Abstract
Antibodies are essential components of adaptive immunity. A typical antibody repertoire comprises an enormous diversity of antigen-binding specificities, which are generated by the genetic processes of recombination and mutation. Accumulating evidence suggests that the immune system can exploit additional strategies to diversify the repertoire of antigen specificities. These unconventional mechanisms exclusively target the antigen-binding sites of immunoglobulins and include the insertion of large amino acid sequences, post-translational modifications, conformational heterogeneity and use of nonprotein cofactor molecules. Here, we describe the different unconventional routes for diversification of antibody specificities. Furthermore, we highlight how the immune system has a much greater level of adaptability and plasticity than previously anticipated, which goes far beyond that encoded in the genome or generated by the acquisition of somatic mutations.
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References
Flajnik, M. F. A cold-blooded view of adaptive immunity. Nat. Rev. Immunol. 18, 438–453 (2018).
Lu, L. L., Suscovich, T. J., Fortune, S. M. & Alter, G. Beyond binding: antibody effector functions in infectious diseases. Nat. Rev. Immunol. 18, 46–61 (2018).
Saada, R., Weinberger, M., Shahaf, G. & Mehr, R. Models for antigen receptor gene rearrangement: CDR3 length. Immunol. Cell Biol. 85, 323–332 (2007).
Collins, A. M. & Jackson, K. J. L. On being the right size: antibody repertoire formation in the mouse and human. Immunogenetics 70, 143–158 (2018).
Wardemann, H. & Busse, C. E. Novel approaches to analyze immunoglobulin repertoires. Trends Immunol. 38, 471–482 (2017).
Imkeller, K. & Wardemann, H. Assessing human B cell repertoire diversity and convergence. Immunol. Rev. 284, 51–66 (2018).
Klein, F. et al. Antibodies in HIV-1 vaccine development and therapy. Science 341, 1199–1204 (2013).
Corti, D. & Lanzavecchia, A. Broadly neutralizing antiviral antibodies. Annu. Rev. Immunol. 31, 705–742 (2013).
Tan, J. et al. A LAIR1 insertion generates broadly reactive antibodies against malaria variant antigens. Nature 529, 105–109 (2016). This article demonstrates that some antibodies isolated from patients with malaria have insertions of LAIR1 protein in their V H regions.
Meyaard, L. et al. LAIR-1, a novel inhibitory receptor expressed on human mononuclear leukocytes. Immunity 7, 283–290 (1997).
Hsieh, F. L. & Higgins, M. K. The structure of a LAIR1-containing human antibody reveals a novel mechanism of antigen recognition. eLife 6, e27311 (2017). This paper reveals the crystal structure of an antibody that incorporates LAIR1 in its V region.
Pieper, K. et al. Public antibodies to malaria antigens generated by two LAIR1 insertion modalities. Nature 548, 597–601 (2017).
Robbiani, D. F. et al. Plasmodium infection promotes genomic instability and AID-dependent B cell lymphoma. Cell 162, 727–737 (2015).
Briney, B. S., Willis, J. R. & Crowe, J. E. Jr. Location and length distribution of somatic hypermutation-associated DNA insertions and deletions reveals regions of antibody structural plasticity. Genes Immun. 13, 523–529 (2012).
Wilson, P. C. et al. Somatic hypermutation introduces insertions and deletions into immunoglobulin V genes. J. Exp. Med. 187, 59–70 (1998).
Bowers, P. M. et al. Nucleotide insertions and deletions complement point mutations to massively expand the diversity created by somatic hypermutation of antibodies. J. Biol. Chem. 289, 33557–33567 (2014).
Kepler, T. B. et al. Immunoglobulin gene insertions and deletions in the affinity maturation of HIV-1 broadly reactive neutralizing antibodies. Cell Host Microbe 16, 304–313 (2014). This article shows that the frequency of indels in V regions is increased in antibodies from individuals infected with HIV-1 and in bNAbs against HIV-1.
Krause, J. C. et al. An insertion mutation that distorts antibody binding site architecture enhances function of a human antibody. mBio 2, e00345–10 (2011).
Klein, F. et al. Somatic mutations of the immunoglobulin framework are generally required for broad and potent HIV-1 neutralization. Cell 153, 126–138 (2013). This work reveals the molecular mechanism of indel-mediated optimization of the neutralizing potential of a bNAb against HIV-1.
