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Nature. 2017 Aug 31;548(7669):597-601. doi: 10.1038/nature23670. Epub 2017 Aug 23.

Public antibodies to malaria antigens generated by two LAIR1 insertion modalities.

Author information

1
Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
2
Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK.
3
Swiss Institute of Bioinformatics (SIB), 1015 Lausanne, Switzerland.
4
Institute for Microbiology, ETH Zurich, Wolfgang-Pauli-Strasse 10, 8093 Zurich, Switzerland.
5
KEMRI-Wellcome Trust Research Programme, CGMRC, PO Box 230, 80108 Kilifi, Kenya.
6
Malaria Research and Training Centre, University of Sciences, Technique, and Technology of Bamako, 91094 Bamako, Mali.
7
Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, 46202 Indianapolis, Indiana, USA.
8
Ifakara Health Institute, Bagamoyo Clinical Trial Unit, P.O. Box 74, Bagamoyo, Tanzania.
9
Swiss Tropical and Public Health Institute, Clinical Immunology Unit, 4002 Basel, Switzerland.
10
University of Basel, Petersplatz 1, 4003 Basel, Switzerland.
11
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852, USA.
12
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.

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.

PMID:
28847005
PMCID:
PMC5635981
DOI:
10.1038/nature23670
[Indexed for MEDLINE]
Free PMC Article

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