title: Autoantibodies specific to a peptide of β2-glycoprotein I cross-react with TLR4, inducing a proinflammatory phenotype in endothelial cells and monocytes.
abstract: β(2)-glycoprotein I (β(2)GPI) is the major antigenic target for antiphospholipid Abs. Anti-β(2)GPI Abs are a heterogeneous population of Igs targeting all domains of the molecule. Abs specific to β(2)GPI domain I are strongly associated with thrombosis and obstetric complications. In the present study, we sought to understand the possible pathogenic mechanism for this subset of anti-β(2)GPI Abs, investigating their potential cross-reactivity with other self-proteins involved in inflammatory or coagulant events. We compared the amino acid sequence of the β(2)GPI domain I with human proteins in a protein databank and identified a peptide sharing 88% identity with an epitope of human TLR4. A high percentage of patients with antiphospholipid syndrome (41%) and systemic lupus erythematosus (50%) presented serum IgG specific to this peptide. Anti-β(2)GPI peptide Abs binding the TLR4 were able to induce NF-κB activation in HEK293 cells that were stably transfected with the TLR4 gene. Anti-β(2)GPI peptide Abs induced activation of TLR4 and triggered interleukin-1 receptor-associated kinase phosphorylation and NF-κB translocation, promoting VCAM expression on endothelial cells and TNF-α release by monocytes. In conclusion, our observations suggest a novel pathogenic mechanism in the TLR4 stimulation by anti-β(2)GPI peptide Abs that links adaptive immune responses with innate immunity in antiphospholipid syndrome and systemic lupus erythematosus.
authors.affiliation: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Tania
authors.initials: T
authors.lastname: Colasanti
authors.forename: Cristiano
authors.initials: C
authors.lastname: Alessandri
authors.forename: Antonella
authors.initials: A
authors.lastname: Capozzi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Sorice
authors.forename: Federica
authors.initials: F
authors.lastname: Delunardo
authors.forename: Agostina
authors.initials: A
authors.lastname: Longo
authors.forename: Marina
authors.initials: M
authors.lastname: Pierdominici
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Conti
authors.forename: Simona
authors.initials: S
authors.lastname: Truglia
authors.forename: Alessandra
authors.initials: A
authors.lastname: Siracusano
authors.forename: Guido
authors.initials: G
authors.lastname: Valesini
authors.forename: Elena
authors.initials: E
authors.lastname: Ortona
authors.forename: Paola
authors.initials: P
authors.lastname: Margutti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016736:Antiphospholipid Syndrome / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001323:Autoantibodies / Q000097:blood*; D016022:Case-Control Studies; D055113:Chronic Periodontitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003429:Cross Reactions; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology*; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult; D053482:beta 2-Glycoprotein I / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D018836:Inflammation Mediators; D016328:NF-kappa B; D010446:Peptide Fragments; D034741:RNA, Small Interfering; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D053482:beta 2-Glycoprotein I