Jennewein, M. F. & Alter, G. The immunoregulatory roles of antibody glycosylation. Trends Immunol. 38, 358–372 (2017).
Moore, K. L. The biology and enzymology of protein tyrosine O-sulfation. J. Biol. Chem. 278, 24243–24246 (2003).
Ouyang, Y., Lane, W. S. & Moore, K. L. Tyrosylprotein sulfotransferase: purification and molecular cloning of an enzyme that catalyzes tyrosine O-sulfation, a common posttranslational modification of eukaryotic proteins. Proc. Natl Acad. Sci. USA 95, 2896–2901 (1998).
Choe, H. et al. Tyrosine sulfation of human antibodies contributes to recognition of the CCR5 binding region of HIV-1 gp120. Cell 114, 161–170 (2003).
Huang, C. C. et al. Structural basis of tyrosine sulfation and VH-gene usage in antibodies that recognize the HIV type 1 coreceptor-binding site on gp120. Proc. Natl Acad. Sci. USA 101, 2706–2711 (2004).
Farzan, M. et al. Tyrosine sulfation of the amino terminus of CCR5 facilitates HIV-1 entry. Cell 96, 667–676 (1999).
Huang, C. C. et al. Structures of the CCR5 N terminus and of a tyrosine-sulfated antibody with HIV-1 gp120 and CD4. Science 317, 1930–1934 (2007). This article shows molecular details about the role of tyrosine sulfation in the interaction of an antibody with its target antigen.
Pejchal, R. et al. Structure and function of broadly reactive antibody PG16 reveal an H3 subdomain that mediates potent neutralization of HIV-1. Proc. Natl Acad. Sci. USA 107, 11483–11488 (2010). This work presents evidence for the functional impact of sulfation of tyrosine in the antibody-mediated neutralization of HIV-1.
Changela, A. et al. Crystal structure of human antibody 2909 reveals conserved features of quaternary structure-specific antibodies that potently neutralize HIV-1. J. Virol. 85, 2524–2535 (2011).
van de Bovenkamp, F. S., Hafkenscheid, L., Rispens, T. & Rombouts, Y. The emerging importance of IgG Fab glycosylation in immunity. J. Immunol. 196, 1435–1441 (2016).
Hamza, N. et al. Ig gene analysis reveals altered selective pressures on Ig-producing cells in parotid glands of primary Sjogren’s syndrome patients. J. Immunol. 194, 514–521 (2015).
Rombouts, Y. et al. Extensive glycosylation of ACPA-IgG variable domains modulates binding to citrullinated antigens in rheumatoid arthritis. Ann. Rheum. Dis. 75, 578–585 (2016).
Hafkenscheid, L. et al. Structural analysis of variable domain glycosylation of anti-citrullinated protein antibodies in rheumatoid arthritis reveals the presence of highly sialylated glycans. Mol. Cell. Proteom. 16, 278–287 (2017).
van de Bovenkamp, F. S. et al. Variable domain N-linked glycans acquired during antigen-specific immune responses can contribute to immunoglobulin G antibody stability. Front. Immunol. 9, 740 (2018).
van de Bovenkamp, F. S. et al. Adaptive antibody diversification through N-linked glycosylation of the immunoglobulin variable region. Proc. Natl Acad. Sci. USA 115, 1901–1906 (2018). This study demonstrates the importance of glycosylation of V regions for the diversification of human antibody repertoires.
Wallick, S. C., Kabat, E. A. & Morrison, S. L. Glycosylation of a VH residue of a monoclonal antibody against alpha (1——6) dextran increases its affinity for antigen. J. Exp. Med. 168, 1099–1109 (1988).
Leibiger, H., Wustner, D., Stigler, R. D. & Marx, U. Variable domain-linked oligosaccharides of a human monoclonal IgG: structure and influence on antigen binding. Biochem. J. 338, 529–538 (1999).
Khurana, S., Raghunathan, V. & Salunke, D. M. The variable domain glycosylation in a monoclonal antibody specific to GnRH modulates antigen binding. Biochem. Biophys. Res. Commun. 234, 465–469 (1997).
Jacquemin, M. et al. Variable region heavy chain glycosylation determines the anticoagulant activity of a factor VIII antibody. J. Thromb. Haemost. 4, 1047–1055 (2006).
Song, R., Oren, D. A., Franco, D., Seaman, M. S. & Ho, D. D. Strategic addition of an N-linked glycan to a monoclonal antibody improves its HIV-1-neutralizing activity. Nat. Biotechnol. 31, 1047–1052 (2013).
