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Immunoglobulins
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
If a group of H or L chain V region amino acid sequences are compared to one another, a greater variety of amino acids occur in certain positions in the sequence. These highly variable areas are designated the hypervariable regions. Intervening between them are the less variable framework regions. It is the hypervariable regions which make contact with antigen. For this reason, they are frequently referred to as complementarity-determining regions (CDR’s, Figure 4–9, also see above).
High-Dose Immune Suppression without Hematopoietic Stem Cells for Autoimmune Diseases
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
More direct data implicating aplastic anemia as an autoimmune disease comes from studies examining T cell diversity using complementarity-determining region (CDR3) spectratyping.12-14 Mature T cells interact through the T cell receptor, a heterodimer comprised of α and β chains. Normally, the diversity of the T cell repertoire is the consequence of somatic recombination events and random nucleotide additions that occur during the joining of the variable (V), diverse (D) and joining (J) segments from the β-chain, and of V and J segments from the α-chain. The hypervariable regions of V-D-J segments termed, CDR3, are responsible for T cell receptor antigen specificity. During normal differentiation, T cells encounter myriad different antigens which results in a polyclonal profile of T cell receptors. When T cells encounter an incriminating foreign antigen or an autoantigen, the preferential expansion of antigen-specific T cells leads to skewing of the T cell repertoire and this can be detected by CDR3 spectratyping. In aplastic anemia, CDR3 spectratyping demonstrates limited heterogeneity of the T cell receptor β-chain (BV), suggesting that there is oligoclonal or even clonal expansion of T cells in response to a specific antigen.12,13,15 Isolated T cell clones from aplastic anemia patients secrete Th1 cytokines and are capable of lysing autologous CD34 cells.14,16 Hence, there is now compelling data to classify acquired aplastic anemia as an autoimmune disease.
Immunoglobulins: Structure and diversity
Published in Gabriel Virella, Medical Immunology, 2019
Actually, certain sequence stretches of the variable regions vary widely from protein to protein, even among proteins sharing the same type of variable regions. For this reason, these highly variable stretches have been designated as hypervariable regions (Figure 5.10). The structure of hypervariable regions is believed to play a critical role in determining antibody specificity, since these regions are believed to be folded in such a way that they determine the three-dimensional structure of the “pouch” where a given epitope of an antigen will fit. In other words, the hypervariable regions will interact to create a paratope whose configuration is complementary to that of a given epitope. Thus, these regions can be also designated as complementarity-determining regions (CDRs). A paratope is determined by three CDR regions (1, 2, 3). CD1 and CD2 are mainly formed by hypervariable regions, while CDR3, the most variable of them, is formed by hypervariable regions but also by other regions of light- and heavy-chain molecules known as diversity and joining regions, described in detail in Chapter 7.
Progress and challenges for the machine learning-based design of fit-for-purpose monoclonal antibodies
Published in mAbs, 2022
Rahmad Akbar, Habib Bashour, Puneet Rawat, Philippe A. Robert, Eva Smorodina, Tudor-Stefan Cotet, Karine Flem-Karlsen, Robert Frank, Brij Bhushan Mehta, Mai Ha Vu, Talip Zengin, Jose Gutierrez-Marcos, Fridtjof Lund-Johansen, Jan Terje Andersen, Victor Greiff
Many-to-many binding: Antibody-antigen binding is mediated by the interaction of AAs at the paratope–epitope interface of the complex. Antibody binding to the epitope is mainly formed by the three hypervariable regions termed complementarity-determining regions (CDRs) situated in each of the antibody heavy and light chains.43 The CDR3 on the heavy chain (CDR3H) is obligate for epitope binding and is on average 15-17 AAs long.44,45 Given that the diversity of antigens is even larger, the recognition of the majority of antigens encountered is ensured by antibody cross-reactivity, which means they may bind multiple epitopes on different proteins with high affinity.46 Epitope binding is therefore encoded in higher-order complex dependencies (correlations between spatially distant AAs in the CDRH3 enabling the binding of conformational epitopes, allowing a higher combination of binding motifs) in the low dimensionality of the antibody sequence space. These strong dependencies reflect 3D binding, where residues that are distant along the sequence can be close in the folded 3D structure. Indeed, the majority of antibody epitopes are thought to be conformational47 – although 85% of epitopes contain one or several contiguous (linear) epitope stretches.45,48 Therefore, to learn the rules of antibody-antigen binding, approaches need to be developed that untangle the non-linear sequence dependencies that govern the antibody, antigen, and antibody-antigen structures in both bound49,50 and unbound51 states.
A perspective toward mass spectrometry-based de novo sequencing of endogenous antibodies
Published in mAbs, 2022
Sebastiaan C. de Graaf, Max Hoek, Sem Tamara, Albert J. R. Heck
Although antibody sequencing at the protein level is still not trivial, it is being applied on a steadily increasing scale in academia and industry. Efforts to extend the sequencing of antibodies to polyclonal mixtures have, however, proven extremely challenging. The first obstacle is sample availability. While recombinant mAb samples are typically available in milligram quantities, polyclonal antibody samples are often derived from clinical samples and thus only available in limited quantities. Because the median concentration of individual clones in plasma is ~1 µg/mL the available protein per individual clone is generally orders of magnitude less compared to mAbs.31 Furthermore, isolation of individual clones is extremely challenging, further complicating the sequencing process, as most software tools are exclusively designed for assembling a single antibody, and therefore fail when data represent several similar Ig sequences. Additionally, in complex endogenous polyclonal antibody mixtures, key sequence evidence on the hypervariable regions is often not detected due to a dilution effect, whereby sequence information from the conserved regions becomes amplified (as the latter is present in every clone) and thus suppresses the signal of the CDRs, which are unique for all clones. Even though the algorithms developed for mAb sequencing are not directly applicable for polyclonal antibody sequencing, they provide a great starting point for developing new tools.
Forensic evaluation of mitochondrial DNA heteroplasmy in Gujarat population, India
Published in Annals of Human Biology, 2022
Mohammed H. M. Alqaisi, Molina Madhulika Ekka, Bhargav C. Patel
The non-coding region (D-loop) is a regulatory region that contains the origin of replication (Anderson et al. 1981; Holland and Parsons 1999; Barshad et al. 2018). It is highly polymorphic and hence referred to as a hypervariable region. There are three hypervariable regions in D-loop: hypervariable region one (HV1) at position 16024–16365, hypervariable region two (HV2) at position 73–340, and hypervariable region three (HV3) at position 340–576 (Greenberg et al. 1983; Wilkinson-Herbots et al. 1996; Ingman and Gyllensten 2003). Genetic variation in the hypervariable regions of mtDNA confers discriminating power in forensic analysis. These variations (polymorphisms) can be used by an investigator to learn more about the genealogy and ethnicity of the questioned sample (Parson and Bandelt 2007; Lee et al. 2011; Amorim et al. 2019). However, when it comes to heteroplasmy, difficulties with mtDNA analysis remain unresolved in court. Thus, it is crucial to analyse heteroplasmy when determining the forensic importance of mtDNA polymorphisms, even more so when the questioned and reference samples differ in the presence of heteroplasmy, which confers inconclusive results in forensic analysis (Nilsson 2007; Parson and Bandelt 2007a).