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Human Monoclonal Antibodies and Immune Modulation in Viral Hepatitis, Schistosomiasis, and HTLV Infection
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Thomas F. Kresina, Garry A. Neil, Steven K. H. Foung
Human monoclonal antibodies from both EBV transformed cell lines and heterohybridomas which bind the nucleocapsid component of the hepatitis C virus [57] have been identified. An IgG1 kappa antibody, designated B12.F8, recognized native nucleoprotein expressed in transfected eukaryotic cells. Epitope mapping studies resolved a conformational epitope between residues 27 and 59, indicating that this antibody recognized a B cell epitope within the immunodominant nucleo-protein terminal subregion. Recent antibody engineering studies [58] have generated a recombinant human antibody using the cDNA coding for the Fab fragment of B12.F8. The recombinant antibody, B12Fab, recognized hepatitis C virus core protein produced in transfected cells, indicating that the antibody could be used as a tool for tissue localization of the virus. Furthermore, the antibody function, when displayed to phage particles, provided a basis for experiments of in vitro affinity maturation and selection of viral mutants.
Primary Biliary Cirrhosis Bench to Bedside
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Shinji Shimoda, Akiyoshi Nishio, Hiromi Ishibashi, M. Eric Gershwin
The E2 enzymes have a common structure, which consists of the N-terminal domain containing the lipoyl group(s); the peripheral subunit-binding domain, responsible, at least in part, for binding the E1 and E3 components together; and the C-terminal inner core domain, which houses the active site responsible for the acetyltransferase activity. Several studies using oligopeptides or recombinant proteins have shown that the predominant epitope of PDC-E2 is located within the lipoyl domain of PDC-E2.39 AMA also react with the outer lipoyl domain, but at a 100-fold lower titer, and only a minority of PBC sera reacts weakly to the E1/E3-binding domain. The mapping of B-cell epitopes using truncated constructs reveals that the reactive AMA to BCOADC-E2, OGDC-E2 and E3BP each also recognize a conformational epitope including the lipoyl domain.40–42 These domains contain the signature motifs of amino acids with lipoic acid covalently bound to lysine residue.
Immunoglobulins
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
We often visualize antibody combining sites as “grasping” since this is a comfortable conceptualization of a relatively stable noncovalent chemical interaction. This “lock and key” idea is also rooted in notions of enzyme and substrate complementarity which has many parallels with antibody-antigen interactions. However, not all epitopes conveniently protrude from an antigen’s surface so that they may be surrounded by CDR amino acid side chains as depicted in Figure 4–16. It is now also clear that paratope structures are not limited to concavities that “hold” epitopes. Combining sites may take on virtually any threedimensional shape. Consider the conformational epitope of hen egg lysozyme (HEL) described in Chapter 3 (Table 3–I). The CDR residues of a HEL-specific antibody making contact with this epitope are listed in Table 4–IV. In this case, the antigen-antibody interaction occurs over a planar surface approximately 750 A2 in area.
Deciphering cross-species reactivity of LAMP-1 antibodies using deep mutational epitope mapping and AlphaFold
Published in mAbs, 2023
Tiphanie Pruvost, Magali Mathieu, Steven Dubois, Bernard Maillère, Emmanuelle Vigne, Hervé Nozach
Substitutions introduced into human LAMP-1 affected antibody recognition in at least two distinct ways. The first was by directly disrupting the interaction with the Fab via the introduction of a mutation in the epitope. The second affected antigen structure in such a way that it distorted the epitope and prevented Fab binding, with longer range effects at distances typically greater than 5 Å from the interface with the antibody. By distinguishing the amino acids present on the surface of LAMP-1 from those embedded in the hydrophobic core of the antigen, the structural information helped discriminate these two types of effects and allowed rapid identification of the ‘functional epitopes’ when adopting the terminology previously proposed by van Regenmortel.36 The DMS data were compared with the crystal structure of the complex between Fab B and the human LAMP-1 first luminal domain or with the AlphaFold model of the full human LAMP-1 protein for both Fabs. This showed that the two Fabs have a conformational epitope with amino acids spread in the primary sequence of the antigen which assemble into a continuous and discrete entity on the surface of the antigen, strongly suggesting the accuracy of the epitope.
Recent trends in next generation immunoinformatics harnessed for universal coronavirus vaccine design
Published in Pathogens and Global Health, 2023
Chin Peng Lim, Boon Hui Kok, Hui Ting Lim, Candy Chuah, Badarulhisam Abdul Rahman, Abu Bakar Abdul Majeed, Michelle Wykes, Chiuan Herng Leow, Chiuan Yee Leow
An epitope is the part of an antigen that is recognized by the adaptive immune system. It binds to specific receptors including antibodies, MHC molecules and T-cell receptors [28]. The binding portion of an antibody is termed a paratope. Epitopes can be either continuous or discontinuous. A continuous or linear epitope is a relatively short (usually 5–6) amino acid sequences recognized by the paratope of a corresponding antibody. In contrast, a discontinuous epitope consists of non-adjacent segments of amino acids, not necessarily from one chain, which form a specific 3D structure, which can also be recognized by antibodies. Since discontinuous epitope arises from a specific 3D fold, it is also known as conformational epitope. Notably, epitopes recognized by B-cell epitopes may contain lipids, nucleic acids or carbohydrates, giving resultant antibodies a vast repertoire while T-cell epitopes are usually peptide fragments. The investigation, identification and development of epitopes are crucial in promoting the advancement of diagnostics and therapeutics [110].
Reverse engineering approach: a step towards a new era of vaccinology with special reference to Salmonella
Published in Expert Review of Vaccines, 2022
Shania Vij, Reena Thakur, Praveen Rishi
The advancements in structural biology, B-cell technologies, and knowledge of pangenome have not only improved the assessment and prioritization of bacterial antigens as vaccine candidates but also enabled the better characterization of the immunogenicity of antigens that are identified using in-silico approaches. These advances have led to a new model for rational vaccine design, which can be termed ‘Reverse vaccinology 2.0’ (Figure 3). In this approach, genomics is not only limited to antigen discovery but is also exploited for antigen expression, its conservation, and to have a better understanding of epidemiology. Human monoclonals are employed for the identification of epitopes or protective antigens. Antigen design is instructed after structural characterization of the antigen–antibody complex by conformational epitope mapping studies so as to come up with the atomic details of the immunogenic and protective epitopes, which can be easily recognized by broadly neutralizing antibodies. The incorporation of advanced approaches into the traditional RV scheme has led to reverse vaccinology 2.0 [181]. A schematic illustration of the reverse vaccinology 2.0 approach has been provided in Figure 4.