Sabouri, Z. et al. Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity. Proc. Natl Acad. Sci. USA 111, E2567–E2575 (2014).
Chuang, G. Y. et al. Eliminating antibody polyreactivity through addition of N-linked glycosylation. Protein Sci. 24, 1019–1030 (2015).
Boehr, D. D., Nussinov, R. & Wright, P. E. The role of dynamic conformational ensembles in biomolecular recognition. Nat. Chem. Biol. 5, 789–796 (2009).
Tokuriki, N. & Tawfik, D. S. Protein dynamism and evolvability. Science 324, 203–207 (2009).
James, L. C. & Tawfik, D. S. Conformational diversity and protein evolution—a 60-year-old hypothesis revisited. Trends Biochem. Sci. 28, 361–368 (2003).
Yin, J., Beuscher, A. E. 4th, Andryski, S. E., Stevens, R. C. & Schultz, P. G. Structural plasticity and the evolution of antibody affinity and specificity. J. Mol. Biol. 330, 651–656 (2003).
Manivel, V., Sahoo, N. C., Salunke, D. M. & Rao, K. V. Maturation of an antibody response is governed by modulations in flexibility of the antigen-combining site. Immunity 13, 611–620 (2000).
Manivel, V., Bayiroglu, F., Siddiqui, Z., Salunke, D. M. & Rao, K. V. The primary antibody repertoire represents a linked network of degenerate antigen specificities. J. Immunol. 169, 888–897 (2002).
Notkins, A. L. Polyreactivity of antibody molecules. Trends Immunol. 25, 174–179 (2004).
Eisen, H. N. & Chakraborty, A. K. Evolving concepts of specificity in immune reactions. Proc. Natl Acad. Sci. USA 107, 22373–22380 (2010).
Wedemayer, G. J., Patten, P. A., Wang, L. H., Schultz, P. G. & Stevens, R. C. Structural insights into the evolution of an antibody combining site. Science 276, 1665–1669 (1997).
Jimenez, R., Salazar, G., Baldridge, K. K. & Romesberg, F. E. Flexibility and molecular recognition in the immune system. Proc. Natl Acad. Sci. USA 100, 92–97 (2003).
Jimenez, R., Salazar, G., Yin, J., Joo, T. & Romesberg, F. E. Protein dynamics and the immunological evolution of molecular recognition. Proc. Natl Acad. Sci. USA 101, 3803–3808 (2004).
Nguyen, H. P. et al. Germline antibody recognition of distinct carbohydrate epitopes. Nat. Struct. Biol. 10, 1019–1025 (2003).
Zimmermann, J. et al. Antibody evolution constrains conformational heterogeneity by tailoring protein dynamics. Proc. Natl Acad. Sci. USA 103, 13722–13727 (2006).
Thorpe, I. F. & Brooks, C. L. 3rd Molecular evolution of affinity and flexibility in the immune system. Proc. Natl Acad. Sci. USA 104, 8821–8826 (2007).
Schmidt, A. G. et al. Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody. Proc. Natl Acad. Sci. USA 110, 264–269 (2013).
Jeliazkov, J. R. et al. Repertoire analysis of antibody CDR-H3 loops suggests affinity maturation does not typically result in rigidification. Front. Immunol. 9, 413 (2018).
Ovchinnikov, V., Louveau, J. E., Barton, J. P., Karplus, M. & Chakraborty, A. K. Role of framework mutations and antibody flexibility in the evolution of broadly neutralizing antibodies. eLife 7, e33038 (2018).
Acierno, J. P., Braden, B. C., Klinke, S., Goldbaum, F. A. & Cauerhff, A. Affinity maturation increases the stability and plasticity of the Fv domain of anti-protein antibodies. J. Mol. Biol. 374, 130–146 (2007).
Haynes, B. F. et al. Cardiolipin polyspecific autoreactivity in two broadly neutralizing HIV-1 antibodies. Science 308, 1906–1908 (2005).
Liu, M. et al. Polyreactivity and autoreactivity among HIV-1 antibodies. J. Virol. 89, 784–798 (2015).
Mouquet, H. et al. Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation. Nature 467, 591–595 (2010).
Prigent, J. et al. Conformational plasticity in broadly neutralizing HIV-1 antibodies triggers polyreactivity. Cell Rep. 23, 2568–2581 (2018).
