AIM: Humoral sensitization affects transplant outcome, and it is now apparent that human leukocyte antigen (HLA) antibodies are specific for epitopes rather than antigens. Such epitopes can be structurally defined by HLAMatchmaker, an algorithm that considers eplets as critical elements of epitopes recognized by alloantibodies. This study addressed the question how mismatched HLA antigens induce specific antibodies in context with eplet differences with the antibody producer. METHODS: HLA class I-specific human monoclonal antibodies derived from women sensitized during pregnancy were tested in Luminex assays with single allele panels. Their epitope specificity was determined from reactivity patterns and eplet differences between immunizing antigen and the antibody producer. RESULTS: This study focuses on the reactivity patterns of 10 monoclonal antibodies specific for epitopes defined by a mismatched eplet paired with a self-eplet shared between immunizing HLA antigens and HLA antigens of the antibody producer. The eplets in these pairs are between 7 and 16 Å apart, a sufficient distance for contact by two separate complementarity-determining regions of antibody. CONCLUSIONS: These findings demonstrate that immunizing antigens have mismatched eplets that can form antibody-reactive epitopes with self-configurations on the molecular surface. They seem to suggest that HLA antibodies can be produced by autoreactive B cells that have undergone receptor editing to accommodate the recognition of nonself-eplets, the driving force of the humoral alloresponse. This concept enhances our understanding of structural epitope immunogenicity and the interpretation of antibody reactivity patterns with HLA panels.
AIM: Humoral sensitization affects transplant outcome, and it is now apparent that human leukocyte antigen (HLA) antibodies are specific for epitopes rather than antigens. Such epitopes can be structurally defined by HLAMatchmaker, an algorithm that considers eplets as critical elements of epitopes recognized by alloantibodies. This study addressed the question how mismatched HLA antigens induce specific antibodies in context with eplet differences with the antibody producer. METHODS: HLA class I-specific human monoclonal antibodies derived from women sensitized during pregnancy were tested in Luminex assays with single allele panels. Their epitope specificity was determined from reactivity patterns and eplet differences between immunizing antigen and the antibody producer. RESULTS: This study focuses on the reactivity patterns of 10 monoclonal antibodies specific for epitopes defined by a mismatched eplet paired with a self-eplet shared between immunizing HLA antigens and HLA antigens of the antibody producer. The eplets in these pairs are between 7 and 16 Å apart, a sufficient distance for contact by two separate complementarity-determining regions of antibody. CONCLUSIONS: These findings demonstrate that immunizing antigens have mismatched eplets that can form antibody-reactive epitopes with self-configurations on the molecular surface. They seem to suggest that HLA antibodies can be produced by autoreactive B cells that have undergone receptor editing to accommodate the recognition of nonself-eplets, the driving force of the humoral alloresponse. This concept enhances our understanding of structural epitope immunogenicity and the interpretation of antibody reactivity patterns with HLA panels.
Authors: Natasja G de Groot; Corrine M C Heijmans; Marit K H van der Wiel; Jeroen H Blokhuis; Arend Mulder; Lisbeth A Guethlein; Gaby G M Doxiadis; Frans H J Claas; Peter Parham; Ronald E Bontrop Journal: J Immunol Date: 2015-12-18 Impact factor: 5.422
Authors: Cornelis R van der Torren; Jessica S Suwandi; DaHae Lee; Ernst-Jan T Van't Wout; Gaby Duinkerken; Godelieve Swings; Arend Mulder; Frans H J Claas; Zhidong Ling; Pieter Gillard; Bart Keymeulen; Peter In't Veld; Bart O Roep Journal: Cell Transplant Date: 2016-10-10 Impact factor: 4.064
Authors: Marlieke L M Jongsma; Antonius A de Waard; Matthijs Raaben; Tao Zhang; Birol Cabukusta; René Platzer; Vincent A Blomen; Anastasia Xagara; Tamara Verkerk; Sophie Bliss; Xiangrui Kong; Carolin Gerke; Lennert Janssen; Elmer Stickel; Stephanie Holst; Rosina Plomp; Arend Mulder; Soldano Ferrone; Frans H J Claas; Mirjam H M Heemskerk; Marieke Griffioen; Anne Halenius; Hermen Overkleeft; Johannes B Huppa; Manfred Wuhrer; Thijn R Brummelkamp; Jacques Neefjes; Robbert M Spaapen Journal: Immunity Date: 2020-12-02 Impact factor: 31.745