Complement-mediated injury of the kidney: New mechanisms and novel therapies

点击翻译按钮获取中文摘要

The alternative pathway of complement contributes to a wide range of glomerular diseases. Factor H is the main regulator of this innate immune cascade. Although some patients with kidney disease have underlying defects in factor H, complete deficiency of the protein is quite rare. It is not clear why kidney is so frequently the target of alternative pathway-mediated injury. One possible explanation is that endogenous proteins can function as factor H antagonists, effectively creating microenvironments locally deficient in the regulator. The factor H related proteins (FHRs), for example, antagonize binding of factor H to tissue surfaces, including the glomerular basement membrane (GBM). We have also discovered that another class of proteins - the annexins - act as factor H antagonists on kidney surfaces. Although the FHRs and annexins probably block factor H from binding other tissues in the body, the high concentration of alternative pathway proteins within the glomerular capillaries causes preferential activation at this location. Based on these findings, the primary hypothesis of this grant is that is that the GBM is uniquely susceptible to alternative pathway activation because the dysregulatory proteins (FHRs and annexins) effectively block factor H from binding this surface, yet it is simultaneously exposed to high concentrations of activating proteins. Alternative pathway activation within the glomerulus generates C3a and C5a, which ligate receptors on resident myeloid cells and create an inflammatory milieux within the kidney. Complement fragments generated in the kidney also stimulate T cells and B cells systemically. To test this hypothesis, the following specific aims will be pursued. Aim 1) Characterize the effects of dysregulatory proteins in the kidney. We will use in vitro and in vivo models to explore the molecular mechanisms that cause alternative pathway activation in the kidney. Aim 2. Examine the downstream effects of AP activation in the kidney. In this aim we will explore the downstream effects of glomerular complement activation on cells throughout the kidney. We will also examine whether complement activation in the glomeruli affects the adaptive immune response systemically. This could represent a mechanism by which inflammation in the kidney increases production of autoantibodies, creating a positive feed-back loop. Aim 3. Test novel strategies for blocking complement activation in the kidney. In this aim we will test the ability of novel engineered proteins to reverse alternative pathway dysregulation in the kidney. The project is expected to provide an overarching explanation for why the kidney - among all the organs - is so uniquely susceptible to alternative pathway-mediated injury. These studies will also test strategies for specifically blocking kidney inflammation. By targeting the underlying molecular triggers of complement activation in the kidney, drugs can be designed to inhibit these pathologic processes without blocking complement-mediated immunity systemically. This approach is expected to be both more effective and safer than currently available treatments.