Erijman, A., Aizner, Y. & Shifman, J. M. Multispecific recognition: mechanism, evolution, and design. Biochemistry 50, 602–611 (2011).
Vogt, A. D. & Di Cera, E. Conformational selection or induced fit? A critical appraisal of the kinetic mechanism. Biochemistry 51, 5894–5902 (2012).
Foote, J. & Milstein, C. Conformational isomerism and the diversity of antibodies. Proc. Natl Acad. Sci. USA 91, 10370–10374 (1994).
James, L. C. & Tawfik, D. S. Structure and kinetics of a transient antibody binding intermediate reveal a kinetic discrimination mechanism in antigen recognition. Proc. Natl Acad. Sci. USA 102, 12730–12735 (2005).
James, L. C., Roversi, P. & Tawfik, D. S. Antibody multispecificity mediated by conformational diversity. Science 299, 1362–1367 (2003). This study provides structural evidence for the existence of conformational isomerism in some antibodies.
Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003).
Tiller, T. et al. Autoreactivity in human IgG+memory B cells. Immunity 26, 205–213 (2007).
Benckert, J. et al. The majority of intestinal IgA+and IgG+plasmablasts in the human gut are antigen-specific. J. Clin. Invest. 121, 1946–1955 (2011).
Bunker, J. J. et al. Natural polyreactive IgA antibodies coat the intestinal microbiota. Science 358, eean6619 (2017).
Jones, D. D., DeIulio, G. A. & Winslow, G. M. Antigen-driven induction of polyreactive IgM during intracellular bacterial infection. J. Immunol. 189, 1440–1447 (2012).
Mouquet, H. & Nussenzweig, M. C. Polyreactive antibodies in adaptive immune responses to viruses. Cell. Mol. Life Sci. 69, 1435–1445 (2012).
Warter, L., Appanna, R. & Fink, K. Human poly- and cross-reactive anti-viral antibodies and their impact on protection and pathology. Immunol. Res. 53, 148–161 (2012).
Trama, A. M. et al. HIV-1 envelope gp41 antibodies can originate from terminal ileum B cells that share cross-reactivity with commensal bacteria. Cell Host Microbe 16, 215–226 (2014).
Vogt, A. D. & Di Cera, E. Conformational selection is a dominant mechanism of ligand binding. Biochemistry 52, 5723–5729 (2013).
Calarese, D. A. et al. Antibody domain exchange is an immunological solution to carbohydrate cluster recognition. Science 300, 2065–2071 (2003). This paper reveals that a broadly neutralizing HIV-1 antibody uses V-domain swapping for achievement of high-affinity binding to a carbohydrate epitope on the surface of gp120.
Calarese, D. A. et al. Dissection of the carbohydrate specificity of the broadly neutralizing anti-HIV-1 antibody 2G12. Proc. Natl Acad. Sci. USA 102, 13372–13377 (2005).
Barnes, C. O. et al. Structural characterization of a highly-potent V3-glycan broadly neutralizing antibody bound to natively-glycosylated HIV-1 envelope. Nat. Commun. 9, 1251 (2018).
Imkeller, K. et al. Antihomotypic affinity maturation improves human B cell responses against a repetitive epitope. Science 360, 1358–1362 (2018). This study demonstrates that homotypic interaction between V regions of two different antibody molecules facilitates recognition of repetitive antigens.
Zhou, T., Hamer, D. H., Hendrickson, W. A., Sattentau, Q. J. & Kwong, P. D. Interfacial metal and antibody recognition. Proc. Natl Acad. Sci. USA 102, 14575–14580 (2005).
Wojciak, J. M. et al. The crystal structure of sphingosine-1-phosphate in complex with a Fab fragment reveals metal bridging of an antibody and its antigen. Proc. Natl Acad. Sci. USA 106, 17717–17722 (2009). References 82 and 83 show that certain antibodies use Ca 2+ ions as an interfacial cofactor for antigen recognition.
Stearns, D. J., Kurosawa, S., Sims, P. J., Esmon, N. L. & Esmon, C. T. The interaction of a Ca2+-dependent monoclonal antibody with the protein C activation peptide region. Evidence for obligatory Ca2+ binding to both antigen and antibody. J. Biol. Chem. 263, 826–832 (1988).
Dimitrov, J. D. et al. Ferrous ions and reactive oxygen species increase antigen-binding and anti-inflammatory activities of immunoglobulin G. J. Biol. Chem. 281, 439–446 (2006).
