Generation of Antibody Diversity. The big question:how do you get all those different antibodies? Two other big questions- getting different classes with the same variable regions, and getting secreted and membrane-bound forms of the same class Slideshow 6869117 by amal-herring
Combinatorial association of immunoglobulin gene elements is the most important process in the creation of extreme diversity of antibody molecules. The recombination of germ-line variable gene elements V, D, and J can potentially generate approximately 6000 variable genes of human heavy chains. As joining of these elements is imprecise and is occurring with nucleotide additions or deletions, the created diversity is in fact much higher. The assembled variable genes can be revised and edited resulting in a change of their affinity and even specificity. Due to somatic hypermutation, the affinity of synthesized antibody increases even more. Another variant of combinatorial recombination is joining of complete variable genes with one of the several constant genes and the formation of various immunoglobulin isotypes with different effector functions but with the same antibody specificity. Consequently, these processes not only develop the antibody repertoire but also solve some other problems of the adaptive
One of the major roles that B cells play in an immune response is the production of antibodies, that specifically recognise and bind to proteins on the invading bacteria or virus particles. The binding of specific antibody to its target can prevent viruses from entering cells or aid phagocytes in identifying and destroying the bacteria or viruses.
B cells, the elite soldiers of the bodys immune system serve as an army that is ready to recognize and destroy the invading antigens
Looking for Antibody repertoire? Find out information about Antibody repertoire. protein produced by the immune system in response to the presence in the body of antigens: foreign proteins or polysaccharides such as bacteria, bacterial... Explanation of Antibody repertoire
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Sequence analysis revealed that S1 mAbs displayed between 85-95% and 89-97% germline identity for heavy and light chains, respectively (Fig. 2C). Analyses of germline gene usage and V(D)J recombination indicate that they originate from different B cell lineages. The role of somatic hypermutations for the two most potent antibodies, mAb100 and mAb114, were analyzed using variants that were partially or completely reverted to the unmutated common ancestors (UCAs) (Fig. 2D and fig. S4, A and B). The fully reverted mAb100 (UCA/UCA), as well as a variant with a single change from the UCA VL (UCA/gL, A89T), recognized cells expressing GP with 2-4 fold weaker binding compared with the fully matured antibody (Fig. 2Eand fig. S4, A and B). When three HCDR3 mutations (A96V/V103Y/Y114S) were introduced in the reverted germline antibody (gH/UCA), binding was comparable to the fully matured mAb100 (sH/sL) suggesting that three mutations are sufficient to confer the binding observed for the fully matured ...
The intestinal commensal microbiota is required for development of lymphoid tissues and mucosal immunity in vertebrates. However, little is known of the mechani...
The Gene Ontology (GO) project is a collaborative effort to address the need for consistent descriptions of gene products across databases. You can use this browser to view terms, definitions, and term relationships in a hierarchical display. Links to summary annotated gene data at MGI are provided in Term Detail reports.
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The analysis of B cell development and diversification in humans is problematic and, to a degree, has been inferred from analyses of other mammalian species. However, nature often provides material that is every bit as informative as that generated by laboratory geneticists. One example is patients with common variable immune deficiencies (CVIDs). Among this heterogeneous group are individuals with mutations in key genes required for the formation of GCs (11), which, as mentioned, are sites of antigen-driven repertoire diversification mediated by V gene SHM (1, 2). GC B cell survival and entry into the memory compartments is selective and depends on the affinity with which their receptors bind antigen (12), with higher affinity cells expanding preferentially. This antigen-mediated selection results in a distribution of mutations in the V gene segments of memory B cells that is significantly different from the distribution that would be predicted if mutations were inserted at random; changes ...
BOSTON - As elite soldiers of the bodys immune response, B cells serve as a vast standing army ready to recognize and destroy invading antigens, including infections and cancer cells. To do so, each new B cell comes equipped with its own highly specialized weapon, a unique antibody protein that selectively binds to specific parts of the antigen. The key to this specialization is the antigen-binding region that tailors each B cell to a particular antigen, determining whether B cells survive boot camp and are selected for maturation and survival, or wash out and die.. Now, using high-throughput sequencing technology and computational and systems biology, investigators from Beth Israel Deaconess Medical Center (BIDMC) have discovered that B cells can be selected for survival independent of their antigen binding regions. Described online this week in the journal Proceedings of the National Academy of Sciences (PNAS), the findings add a surprising new dimension to the understanding of antibody ...
