JOHN PATTERSON ATKINSON

..A mouse model of HUS designed to mirror human mutations in FH has now been developed, providing new understanding of the molecular pathogenesis of complement-related endothelial disorders...

..These types of functional assays will eventually replace the more laborious, less physiologic, and less informative approaches currently in use to monitor complement activation...

..Thus, this work establishes a feedback loop whereby FcgammaR expression and function are enhanced, a very desirable event in concert with an infection but potentially deleterious in autoimmunity...

..Specifically, interaction of complement component 5a (C5a) with its receptor is necessary for thrombosis of placental vasculature. Inhibition of complement activation may have a therapeutic role in this disease...

..By contrast, MCP deficiency can be corrected in part by a renal allograft. However, caution in the use of live-related donations is needed because of the high rates of incomplete penetrance of the described mutations...

..Mutations at the C3b.Bb interface interfere with the normal dissociation of C3b from Bb, whether it is spontaneous or promoted by DAF, CR1, or factor H...

..A response to acute injury or chronic debris accumulation must be appropriately balanced. In either case, too much activation or too little regulation promotes undesirable tissue damage and human disease...

..They imply that there is constant turnover on cells of the AP pathway which functions as an immune surveillance system for pathogens and altered self...

..Our results add new information relative to the necessity for appropriate expression levels of MCP and further implicate the alternative pathway in disease processes such as aHUS...

..This review describes lessons learned and the application of this model for functionally characterizing mutations in regulators associated with atypical hemolytic uremic syndrome...

..Both the R69W and A304V MCP mutations were deficient in their ability to control the alternative pathway of complement activation on a cell surface, illustrating the importance of modeling transmembrane proteins in situ...

..These results provide insights related to the complement inhibitory activities of poxviral inhibitors of complement and describe a mAb with therapeutic potential...

..The properdin-directed model is consistent with a proposal made by Pillemer and his colleagues >50 years ago...

..The excessive complement activation for a given degree of damage may result in generation of a procoagulant state and aHUS...

....

..In this study, we tested the hypothesis that complement participates in the development of AAA by providing the necessary chemotactic signal that recruits neutrophils to the aortic wall...

..These findings represent an instructive example of how a positive regulator of an innate immune recognition and effector pathway is controlled. A rationale for such a means to supply properdin for immune reactions is proposed...

..Accordingly, extracellular NS1 may function to minimize immune system targeting of West Nile virus by decreasing complement recognition of infected cells...

..Thus, gene therapy with targeted regulators represents a treatment option to provide a long-term and sustained protein supply for the site-specific blockade of undesirable complement activation...

..However, if the alternative pathway mediates C3b deposition, then MCP's cofactor activity is sufficient to restrict complement activation...

..These observations increase our understanding of the mechanism of DAA. In addition, a more potent decay-accelerating form of CR1 was generated...

..Thus, the lack of cTreg function in optimizing B-cell responses could explain why some CD46-deficient patients develop common variable immunodeficiency...

..Furthermore, structural differences in erythrocyte CR1 between human and non-human primates are probably explained by the selective pressure of malaria...

..This approach should therefore be applicable for diseases caused by a membrane protein deficiency such as paroxysmal nocturnal hemoglobinuria (PNH)...

..In addition, we speculate that this "targeted and restricted" form of complement activation on host cells is a common strategy to handle modified self...

..Herein, we review this pathway for the induction of Tregs, focusing on a role for the complement system and especially signaling through CD46 on human T-cells...

..Differential binding of soluble NS1 by tissue endothelium and subsequent recognition by anti-NS1 antibodies could contribute to the selective vascular leakage syndrome that occurs during severe secondary DENV infection...

..Finally, highlighting its importance in protecting cells against excessive complement activation is the discovery that even a heterozygous deficiency of CD46 predisposes to hemolytic uremic syndrome...

..These results suggest the possibility of using the single-chain Ab fragment-mediated targeting concept of complement regulatory proteins to restrict complement inhibition to the site of its excessive activation...

..This highlights the importance of defining and characterizing the underlying genetic defects in patients with aHUS...

..This Review focuses on the evolving role of the complement system in the regulation of T-cell responses, from directing the initiation phase, through driving lineage commitment, to regulating the contraction phase...

..Moreover, these studies may provide additional mechanistic information for therapeutic interventions in drug design for T cell lymphomas, immunodeficiencies, autoimmune diseases, and transplantation rejection. ..