Baker, H., Frank, O., Feingold, S. & Leevy, C. M. Vitamin distribution in human plasma proteins. Nature 215, 84–85 (1967).
Innis, W. S., McCormick, D. B. & Merrill, A. H. Jr. Variations in riboflavin binding by human plasma: identification of immunoglobulins as the major proteins responsible. Biochem. Med. 34, 151–165 (1985).
Watson, C. D. & Ford, H. C. High-affinity binding of riboflavin and FAD by immunoglobulins from normal human serum. Biochem. Int. 16, 1067–1074 (1988).
Nieva, J., Kerwin, L., Wentworth, A. D., Lerner, R. A. & Wentworth, P. Jr. Immunoglobulins can utilize riboflavin (Vitamin B2) to activate the antibody-catalyzed water oxidation pathway. Immunol. Lett. 103, 33–38 (2006).
Stoppini, M. et al. Characterization of the two unique human anti-flavin monoclonal immunoglobulins. Eur. J. Biochem. 228, 886–893 (1995).
Zhu, X. et al. Cofactor-containing antibodies: crystal structure of the original yellow antibody. Proc. Natl Acad. Sci. USA 103, 3581–3585 (2006).
Rajagopalan, K. et al. Novel unconventional binding site in the variable region of immunoglobulins. Proc. Natl Acad. Sci. USA 93, 6019–6024 (1996).
Karjalainen, K. & Makela, O. Concentrations of three hapten-binding immunoglobulins in pooled normal human serum. Eur. J. Immunol. 6, 88–93 (1976).
McEnaney, P. J., Parker, C. G., Zhang, A. X. & Spiegel, D. A. Antibody-recruiting molecules: an emerging paradigm for engaging immune function in treating human disease. Chem. Biol. 7, 1139–1151 (2012).
Dimitrov, J. D. et al. Antibodies use heme as a cofactor to extend their pathogen elimination activity and to acquire new effector functions. J. Biol. Chem. 282, 26696–26706 (2007). This study shows that some antibodies use haem as a cofactor for the diversification of antigen-binding specificity.
Wagener, F. A. et al. Different faces of the heme-heme oxygenase system in inflammation. Pharmacol. Rev. 55, 551–571 (2003).
Soares, M. P. & Bozza, M. T. Red alert: labile heme is an alarmin. Curr. Opin. Immunol. 38, 94–100 (2016).
Roumenina, L. T., Rayes, J., Lacroix-Desmazes, S. & Dimitrov, J. D. Heme: modulator of plasma systems in hemolytic diseases. Trends Mol. Med. 22, 200–213 (2016).
McIntyre, J. A. The appearance and disappearance of antiphospholipid autoantibodies subsequent to oxidation—reduction reactions. Thromb. Res. 114, 579–587 (2004).
McIntyre, J. A., Wagenknecht, D. R. & Faulk, W. P. Autoantibodies unmasked by redox reactions. J. Autoimmun. 24, 311–317 (2005).
McIntyre, J. A., Wagenknecht, D. R. & Faulk, W. P. Redox-reactive autoantibodies: detection and physiological relevance. Autoimmun. Rev. 5, 76–83 (2006).
McIntyre, J. A. & Faulk, W. P. Redox-reactive autoantibodies: biochemistry, characterization, and specificities. Clin. Rev. Allergy Immunol. 37, 49–54 (2009).
Lecerf, M. et al. Prevalence and gene characteristics of antibodies with cofactor-induced HIV-1 specificity. J. Biol. Chem. 290, 5203–5213 (2015).
Gupta, N. et al. Neutralization of Japanese encephalitis virus by heme-induced broadly reactive human monoclonal antibody. Sci. Rep. 5, 16248 (2015).
Hadzhieva, M. et al. Mechanism and functional implications of the heme-induced binding promiscuity of IgE. Biochemistry 54, 2061–2072 (2015).
Dimitrov, J. D. et al. A cryptic polyreactive antibody recognizes distinct clades of HIV-1 glycoprotein 120 by an identical binding mechanism. J. Biol. Chem. 289, 17767–17779 (2014).
Kuhl, T. & Imhof, D. Regulatory Fe(II/III) heme: the reconstruction of a molecule’s biography. Chembiochem 15, 2024–2035 (2014).
