A LAIR1 insertion generates broadly reactive antibodies against malaria variant antigens
| Autor: | Chiara Silacci Fregni, Sonia Barbieri, Mathilde Foglierini, Luca Piccoli, David Jarrossay, Abdirahman I. Abdi, Kevin Marsh, Davide Corti, Siro Bianchi, Roger Geiger, Blanca Fernandez-Rodriguez, Peter C. Bull, Juliana Wambua, Federica Sallusto, Philip Bejon, Claire M. Tully, Francis M. Ndungu, Joshua Tan, Antonio Lanzavecchia, Vandana Thathy, Kathrin Pieper |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Erythrocytes medicine.drug_class Molecular Sequence Data Plasmodium falciparum Protozoan Proteins Antigens Protozoan Monoclonal antibody Article Epitope 03 medical and health sciences Antigen Antibody Specificity Malaria Vaccines medicine Antigenic variation Humans Amino Acid Sequence Receptors Immunologic Conserved Sequence Genetics B-Lymphocytes Multidisciplinary biology Malaria vaccine Antibodies Monoclonal Membrane Proteins biology.organism_classification Antigenic Variation Kenya Virology Clone Cells Malaria Protein Structure Tertiary 3. Good health Mutagenesis Insertional 030104 developmental biology DNA Transposable Elements biology.protein Epitopes B-Lymphocyte Immunoglobulin superfamily Collagen Antibody |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/nature16450 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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