Structural Basis for the Recognition in an Idiotype-Anti- Idiotype Antibody Complex Related to Celiac Disease Anna Vangone 1¤ , Safwat Abdel-Azeim 2 , Ivana Caputo 1,3 , Daniele Sblattero 4 , Roberto Di Niro 5 , Luigi Cavallo 2,1 , Romina Oliva 6 * 1 Department of Chemistry and Biology, University of Salerno, Fisciano, Salerno, Italy, 2 Kaust Catalysis Center, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia, 3 European Laboratory for the Investigation of Food-Induced Diseases (ELFID), University Federico II, Naples, Italy, 4 Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara, Italy, 5 Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 6 Department of Sciences and Technologies, University ‘‘Parthenope’’ of Naples, Naples, Italy Abstract Anti-idiotype antibodies have potential therapeutic applications in many fields, including autoimmune diseases. Herein we report the isolation and characterization of AIM2, an anti-idiotype antibody elicited in a mouse model upon expression of the celiac disease-specific autoantibody MB2.8 (directed against the main disease autoantigen type 2 transglutaminase, TG2). To characterize the interaction between the two antibodies, a 3D model of the MB2.8-AIM2 complex has been obtained by molecular docking. Analysis and selection of the different obtained docking solutions was based on the conservation within them of the inter-residue contacts. The selected model is very well representative of the different solutions found and its stability is confirmed by molecular dynamics simulations. Furthermore, the binding mode it adopts is very similar to that observed in most of the experimental structures available for idiotype-anti-idiotype antibody complexes. In the obtained model, AIM2 is directed against the MB2.8 CDR region, especially on its variable light chain. This makes the concurrent formation of the MB2.8-AIM2 complex and of the MB2.8-TG2 complex incompatible, thus explaining the experimentally observed inhibitory effect on the MB2.8 binding to TG2. Citation: Vangone A, Abdel-Azeim S, Caputo I, Sblattero D, Di Niro R, et al. (2014) Structural Basis for the Recognition in an Idiotype-Anti-Idiotype Antibody Complex Related to Celiac Disease. PLoS ONE 9(7): e102839. doi:10.1371/journal.pone.0102839 Editor: Danilo Roccatano, Jacobs University Bremen, Germany Received April 6, 2014; Accepted June 21, 2014; Published July 30, 2014 Copyright: ß 2014 Vangone et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Funding: IC and RO were supported by the Italian MIUR (Ministero dell’Istruzione, dell’ Universita ` della Ricerca; Grant PRIN2008). RO was also supported by Regione Campania (LR5-2002-AF2008). DS was supported by EC Marie Curie Research Training Network (contract n. MRTN-CT-20010-289964). LC was supported by the King Abdullah University of Science and Technology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * Email: romina.oliva@uniparthenope.it ¤ Current address: Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands Introduction It has been long established that the structural basis for antigen (Ag) recognition by antibodies (Abs) relies on the length and sequence variability of the six Ab complementary determining regions (CDRs) [1]. Based on the combinatorial origin of this limited region, made by about 70 residues, antibodies are able to recognize almost an infinite variety of antigens, from small organic molecules to proteins. Interestingly, antibodies can be antigenic themselves, being recognized by other antibodies and thus creating a network, through which immunoglobulins expression may be controlled. According to the ‘‘idiotypic network hypothesis’’ [2], under specific immunological conditions, antigen stimulation leads to the production of idiotype antibodies (termed Ab1) against Ag, characterized by specific antigenic-determinants (the ‘‘idiotopes’’). The unique structure of the Ab1 antigen-binding site can generate in turn the production of a series of anti-idiotype antibodies, termed Ab2s, which are directed against the Ab1 antigenic- determinants (Figure 1a) and may or may not represent an image of the original Ag. Finally, anti-anti-idiotypes antibodies (Ab3s) can be induced by the presence of Ab2, which may have binding capabilities similar to those of Ab1, thus recognizing the original antigen. An anti-idiotype antibody can be classified as: i) ‘‘Ab2- alpha’’(Ab2a); ii) ‘‘Ab2-beta’’ (Ab2b); iii)‘‘Ab2-gamma’’ (Ab2c), on the basis of their ability to inhibit the binding of Ab1 to the original antigen (see Figure 1a) [3,4]. Several experimental evidences have demonstrated the crucial role played by the idiotypic Ab1-Ab2-Ab3 network in the regulation of immune response to both external and self antigens [4,5]. In recent years, extensive research has been devoted to the possible therapeutic application of anti-idiotype antibodies. Ab2s have been the basis for developing new generation vaccines [6,7] and novel therapeutic approaches for the treatment of tumours [7,8], such as breast cancer [9,10], colorectal carcinoma [11], melanoma and ovarian lymphoma [12,13]. They have also been suggested for the design of anti-HIV strategies for AIDS [14,15] and as potent anticoagulants to restore normal haemostasis [16]. The idiotypic network has also been shown to have a fundamental role in the autoimmune diseases. While the factors leading to the onset of the autoimmune response remain obscure, the idiotypic disregulation is now indeed recognized as a major PLOS ONE | www.plosone.org 1 July 2014 | Volume 9 | Issue 7 | e102839