title: A LAIR1 insertion generates broadly reactive antibodies against malaria variant antigens.
abstract: Plasmodium falciparum antigens expressed on the surface of infected erythrocytes are important targets of naturally acquired immunity against malaria, but their high number and variability provide the pathogen with a powerful means of escape from host antibodies. Although broadly reactive antibodies against these antigens could be useful as therapeutics and in vaccine design, their identification has proven elusive. Here we report the isolation of human monoclonal antibodies that recognize erythrocytes infected by different P. falciparum isolates and opsonize these cells by binding to members of the RIFIN family. These antibodies acquired broad reactivity through a novel mechanism of insertion of a large DNA fragment between the V and DJ segments. The insert, which is both necessary and sufficient for binding to RIFINs, encodes the entire 98 amino acid collagen-binding domain of LAIR1, an immunoglobulin superfamily inhibitory receptor encoded on chromosome 19. In each of the two donors studied, the antibodies are produced by a single expanded B-cell clone and carry distinct somatic mutations in the LAIR1 domain that abolish binding to collagen and increase binding to infected erythrocytes. These findings illustrate, with a biologically relevant example, a novel mechanism of antibody diversification by interchromosomal DNA transposition and demonstrate the existence of conserved epitopes that may be suitable candidates for the development of a malaria vaccine.
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.|KEMRI-Wellcome Trust Research Programme, CGMRC, PO Box 230, 80108 Kilifi, Kenya.|Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK.
authors.forename: Joshua
authors.initials: J
authors.lastname: Tan
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Pieper
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Piccoli
authors.affiliation: KEMRI-Wellcome Trust Research Programme, CGMRC, PO Box 230, 80108 Kilifi, Kenya.
authors.forename: Abdirahman
authors.initials: A
authors.lastname: Abdi
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors.forename: Mathilde Foglierini
authors.initials: MF
authors.lastname: Perez
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.|Institute for Microbiology, ETH Zurich, Wolfgang-Pauli-Strasse 10, 8093 Zurich, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Geiger
authors.affiliation: KEMRI-Wellcome Trust Research Programme, CGMRC, PO Box 230, 80108 Kilifi, Kenya.
authors.forename: Claire Maria
authors.initials: CM
authors.lastname: Tully
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Jarrossay
authors.affiliation: KEMRI-Wellcome Trust Research Programme, CGMRC, PO Box 230, 80108 Kilifi, Kenya.
authors.forename: Francis
authors.initials: F
authors.lastname: Maina Ndungu
authors.affiliation: KEMRI-Wellcome Trust Research Programme, CGMRC, PO Box 230, 80108 Kilifi, Kenya.
authors.forename: Juliana
authors.initials: J
authors.lastname: Wambua
authors.affiliation: KEMRI-Wellcome Trust Research Programme, CGMRC, PO Box 230, 80108 Kilifi, Kenya.|Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Bejon
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors.forename: Chiara Silacci
authors.initials: CS
authors.lastname: Fregni
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors.forename: Blanca
authors.initials: B
authors.lastname: Fernandez-Rodriguez
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors.forename: Sonia
authors.initials: S
authors.lastname: Barbieri
authors.affiliation: Humabs BioMed SA, 6500 Bellinzona, Switzerland.
authors.forename: Siro
authors.initials: S
authors.lastname: Bianchi
authors.affiliation: KEMRI-Wellcome Trust Research Programme, CGMRC, PO Box 230, 80108 Kilifi, Kenya.|Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.affiliation: KEMRI-Wellcome Trust Research Programme, CGMRC, PO Box 230, 80108 Kilifi, Kenya.
authors.forename: Vandana
authors.initials: V
authors.lastname: Thathy
authors.affiliation: Humabs BioMed SA, 6500 Bellinzona, Switzerland.
authors.forename: Davide
authors.initials: D
authors.lastname: Corti
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors.forename: Federica
authors.initials: F
authors.lastname: Sallusto
authors.affiliation: KEMRI-Wellcome Trust Research Programme, CGMRC, PO Box 230, 80108 Kilifi, Kenya.|Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Bull
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.|Institute for Microbiology, ETH Zurich, Wolfgang-Pauli-Strasse 10, 8093 Zurich, Switzerland.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lanzavecchia
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D000918:Antibody Specificity; D000940:Antigenic Variation / Q000276:immunology*; D000953:Antigens, Protozoan / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D002999:Clone Cells / Q000166:cytology / Q000276:immunology; D003094:Collagen / Q000276:immunology / Q000378:metabolism; D017124:Conserved Sequence / Q000276:immunology; D004251:DNA Transposable Elements / Q000235:genetics / Q000276:immunology; D018985:Epitopes, B-Lymphocyte / Q000737:chemistry / Q000276:immunology; D004912:Erythrocytes / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D006801:Humans; D007630:Kenya; D008288:Malaria / Q000276:immunology* / Q000469:parasitology; D017780:Malaria Vaccines / Q000737:chemistry / Q000276:immunology; D008565:Membrane Proteins / Q000737:chemistry / Q000276:immunology; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional / Q000235:genetics*; D010963:Plasmodium falciparum / Q000276:immunology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D015800:Protozoan Proteins / Q000737:chemistry / Q000276:immunology; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000953:Antigens, Protozoan; D004251:DNA Transposable Elements; D018985:Epitopes, B-Lymphocyte; D017780:Malaria Vaccines; D008565:Membrane Proteins; D015800:Protozoan Proteins; C534665:RIFIN protein, Plasmodium falciparum; D011971:Receptors, Immunologic; C108073:leukocyte-associated immunoglobulin-like receptor 1; D003094:Collagen