title: Specific cross-reaction of anti-dsDNA antibody with platelet integrin GPIIIa49-66.
abstract: Anti-platelet autoantibodies are frequently found in systemic lupus erythematosus (SLE) patients and contribute to the development of SLE-associated immunologic thrombocytopenia (SLE-ITP). Although the correlation of anti-dsDNA autoantibody with platelet-associated antibody has been reported, the potential mechanism underlying such a correlation is incompletely understood. We have reported that anti-platelet integrin GPIIIa49-66 (CAPESIEFPVSEARVLED) autoantibodies play a major role in the development of HIV-1-related thrombocytopenia (HIV-1-ITP). The strong negative charge of GPIIIa49-66 prompts us to investigate whether GPIIIa49-66 can be an epitope mimicking dsDNA. We report here that anti-GPIIIa49-66 antibodies are found in three out of nine SLE-ITP patients. Double-stranded (ds) DNA competitively inhibited the binding of purified patient anti-dsDNA antibodies to GPIIIa49-66 peptide. Both polyclonal and monoclonal anti-GPIIIa49-66 antibodies are able to cross-react with dsDNA. Consistent with previous reports, the DNA binding activities of anti-GPIIIa49-66 antibodies are mainly dependent on the positively charged amino acid in the heavy-chain complementarity-determining region 3 (HCDR3). The HCDR3 of human SLE anti-dsDNA monoclonal antibody (mAb) 412.67 demonstrates a similar positively charged amino acid chain orientation compared with that of anti-GPIIIa49-66 mAb A11, and it cross-reacts with GPIIIa49-66 peptide. Purified anti-GPIIIa49-66 antibodies from SLE-ITP patients are able to induce platelet fragmentation in vitro and to induce thrombocytopenia in vivo. Thus, our data suggest that specific epitope cross-reaction between GPIIIa49-66 and dsDNA could be a mechanism involved in the development of SLE-associated thrombocytopenia.
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Suying
authors.initials: S
authors.lastname: Dang
authors.forename: Jianhui
authors.initials: J
authors.lastname: Wang
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nardi
authors.forename: Hong
authors.initials: H
authors.lastname: Zan
authors.forename: Paolo
authors.initials: P
authors.lastname: Casali
authors.forename: Zongdong
authors.initials: Z
authors.lastname: Li
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D001792:Blood Platelets / Q000276:immunology; D022801:Complementarity Determining Regions / Q000276:immunology; D003429:Cross Reactions / Q000276:immunology*; D004247:DNA / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology*; D010976:Platelet Count; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000276:immunology*; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000276:immunology*; D011897:Random Allocation
chemical_list: D000888:Antibodies, Anti-Idiotypic; D022801:Complementarity Determining Regions; D000939:Epitopes; D010446:Peptide Fragments; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C106958:platelet glycoprotein (GP)IIIa 49-66; D004247:DNA