Djoumerska-Alexieva, I., Roumenina, L. T., Stefanova, T., Vassilev, T. & Dimitrov, J. D. Heme-exposed pooled therapeutic IgG improves endotoxemia survival. Inflammation 40, 117–122 (2017).
Pavlovic, S. et al. Intravenous immunoglobulins exposed to heme (heme IVIG) are more efficient than IVIG in attenuating autoimmune diabetes. Clin. Immunol. 138, 162–171 (2010).
Vihinen, M., Torkkila, E. & Riikonen, P. Accuracy of protein flexibility predictions. Proteins 19, 141–149 (1994).
Radivojac, P. et al. Protein flexibility and intrinsic disorder. Protein Sci. 13, 71–80 (2004).
Sigounas, G., Harindranath, N., Donadel, G. & Notkins, A. L. Half-life of polyreactive antibodies. J. Clin. Immunol. 14, 134–140 (1994).
Robin, G. et al. Restricted diversity of antigen binding residues of antibodies revealed by computational alanine scanning of 227 antibody-antigen complexes. J. Mol. Biol. 426, 3729–3743 (2014).
Hong, B. et al. In-depth analysis of human neonatal and adult IgM antibody repertoires. Front. Immunol. 9, 128 (2018).
Brooks, C. L., Rossotti, M. A. & Henry, K. A. Immunological functions and evolutionary emergence of heavy-chain antibodies. Trends Immunol. 39, 956–960 (2018).
Wang, F. et al. Reshaping antibody diversity. Cell 153, 1379–1393 (2013).
de Villartay, J. P., Fischer, A. & Durandy, A. The mechanisms of immune diversification and their disorders. Nat. Rev. Immunol. 3, 962–972 (2003).
Westra, E. R., Sunderhauf, D., Landsberger, M. & Buckling, A. Mechanisms and consequences of diversity-generating immune strategies. Nat. Rev. Immunol. 17, 719–728 (2017).
Benedict, C. L., Gilfillan, S., Thai, T. H. & Kearney, J. F. Terminal deoxynucleotidyl transferase and repertoire development. Immunol. Rev. 175, 150–157 (2000).
Neuberger, M. S. Antibody diversification by somatic mutation: from Burnet onwards. Immunol. Cell. Biol. 86, 124–132 (2008).
Peled, J. U. et al. The biochemistry of somatic hypermutation. Annu. Rev. Immunol. 26, 481–511 (2008).
Scheid, J. F. et al. Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science 333, 1633–1637 (2011).
Pettersen, E. F. et al. UCSF Chimera — a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).
Dimitrov, J. D. & Vassilev, T. L. Cofactor-mediated protein promiscuity. Nat. Biotechnol. 27, 892 (2009).
Sivasubramanian, A., Sircar, A., Chaudhury, S. & Gray, J. J. Toward high-resolution homology modeling of antibody Fv regions and application to antibody-antigen docking. Proteins 74, 497–514 (2009).
Grosdidier, A., Zoete, V. & Michielin, O. SwissDock, a protein-small molecule docking web service based on EADock DSS. Nucleic Acids Res. 39, W270–W277 (2011).
Acknowledgements
This work was supported by INSERM, France, and a European Research Council Starting Grant (Project CoBABATI ERC-StG-678905 to J.D.D.).
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Nature Reviews Immunology thanks G. Alter, P. Wilson and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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All authors contributed to writing the article. J.D.D. and S.L.-D. were involved in discussing the content of the article and in researching data for the article. J.D.D., A.K. and S.L.-D. contributed to the review and editing of the manuscript before submission.
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Glossary
- Elbow region
-
A region of immunoglobulin molecule situated between the variable domain and the first constant domain.
- Activation-induced cytidine deaminase
-
(AID). An enzyme responsible for the introduction of somatic mutations in variable regions and for a class switch of immunoglobulins.
- Paratope
-
The part of the antigen-binding site of an antibody molecule that is directly involved in interaction with the target antigen.
- Epitope
-
The part of the antigen that is recognized by the paratope of an antibody, that is, the complementary part of the paratope.
- γ-Globulin fraction
-
A fraction of human serum that consists mainly of immunoglobulins.
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Kanyavuz, A., Marey-Jarossay, A., Lacroix-Desmazes, S. et al. Breaking the law: unconventional strategies for antibody diversification. Nat Rev Immunol 19, 355–368 (2019). https://doi.org/10.1038/s41577-019-0126-7
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DOI: https://doi.org/10.1038/s41577-019-0126-7
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