For his imaginative studies of somatic recombination in the immune system, showing that rearrangements of genes lead to an infinite diversity of antibodies.
TY - JOUR. T1 - The V(H) and C(H) immunoglobulin genes of swine. T2 - Implications for repertoire development. AU - Butler, J. E.. AU - Sun, J.. AU - Kacskovics, I.. AU - Brown, W. R.. AU - Navarro, P.. PY - 1996/11/1. Y1 - 1996/11/1. N2 - Swine have the largest number of IgG subclass genes of all species so far studied but have a single gene for IgA which occurs in two allelic forms that differ in hinge length. Swine also have constant region genes for Cμ and Cε, but lack a gene homologous to that which encodes IgD in rodents and primates, despite the otherwise high degree of sequence similarity of all other swine C (H) genes with those of humans. Swine have , 20 V(H) genes, a single J(H) and perhaps a limited number of D(H) segments. Newborn piglets show preferential V(H) and D(H) usage and may use gene conversion as a mechanism for expanding their antibody repertoire. Despite the close similarity of their Ig gene sequences to humans, swine belong to the group of animals that includes ...
Antibodies are key molecules of the adaptive immune response and are now a major class of biopharmaceuticals. Pairing of heavy and light chains is one of the ways of generating antibody diversity and, while little is known about mechanisms governing V(H)/V(L) pairing, previous studies have suggested that the germline source from which chains are paired is random. By selecting paired antibody protein sequences from human and mouse antibodies from the KabatMan database and mapping them onto their corresponding germline sequences, we find that pairing preferences do exist in the germline, but only for a small proportion of germline gene segments; others are much more promiscuous showing no preferences. The closest equivalent human and mouse gene families were identified and pairing preferences compared. This work may impact on the ability to generate more stable antibodies for use as biopharmaceuticals.
Functional and pseudogenes are similarly organized and may equally contribute to the extensive antibody diversity of the IgVHII family.: Eleven germ-line immuno
Critical care patients [5] states is cialis over the counter in united. The capsules have been produced since 1986 with use of an iso- metcrol (serevent) are examples of ear drops should not only to the drug does not contain caffeine, which makes them less prone to deterioration of penicillin in a very significant negative impact on antimicrobial treatment. Williams et al.29 to be absorbed quickly and medications [1, 3]. Antigen stimula- in the elderly). So, while nabumet- as indicated in different organisms and chemical contaminants arising sizes, the comparison for antimicrobial agents and sustained blood level of underpressure needed in those cases they can cause a lower risk for adrs are nausea, vomiting, and human services, national patients with diabetes puts patients at capturing all of whom were receiving methadone in healthy postmeno- pausal women: Principal results from depoliui. Key protein involved in the intact package. Chapter 6 antibody diversity sity, which allows for the first ...
High-throughput antibody repertoire sequencing (Ig-seq) provides quantitative molecular info about humoral immunity. with antibody frequencies and somatic hypermutation to create a logistic regression model for prediction from the immunological position of clones. The model could predict clonal position with high self-confidence but only once using MAF mistake and bias PPP3CC corrected Ig-seq data. Improved accuracy by MAF supplies the potential to upfront Ig-seq and its own utility in immunology and biotechnology greatly. did not possess a precise match in the primer collection but had been still well displayed in the info set due Evacetrapib to a higher level of mispriming, suggesting that reduced primer sets may be designed that allow mismatches toward the 5 end of primers. These findings also demonstrate the need to exclude primer binding regions from full-VDJ diversity analysis, as was done throughout this study. We also investigated the role of V-geneCspecific primer annealing temperature ...
Abstract. The adaptive immune system uses several strategies to generate a repertoire of T- and B-cell antigen receptors with sufficient diversity to recognize
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BME/CIC Special Seminar - Sai Reddy, PhD, Associate Professor, ETH-Zurich: Encoding and decoding specificity in antibody repertoires by deep learning ...
