Public antibodies to malaria antigens generated by two LAIR1 insertion modalities

Kathrin Pieper, Joshua Tan, Luca Piccoli, Mathilde Foglierini, Sonia Barbieri, Yiwei Chen, Chiari Silacci-Fregni, Tobias Wolf, David Jarrossay, Marica Anderle, Abdirahman Abdi, Francis M. Ndungu, Ogobara K. Doumbo, Boubacar Traore, Tuan M. Tran, Said Jonho, Isabelle Zenklusen, Peter D. Crompton, Claudia Daubenberger, Peter C. Bull & 2 others Federica Sallusto, Antonio Lanzavecchia

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 erythrocytes2. 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.
Original languageEnglish (US)
Pages (from-to)597-601
Number of pages5
JournalNature
Volume548
DOIs
StatePublished - Aug 31 2017

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Malaria
Antigens
Antibodies
Exons
B-Lymphocytes
Blood Donors
Erythrocytes
Tissue Donors
Bispecific Antibodies
Cell Engineering
Chromosomes, Human, Pair 19
Camelus
Antibody-Producing Cells
DNA
Plasmodium falciparum
Elbow
Antibody Formation
Fever
Collagen
Complementary DNA

Cite this

Pieper, K., Tan, J., Piccoli, L., Foglierini, M., Barbieri, S., Chen, Y., ... Lanzavecchia, A. (2017). Public antibodies to malaria antigens generated by two LAIR1 insertion modalities. Nature, 548, 597-601. https://doi.org/doi:10.1038/nature23670

Public antibodies to malaria antigens generated by two LAIR1 insertion modalities. / Pieper, Kathrin; Tan, Joshua; Piccoli, Luca; Foglierini, Mathilde; Barbieri, Sonia; Chen, Yiwei; Silacci-Fregni, Chiari; Wolf, Tobias; Jarrossay, David; Anderle, Marica; Abdi, Abdirahman; Ndungu, Francis M.; Doumbo, Ogobara K.; Traore, Boubacar; Tran, Tuan M.; Jonho, Said; Zenklusen, Isabelle; Crompton, Peter D.; Daubenberger, Claudia; Bull, Peter C.; Sallusto, Federica; Lanzavecchia, Antonio.

In: Nature, Vol. 548, 31.08.2017, p. 597-601.

Research output: Contribution to journalArticle

Pieper, K, Tan, J, Piccoli, L, Foglierini, M, Barbieri, S, Chen, Y, Silacci-Fregni, C, Wolf, T, Jarrossay, D, Anderle, M, Abdi, A, Ndungu, FM, Doumbo, OK, Traore, B, Tran, TM, Jonho, S, Zenklusen, I, Crompton, PD, Daubenberger, C, Bull, PC, Sallusto, F & Lanzavecchia, A 2017, 'Public antibodies to malaria antigens generated by two LAIR1 insertion modalities', Nature, vol. 548, pp. 597-601. https://doi.org/doi:10.1038/nature23670
Pieper K, Tan J, Piccoli L, Foglierini M, Barbieri S, Chen Y et al. Public antibodies to malaria antigens generated by two LAIR1 insertion modalities. Nature. 2017 Aug 31;548:597-601. https://doi.org/doi:10.1038/nature23670
Pieper, Kathrin ; Tan, Joshua ; Piccoli, Luca ; Foglierini, Mathilde ; Barbieri, Sonia ; Chen, Yiwei ; Silacci-Fregni, Chiari ; Wolf, Tobias ; Jarrossay, David ; Anderle, Marica ; Abdi, Abdirahman ; Ndungu, Francis M. ; Doumbo, Ogobara K. ; Traore, Boubacar ; Tran, Tuan M. ; Jonho, Said ; Zenklusen, Isabelle ; Crompton, Peter D. ; Daubenberger, Claudia ; Bull, Peter C. ; Sallusto, Federica ; Lanzavecchia, Antonio. / Public antibodies to malaria antigens generated by two LAIR1 insertion modalities. In: Nature. 2017 ; Vol. 548. pp. 597-601.
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AU - Pieper, Kathrin

AU - Tan, Joshua

AU - Piccoli, Luca

AU - Foglierini, Mathilde

AU - Barbieri, Sonia

AU - Chen, Yiwei

AU - Silacci-Fregni, Chiari

AU - Wolf, Tobias

AU - Jarrossay, David

AU - Anderle, Marica

AU - Abdi, Abdirahman

AU - Ndungu, Francis M.

AU - Doumbo, Ogobara K.

AU - Traore, Boubacar

AU - Tran, Tuan M.

AU - Jonho, Said

AU - Zenklusen, Isabelle

AU - Crompton, Peter D.

AU - Daubenberger, Claudia

AU - Bull, Peter C.

AU - Sallusto, Federica

AU - Lanzavecchia, Antonio

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N2 - 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 erythrocytes2. 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.

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