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Breaking the law: unconventional strategies for antibody diversification


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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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.

Correspondence to Jordan D. Dimitrov.

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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.


The part of the antigen-binding site of an antibody molecule that is directly involved in interaction with the target antigen.


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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Further reading

Fig. 1: Diversification of antibody specificity by incorporation of non-immunoglobulin sequences in the V region.
Fig. 2: Diversification of antibody specificity through post-translational modifications in the antigen-binding site.
Fig. 3: Diversification of antibody specificity by conformational dynamics and reconfiguration of the antigen-binding site.
Fig. 4: Diversification of antibody specificity by use of cofactor molecules.
Fig. 5: Different levels of diversification of antibody repertoires.