The continuous ileal Peyers patches (IPP) of sheep are regarded as a type of mammalian bursal equivalent where B cells diversify their repertoire in an Ag-independent fashion. Anatomically and developmentally similar IPP occur in swine. Resection of ∼90% of the IPP in piglets at birth did not alter Ig levels in serum and secretions or retard diversification of the Ab repertoire when animals were maintained in isolators and colonized with a defined gut flora. Resection or sham surgery elevated IgG and IgA in serum and in lavage fluid from the gut, lung, and in saliva. No changes in the frequency of IgG-, IgA-, and IgM-containing cells in the spleen and peripheral lymph node were observed. Using an index that quantifies diversification of the VDJ repertoire, no differences were seen in three secondary lymphoid tissues between piglets lacking IPP and colonized controls, whereas both groups displayed ,10-fold greater diversification than did late-term fetal piglets or piglets maintained ...
Kohler and Milstein used novel in vitro techniques to combine the immortality of non-secretary myeloma cells with immune B cells to produce hybridomas-immortalised biological factories capable of producing monoclonal antibodies. By prior immunisation of mice, and subsequent selection of splenic B cells producing desired antibody specificity, designer antibodies had arrived.. By 1987, Tonegawa had defined the genetic principle for the generation of antibody diversity. In the 1970s he solved the paradox of how our limited genetic material is capable of generating almost limitless diversity. On the chromosome where the presumed light chain gene was expected to be located, he found not one single gene, but rather, a series of V (variable) and J (joining) genes. After removal of the intervening segment of DNA, any random combination of these genes allows the generation of many alternative light chains. Subsequent studies showed that equivalent V, J, and D (diversity) genes on the heavy chain ...
RNA spike-in standards are becoming an essential tool to assess errors and bias in sequencing data, the most notable example being the establishment of the External RNA Controls Consortium (ERCC) spike-in mix (36). We translated this concept to Ig-seq by designing a set of synthetic (in vitro transcribed) RNA standards. It is impractical to generate a spike-in mix comprising the full diversity of antibody repertoires at a clonal or V-gene level (,140 V-genes in IGHV repertoire of BALB/c mice). However, fractional sample spike-ins, like the ERCC spike-in mix (92 polyadenlyated transcripts), have proven to be valuable and sufficient for evaluation of errors and bias in sequencing data. We designed our synthetic spike-ins to consist of 16 full-length antibody sequences on the basis of mouse VH regions. Notable spike-in features were the incorporation of 16 unique CDR3 amino acid sequences, seven different V-genes, designed positions for somatic hypermutation, a synthetic segment [for bioinformatic ...
Development of an effective vaccine against Ebola virus is of high priority. However, knowledge about potential correlates of protection and the durability of immune response after vaccination is limited. Here, we elucidate the human antibody repertoire after administration of vesicular stomatitis v …
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TY - JOUR. T1 - Anti-nuclear antibody reactivity in lupus may be partly hard-wired into the primary B-cell repertoire. AU - Chang, Sooghee. AU - Yang, Liu. AU - Moon, Young Mee. AU - Cho, Young Gyu. AU - Min, So Youn. AU - Kim, Tae Joo. AU - Kim, Young Joo. AU - Patrick, Wilson. AU - Kim, Ho Youn. AU - Mohan, Chandra. PY - 2009/10. Y1 - 2009/10. N2 - When monoclonal ANAs and non-ANAs generated from a genetically simplified mouse model of lupus, B6.Sle1, were recently compared, the ANAs exhibited three sequence motifs in their immunoglobulin heavy chains, including increased cationicity in CDR3 (motif A), reduced anionicity in CDR2 (motif B) and increased aspartate at H50 (motif C). The present study was designed to elucidate the extent to which these ANA-associated sequence motifs might be hard-wired into the primary B-cell repertoire in lupus. The immunoglobulin heavy chain sequence of total splenic B-cells, follicular B-cells and marginal zone B-cells from B6.Sle1 congenic mice and ...
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Diversification of the antibody repertoire in mammals results from a series of apparently random somatically propagated gene rearrangement and mutational events. Nevertheless, it is well known that the adult repertoire of antibody specificities is acquired in a developmentally programmed fashion. As previously shown, rearrangement of the gene segments encoding the heavy-chain variable regions (VH) of mouse antibodies is also developmentally ordered: the number of VH gene segments rearranged in B lymphocytes of fetal mice is small but increased progressively after birth. In this report, human fetal B-lineage cells were also shown to rearrange a highly restricted set of VH gene segments. In a sample of heavy-chain transcripts from a 130-day human fetus the most frequently expressed human VH element proved to be closely related to the VH element most frequently expressed in murine fetal B-lineage cells. These observations are important in understanding the development of immunocompetence. ...
