title: CD4+ T cells from patients with acquired thrombotic thrombocytopenic purpura recognize CUB2 domain-derived peptides.
abstract: Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder resulting from the development of autoantibodies against ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). HLA-DRB1*11 provides a risk factor for developing acquired TTP. Pulsing of antigen-presenting cells from HLA-DRB1*11- and HLA-DRB1*03-positive individuals with ADAMTS13 resulted in presentation of peptides derived from the CUB2 domain of ADAMTS13 with core sequences FINVAPHAR or ASYILIRD. Here, we assessed whether FINVAPHAR- or ASYILIRD-reactive CD4(+)T cells are present in peripheral blood mononuclear cells from HLA-DRB1*11 and HLA-DRB1*03-positive subjects with acquired TTP. The presence of ADAMTS13-reactive CD4(+)T cells was addressed by flow cytometry and the expression of activation marker CD40 ligand by CD4(+)T cells. FINVAPHAR-reactive CD4(+)T cells were identified in an HLA-DRB1*11-positive patient during the acute phase of the disease whereas ASYILIRD-positive CD4(+)T cells were identified in a DRB1*03-positive patient with acquired TTP. Frequencies of CUB2 domain-reactive CD4(+)T cells ranged from 3.3% to 4.5%. Control peptides in which the anchor residues were modified did not induce activation of CD4(+)T cells. Taken together, our data provide evidence for the involvement of CUB2 domain-reactive CD4(+)T cells in the etiology of acquired TTP.
authors.affiliation: Department of Plasma Proteins.
authors.forename: Fabian C
authors.initials: FC
authors.lastname: Verbij
authors.affiliation: Immunopathology, and.
authors.forename: Annelies W
authors.initials: AW
authors.lastname: Turksma
authors.affiliation: Department of Plasma Proteins.
authors.forename: Femke
authors.initials: F
authors.lastname: de Heij
authors.affiliation: Department of Plasma Proteins.
authors.forename: Paul
authors.initials: P
authors.lastname: Kaijen
authors.affiliation: Immunogenetics, Sanquin-Academic Medical Center Landsteiner Laboratory, Amsterdam, The Netherlands; and.
authors.forename: Neubury
authors.initials: N
authors.lastname: Lardy
authors.affiliation: Department of Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Rob
authors.identifier: http://orcid.org/0000-0002-7844-4774
authors.initials: R
authors.lastname: Fijnheer
authors.affiliation: Department of Plasma Proteins.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Sorvillo
authors.affiliation: Immunopathology, and.
authors.forename: Anja
authors.initials: A
authors.lastname: ten Brinke
authors.affiliation: Department of Plasma Proteins.
authors.forename: Jan
authors.identifier: http://orcid.org/0000-0003-4585-2621
authors.initials: J
authors.lastname: Voorberg
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry / Q000276:immunology*; D000071120:ADAMTS13 Protein; D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D059811:HLA-DRB1 Chains / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D017434:Protein Structure, Tertiary; D011697:Purpura, Thrombotic Thrombocytopenic / Q000276:immunology* / Q000473:pathology
chemical_list: D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; C508422:HLA-DRB1*11 antigen; D010455:Peptides; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human