information, initiate reactions, and perform a wide variety of functions. The complement system is part of the immune system and consists of approximately 30 different proteins. Once the complement cascade is "activated," one activation step follows another. This end in a protein complex that dissolves (lysis) the pathogen or coats (opsonizes) the toxin, rendering it harmless. Looking more closely at the activation steps, it becomes clear that the structure of the individual proteins, with their helices, folding sheets, and loops, forms the basis of their properties and functions. For example, one protein changes its structure by binding to another protein so that it can be cut by a third protein. This changes its function again and initiates the next step in the activation cascade. This cascade is important so that the final process is not determined by just one step, which could lead to malfunctions. We addressed the question of how the first step of the activation cascade is initiated and what fine adjustments are involved. To do this, we had to look at the links between the invader -immunologically known as the "antigen"-and the first protein in the complement cascade. This protein is called C1q. The connecting proteins are immunoglobulins, which are present in our bodies as natural initiators of various defense strategies. In our project "Complement Activation by Pentameric and Hexameric IgMs," we investigated the binding of various immunoglobulins and the transfer of information to the first protein in the complement cascade, C1q. In the course of the laboratory work, the individual proteins and also mutants thereof were produced. The proteins were then examined for their binding properties and functionality. The analyses allowed conclusions to be drawn about the important regions in the protein that can be used for research into diseases and the development of new drugs.