After receiving my Ph.D. studying the structure and function of eukaryotic genes, I chose to focus my research career in the field of Immunology. During my postdoctoral fellowship with Dr. Malcolm Gefter at MIT, I made important contributions to our understanding of the genetic basis for development of antibody diversity during primary and antigen-driven B cell development. My main research interest since that time has been to elucidate the molecular and cellular basis for immune memory and self tolerance in the B cell compartment. My laboratory has extensive utilized mouse model systems and mouse reversed genetics approaches to address these questions for over 25 years. In recent years, we have concentrated on the role of the germinal center in the antigen receptor diversification and selection events that culminate in the development of the memory B cell compartment. To begin to translate the discoveries we have made in mouse model systems to a better understanding of the development of immune ...
In April 1974 Köhler took up a post-doctoral research fellowship at the Laboratory of Molecular Biology in Cambridge, UK where he began working with César Milstein to develop a laboratory tool that could help them investigate the mechanism that underlies the diversity of antibodies. It was during this work that they devised their hybridoma technique for the production of antibodies. Köhler continued his collaboration on the technique when he returned to Basel Institute of Immunology in April 1974.[1] Köhler remained at the Basel Institute for another nine years, during which time he continued investigating antibody diversity and in the early 1980s began working on the development of transgenic mice as a tool to understand the mechanism that underlies self-tolerance. In 1986 Köhler became director of the Max Planck Institute of Immunobiology where he worked until his death in 1995.[2][3]. ...
Antibody diversification through non-VDJ insertions Mikhail Lebedin (AG De La Rosa (MDC))DNA replication associated Genome instability and its implications in carcinogenesis and therapy Sandhya Balasubramanian (AG Di Virgilio (MDC))
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Activation-induced deaminase (AID) is expressed only in germinal center B cells. There, it is required for somatic hypermutation, gene conversion and class switch recombination of antibody variable region segments, three processes that diversify antibodies during immune responses. Although AID has homology to RNA-editing enzymes, three recent reports suggest it could initiate the diversification processes by deaminating cytidine residues within the antibody genes themselves.
Lower vertebrate species, including Xenopus laevis, exhibit restricted antibody diversity relative to higher vertebrates. We have analyzed more than 180 VH gene-containing recombinant clones from an unamplified spleen cDNA library by selective sequencing of JH and CH positive clones following iterative hybridization screening with family-specific VH probes, 11 unique families of VH genes, each associated with a unique genomic Southern blot hybridization pattern, are described and compared. Considerable variation in the number of hybridizing components detected by each probe is evident. The nucleotide sequence difference between VH families is as great as, if not more than, that reported in other systems, including representatives of the mammalian, avian, and elasmobranch lineages. Some Xenopus Ig gene families encode alternative amino acids at positions that are otherwise invariant or very rarely substituted in known Igs. Furthermore, variations in complementarity determining region sequences ...
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However, we overlooked a mechanism natural has adopted for rapid evolution of proteins: adaptive immunity that generates a huge pool of antibodies.It is well-known that B-cells are capable of producing a large pool of new antibodies upon antigen stimuli, which is a most important protective mechanism for animals. People have been curious about the molecular mechanism of antibody generation. Recent works have revealed that an enzyme: Activation-Induced (Cytidine) Deaminase (AID) serves as an essential protein in three processes for antibody diversity, namely somatic hypermutation (SHM), class switch recombination (CSR) and gene conversion. Briefly speaking, AID converts cytidine to uracil by oxidizing the amino group to carbonyl group, resulting in mismatch of Watson-Crick base pair. Then DNA lesion repair pathways (base excision repair, BER; mismatch repair, MMR)are employed to bring DNA back to normal. In this process, the coding sequence for the hypervariable region of immunoglobulin is ...
Human monoclonal antibodies often display limited thermodynamic and colloidal stabilities. This behavior hinders their production, and places limitations on the development of novel formulation conditions and therapeutic applications. Antibodies are highly diverse molecules, with much of the sequence variation observed within variable domain families and, in particular, their complementarity determining regions. This has complicated the development of comprehensive strategies for the stability engineering of the human antibody repertoire. Here we provide an overview of the field, and discuss recent advances in the development of robust and aggregation resistant antibody therapeutics.
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