Molecular analysis of complement activation via the classical pathway

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The human immune system uses two main weapons to counter invading pathogens: adaptive immunity, which includes the production of antibodies that develop over time to target invading bacteria; and innate immunity, which is ever present and recognizes conserved parts of bacteria, such as their cell walls. The complement cascade provides a bridge between innate and adaptive immunity: it destroys bacteria directly via innate processes and helps to direct and stimulate an effective adaptive response. Because of its central role, complement dysfunction is associated with a range of human diseases, including severe bacterial infections, kidney disease and autoimmune diseases such as lupus and rheumatoid arthritis. One of the main pathways of complement activation is known as the classical pathway, in which complement proteins bind to bacteria and set off a chain of reactions directed at killing them. In this grant proposal, we aim to develop a thorough understanding this pathway by studying the way in which the components interact with each other to initiate the reaction cascade. We have already established methods for producing key elements using recombinant DNA technology so that their mode of action can be investigated in a systematic way. As well as providing novel information that will help us to understand how complement works, this project will also foster the development of novel reagents which can be used to change complement activity. For example, inhibitors of complement could be used to prevent tissue damage in conditions where complement activates at the wrong time or place. Similarly, modified components can be used to bind and neutralize specific targets such as antibiotic resistant bacteria or diseased cells.