title: Complement activation in diseases presenting with thrombotic microangiopathy.
abstract: The complement system contains a great deal of biological "energy". This is demonstrated by the atypical hemolytic uremic syndrome (aHUS), which is a thrombotic microangiopathy (TMA) characterized by endothelial and blood cell damage and thrombotic vascular occlusions. Kidneys and often also other organs (brain, lungs and gastrointestinal tract) are affected. A principal pathophysiological feature in aHUS is a complement attack against endothelial cells and blood cells. This leads to platelet activation and aggregation, hemolysis, prothrombotic and inflammatory changes. The attacks can be triggered by infections, pregnancy, drugs or trauma. Complement-mediated aHUS is distinct from bacterial shiga-toxin (produced e.g. by E. coli O:157 or O:104 serotypes) induced "typical" HUS, thrombotic thrombocytopenic purpura (TTP) associated with ADAMTS13 (an adamalysin enzyme) dysfunction and from a recently described disease related to mutations in intracellular diacylglycerol kinase ε (DGKE). Mutations in proteins that regulate complement (factor H, factor I, MCP/CD46, thrombomodulin) or promote (C3, factor B) amplification of its alternative pathway or anti-factor H antibodies predispose to aHUS. The fundamental defect in aHUS is an excessive complement attack against cellular surfaces. This can be due to 1) an inability to regulate complement on self cell surfaces, 2) hyperactive C3 convertases or 3) complement activation and coagulation promoting changes on cell surfaces. The most common genetic cause is in factor H, where aHUS mutations disrupt its ability to recognize protective polyanions on surfaces where C3b has become attached. Most TMAs are thus characterized by misdirected complement activation affecting endothelial cell and platelet integrity.
authors.affiliation: Department of Bacteriology and Immunology, Haartman Institute, PO Box 21, FI-00014 University of Helsinki, Helsinki, Finland. seppo.meri@helsinki.fi
authors.forename: Seppo
authors.initials: S
authors.lastname: Meri
mesh_terms: D065766:Atypical Hemolytic Uremic Syndrome; D001323:Autoantibodies / Q000276:immunology; D003167:Complement Activation / Q000235:genetics / Q000276:immunology*; D003176:Complement C3 / Q000235:genetics / Q000276:immunology; D011415:Complement Factor B / Q000235:genetics / Q000276:immunology; D017242:Complement Factor H / Q000235:genetics / Q000276:immunology; D017244:Complement Factor I / Q000235:genetics / Q000276:immunology; D003170:Complement Pathway, Alternative / Q000235:genetics / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051916:Membrane Cofactor Protein; D011697:Purpura, Thrombotic Thrombocytopenic / Q000235:genetics / Q000276:immunology; D018180:Thrombomodulin / Q000235:genetics / Q000276:immunology; D057049:Thrombotic Microangiopathies / Q000235:genetics / Q000276:immunology
chemical_list: D001323:Autoantibodies; D003176:Complement C3; D051916:Membrane Cofactor Protein; D018180:Thrombomodulin; D017242:Complement Factor H; D017244:Complement Factor I; D011415:Complement Factor B
keywords: ADAMTS13; AP; CCP; CD46; Complement factor H; Complement regulation; DDD; DGKE; FH; Hemolytic uremic syndrome; Microangiopathy; PNH; STEC; Shiga-toxin producing E. coli; TMA; TTP; Thrombosis; a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; aHUS; alternative pathway; atypical hemolytic syndrome; complement control protein domain; dense deposit disease; diacylglycerol kinase ε; factor H; paroxysmal nocturnal hemoglobinuria; thrombotic microangiopathy; thrombotic thrombocytopenic purpura