Antonio Lanzavecchia "Anticorpi neutralizzanti ad ampio spettro e un nuovo meccanismo di diversificazione" - 12 Novembre 2015 ore 17.00

Prof. Antonio Lanzavecchia, Ordinario di Immunologia Umana, Politecnico Federale di Zurigo, Svizzera


"Anticorpi neutralizzanti ad ampio spettro e un nuovo meccanismo di diversificazione"

 

We have developed cell culture-based high-throughput methods to interrogate with high efficiency human memory B cell and plasma cell repertoires and to isolate antibodies selected on the basis of their neutralizing potency and breadth. Relevant examples are antibodies that neutralize all influenza A viruses1 or even four paramyxoviruses2. By targeting conserved structures, these broadly neutralizing antibodies are less prone to select escape mutants and are therefore promising candidates for prophylaxis and therapy of infections, as well as tools for vaccine design3. The value of such a target-agnostic approach to vaccine design is illustrated by our discovery of extremely potent antibodies that neutralize human cytomegalovirus, which led to the identification of their viral ligand4, a pentameric complex that was finally produced and tested as an effective vaccine5. By reconstructing the genealogy trees of specific B cell clones, we investigate the role of somatic mutations in affinity maturation and in generation of antibody variants with broader or different specificity. We found that affinity maturation is achieved rapidly, often through a single mutation, but numerous redundant mutations accumulate, leading to extensive intraclonal diversification that may broaden reactivity against homologous viruses6. In some cases however, somatic mutations appear to be able to generate autoantibodies, as found in patients with pemphigus and autoimmune pulmonary alveolar proteinosis7.8. Recently, while searching for antibodies that broadly bind to malaria variant antigens, we discovered a new mechanism of antibody diversification, which relies on the interchromosomal transposition of genomic DNA sequences into rearranging immunoglobulin genes, followed by somatic mutations9. In my presentation I will briefly review our work on the role of somatic mutations in affinity maturation and intraclonal diversification and discuss, in more details, the recent findings on the antibodies against malaria variant antigens generated by interchromosomal DNA transposition, their properties and the nature of the target antigens.

(1) Corti et al. Science 333, 850 (2011); (2) Corti, et al., Nature 501, 439 (2013); (3) Corti & Lanzavecchia Annu Rev Immunol. 31, 705 (2013); (4) Macagno et al., J Virol 84, 1005 (2010); (5) Kabanova et al. PNAS 111, 17965 (2014); (6) Pappas et al., Nature 516, 418 (2014); (7) Di Zenzo et al., J Clin Invest 122, 3781 (2012); (8) Piccoli et al. Nat Commun. 6:7375. (2015); (9) Tan et al, submitted