title: Fibrinogen-specific antibody induces abdominal aortic aneurysm in mice through complement lectin pathway activation.
abstract: Abdominal aortic aneurysm (AAA) is a common vascular disease associated with high mortality rate due to progressive enlargement and eventual rupture. There is currently no established therapy known to alter the rate of aneurysmal expansion. Thus, understanding the processes that initiate and sustain aneurysmal growth is pivotal for the development of medical therapies aimed at halting disease progression. Using an elastase-induced AAA mouse model that recapitulates key features of human AAA, we previously reported that a natural IgG antibody directs alternative pathway complement activation and initiates the inflammatory process that culminates in aneurysmal development. The target of this natural antibody, however, was unknown. Herein we identify a natural IgG that binds to fibrinogen deposited in elastase-perfused aortic tissues, activates the complement lectin pathway (LP), and induces AAA. Moreover, we establish that alterations in the glycosylation patterns of this antibody critically affect its ability to activate the LP in vivo. We find that LP activation precedes the alternative pathway and absence of the LP complement protein mannan-binding lectin abrogates elastase-induced AAA. In human AAA tissues the mouse anti-fibrinogen antibody recognizes epitopes that localize to the same areas that stain positively for mannan-binding lectin, which suggests that the complement LP is engaged in humans as well. Lastly, we demonstrate that circulating antibodies in a subset of AAA patients react against fibrinogen or fibrinogen-associated epitopes in human aneurysmal tissues. Our findings support the concept that an autoimmune process directed at aortic wall self-antigens may play a central role in the immunopathogenesis of AAA.
authors.affiliation: Division of Rheumatology, Department of Medicine, and Division of Vascular Surgery, Department of Surgery, Washington University in St. Louis, St. Louis, MO 63124.
authors.forename: Hui-fang
authors.initials: HF
authors.lastname: Zhou
authors.forename: Huimin
authors.initials: H
authors.lastname: Yan
authors.forename: Paula
authors.initials: P
authors.lastname: Bertram
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.forename: Luke E
authors.initials: LE
authors.lastname: Springer
authors.forename: Robert W
authors.initials: RW
authors.lastname: Thompson
authors.forename: John A
authors.initials: JA
authors.lastname: Curci
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hourcade
authors.forename: Christine T N
authors.initials: CT
authors.lastname: Pham
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000209:etiology* / Q000276:immunology; D015153:Blotting, Western; D003167:Complement Activation / Q000276:immunology*; D037582:Complement Pathway, Mannose-Binding Lectin / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005340:Fibrinogen / Q000276:immunology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology* / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D010196:Pancreatic Elastase
chemical_list: D016326:Extracellular Matrix Proteins; D007074:Immunoglobulin G; D005340:Fibrinogen; D010196:Pancreatic Elastase