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Public antibodies to malaria antigens generated by two LAIR1 insertion modalities

Pieper, Kathrin and Tan, Joshua and Piccoli, Luca and Foglierini, Mathilde and Barbieri, Sonia and Chen, Yiwei and Silacci-Fregni, Chiara and Wolf, Tobias and Jarrossay, David and Anderle, Marica and Abdi, Abdirahman and Ndungu, Francis M. and Doumbo, Ogobara K. and Traore, Boubacar and Tran, Tuan M. and Jongo, Said and Zenklusen, Isabelle and Crompton, Peter D. and Daubenberger, Claudia and Bull, Peter C. and Sallusto, Federica and Lanzavecchia, Antonio. (2017) Public antibodies to malaria antigens generated by two LAIR1 insertion modalities. Nature, 548 (7669). pp. 597-601.

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Official URL: http://edoc.unibas.ch/56058/

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Abstract

In two previously described donors, the extracellular domain of LAIR1, a collagen-binding inhibitory receptor encoded on chromosome 19 (ref. 1), was inserted between the V and DJ segments of an antibody. This insertion generated, through somatic mutations, broadly reactive antibodies against RIFINs, a type of variant antigen expressed on the surface of Plasmodium falciparum-infected erythrocytes. To investigate how frequently such antibodies are produced in response to malaria infection, we screened plasma from two large cohorts of individuals living in malaria-endemic regions. Here we report that 5-10% of malaria-exposed individuals, but none of the European blood donors tested, have high levels of LAIR1-containing antibodies that dominate the response to infected erythrocytes without conferring enhanced protection against febrile malaria. By analysing the antibody-producing B cell clones at the protein, cDNA and gDNA levels, we characterized additional LAIR1 insertions between the V and DJ segments and discovered a second insertion modality whereby the LAIR1 exon encoding the extracellular domain and flanking intronic sequences are inserted into the switch region. By exon shuffling, this mechanism leads to the production of bispecific antibodies in which the LAIR1 domain is precisely positioned at the elbow between the VH and CH1 domains. Additionally, in one donor the genomic DNA encoding the VH and CH1 domains was deleted, leading to the production of a camel-like LAIR1-containing antibody. Sequencing of the switch regions of memory B cells from European blood donors revealed frequent templated inserts originating from transcribed genes that, in rare cases, comprised exons with orientations and frames compatible with expression. These results reveal different modalities of LAIR1 insertion that lead to public and dominant antibodies against infected erythrocytes and suggest that insertion of templated DNA represents an additional mechanism of antibody diversification that can be selected in the immune response against pathogens and exploited for B cell engineering.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Clinical Immunology (Daubenberger)
UniBasel Contributors:Daubenberger, Claudia
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Macmillan
ISSN:0028-0836
e-ISSN:1476-4687
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:20 Oct 2017 06:23
Deposited On:20 Oct 2017 06:23

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