The relative importance of local and systemic complement production in ischaemia, transplantation and other pathologies

Besides a critical role in innate host defence, complement activation contributes to inflammatory and immunological responses in a number of pathological conditions. Many tissues outside the liver (the primary source of complement) synthesise a variety of complement proteins, either constitutively or response to noxious stimuli. The significance of this local synthesis of complement has become clearer as a result of functional studies. It revealed that local production not only contributes to the systemic pool of complement but also influences local tissue injury and provides a link with the antigen-specific immune response. Extravascular production of complement seems particularly important at locations with poor access to circulating components and at sites of tissue stress responses, notably portals of entry of invasive microbes, such as interstitial spaces and renal tubular epithelial surfaces. Understanding the relative importance of local and systemic complement production at such locations could help to explain the differential involvement of complement in organ-specific pathology and inform the design of complement-based therapy. Here, we will describe the lessons we have learned over the last decade about the local synthesis of complement and its association with inflammatory and immunological diseases, placing emphasis on the role of local synthesis of complement in organ transplantation.