Antonio Lanzavecchia "Antibody repertoires: the power of clonal selection and a new mechanism of diversification" - 26 novembre 2020 ore 17.00

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Antonio Lanzavecchia, Istituto Nazionale di Genetica Molecolare, INGM, Milano;
Vir Biotechnology, Bellinzona, Svizzera


"Antibody repertoires: the power of clonal selection and a new mechanism of diversification"

We use cell culture-based high-throughput methods to interrogate human memory B cell and plasma cell repertoires and isolate antibodies selected on the basis of their neutralizing potency and breadth. Recently, we focused our analysis on the antibody response to the blood stage and pre-erythrocytic stage of P. falciparum parasites. We discovered that up to 10% of malaria infected individuals produce a new type of antibodies that contain a large templated insertion that comprises the entire extracellular domain of LAIR1, a collagen binding inhibitory receptor encoded on chromosome 19. In the clones producing LAIR1-containing antibodies the insertions are found either between V and DJ segments or in the switch region, leading to the positioning of the LAIR1 domain on the tip of HCDR3 or in the VH-CH1 elbow. The inserted LAIR1 domain is both necessary and sufficient for binding to infected erythrocytes and somatic mutations abolish collagen binding and modulate binding activity to the parasite antigens, which we identified as distinct RIFINs. Templated insertions derived from transcribed genes are frequently found in memory B cells of healthy individuals, suggesting that this mechanism represents a new and general mode of antibody diversification.

In another study, we analysed the antibody response of African individuals that were immunized by repeated injection of irradiated sporozoites and found to be protected from a challenge with infectious sporozoites. All isolated IgG antibodies bound to the circumsporozoite protein (CSP) and recognized distinct epitopes in its N terminus, NANP-repeat region, and C terminus. Strikingly, the most effective antibodies, as determined in a humanized mouse model, bound not only to the repeat region, but also to a minimal peptide at the PfCSP N-terminal junction that is not present in the RTS,S vaccine. These dual-specific antibodies were isolated from different donors and were encoded by VH3-30 alleles that encode tryptophan or arginine at position 52. Using structural and mutational data, we identified the elements required for germline recognition and affinity maturation. These potent neutralizing antibodies provide relevant information for lineage-targeted vaccine design and immunization strategies.

References: Tan et al, Nature 529:105 (2016). Pieper et al, Nature 549:597 (2017).
Tan et al, Nat. Med 24:401 (2018)

 

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