title: Autoimmune forms of thrombotic microangiopathy and membranoproliferative glomerulonephritis: Indications for a disease spectrum and common pathogenic principles.
abstract: There is increasing evidence that Thrombotic Thrombocytopenic Purpura (TTP), atypical Hemolytic Uremic Syndrome (aHUS) and Membranoproliferative Glomerulonephritis (MPGN), especially subtype II (also termed Dense Deposit Disease) represent a spectrum of related disorders. Thrombi are common for all three disorders, develop in different microvascular beds and appear relevant for organ dysfunction. TTP not only develops primarily at neurological sites, but also in the kidney and aHUS develops primarily in the kidneys. In TTP thrombi formation occurs subsequently to the release of multimers of von Willebrand Factor (vWF) and in HUS (both typical and atypical) to endothelial cell damage (via toxins or complement dysregulation). In MPGN thrombus formation occurs in the kidney, however, the cause for thrombi development is less clear. In addition autoimmune forms, in which acquired inhibitors in form of autoantibodies are de novo generated, exist for all three disorders. However, the autoantibodies are directed against different antigens. In TTP against ADAMTS 13, the vWF cleaving protease and in the DEAP-HUS (Deficient for CFHR1 and CFHR3 proteins and autoantibody positive) group against the major complement regulator Factor H. Autoantibodies in MPGN are termed C3 Nephritic Factor (C3NeF) and are directed against a neoepitope of the complement C3 convertase C3bBb. Apparently C3NeF stabilizes this convertase and this results in C3 amplification and complement activation. Based on the existence of acquired immune inhibitors and the shared thrombus formation in TTP, aHUS (DEAP-HUS) and MPGN we here address the hypothesis if the three autoimmune forms represent a spectrum of related diseases and share a common pathogenic principle.
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Skerka
authors.forename: Christoph
authors.initials: C
authors.lastname: Licht
authors.forename: Michael
authors.initials: M
authors.lastname: Mengel
authors.forename: Barbara
authors.initials: B
authors.lastname: Uzonyi
authors.forename: Stefanie
authors.initials: S
authors.lastname: Strobel
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
authors.forename: Mihály
authors.initials: M
authors.lastname: Józsi
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D017242:Complement Factor H / Q000276:immunology / Q000378:metabolism; D003165:Complement System Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015432:Glomerulonephritis, Membranoproliferative / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D006463:Hemolytic-Uremic Syndrome / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D006801:Humans; D007668:Kidney / Q000276:immunology / Q000473:pathology; D011697:Purpura, Thrombotic Thrombocytopenic / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D014841:von Willebrand Factor / Q000276:immunology / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D014841:von Willebrand Factor; D017242:Complement Factor H; D003165:Complement System Proteins