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High frequency of shared clonotypes in human B cell receptor repertoires.
Soto C, Bombardi RG, Branchizio A, Kose N, Matta P, Sevy AM, Sinkovits RS, Gilchuk P, Finn JA, Crowe JE
(2019) Nature 566: 398-402
MeSH Terms: Adult, Amino Acid Sequence, Antibodies, Antigens, B-Lymphocytes, Base Sequence, Clone Cells, Female, Fetal Blood, Healthy Volunteers, Humans, Infant, Newborn, Male, Receptors, Antigen, B-Cell, Sequence Analysis, DNA
Show Abstract · Added March 31, 2019
The human genome contains approximately 20 thousand protein-coding genes, but the size of the collection of antigen receptors of the adaptive immune system that is generated by the recombination of gene segments with non-templated junctional additions (on B cells) is unknown-although it is certainly orders of magnitude larger. It has not been established whether individuals possess unique (or private) repertoires or substantial components of shared (or public) repertoires. Here we sequence recombined and expressed B cell receptor genes in several individuals to determine the size of their B cell receptor repertoires, and the extent to which these are shared between individuals. Our experiments revealed that the circulating repertoire of each individual contained between 9 and 17 million B cell clonotypes. The three individuals that we studied shared many clonotypes, including between 1 and 6% of B cell heavy-chain clonotypes shared between two subjects (0.3% of clonotypes shared by all three) and 20 to 34% of λ or κ light chains shared between two subjects (16 or 22% of λ or κ light chains, respectively, were shared by all three). Some of the B cell clonotypes had thousands of clones, or somatic variants, within the clonotype lineage. Although some of these shared lineages might be driven by exposure to common antigens, previous exposure to foreign antigens was not the only force that shaped the shared repertoires, as we also identified shared clonotypes in umbilical cord blood samples and all adult repertoires. The unexpectedly high prevalence of shared clonotypes in B cell repertoires, and identification of the sequences of these shared clonotypes, should enable better understanding of the role of B cell immune repertoires in health and disease.
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15 MeSH Terms
Mimicry of an HIV broadly neutralizing antibody epitope with a synthetic glycopeptide.
Alam SM, Aussedat B, Vohra Y, Meyerhoff RR, Cale EM, Walkowicz WE, Radakovich NA, Anasti K, Armand L, Parks R, Sutherland L, Scearce R, Joyce MG, Pancera M, Druz A, Georgiev IS, Von Holle T, Eaton A, Fox C, Reed SG, Louder M, Bailer RT, Morris L, Abdool-Karim SS, Cohen M, Liao HX, Montefiori DC, Park PK, Fernández-Tejada A, Wiehe K, Santra S, Kepler TB, Saunders KO, Sodroski J, Kwong PD, Mascola JR, Bonsignori M, Moody MA, Danishefsky S, Haynes BF
(2017) Sci Transl Med 9:
MeSH Terms: Animals, Antibodies, Neutralizing, Antibody Specificity, B-Lymphocytes, Cell Lineage, Cell Separation, Clone Cells, Epitopes, Glycopeptides, HIV Antigens, HIV Envelope Protein gp120, HIV-1, Macaca mulatta, Molecular Mimicry, Protein Domains, Protein Multimerization
Show Abstract · Added May 3, 2017
A goal for an HIV-1 vaccine is to overcome virus variability by inducing broadly neutralizing antibodies (bnAbs). One key target of bnAbs is the glycan-polypeptide at the base of the envelope (Env) third variable loop (V3). We have designed and synthesized a homogeneous minimal immunogen with high-mannose glycans reflective of a native Env V3-glycan bnAb epitope (Man-V3). V3-glycan bnAbs bound to Man-V3 glycopeptide and native-like gp140 trimers with similar affinities. Fluorophore-labeled Man-V3 glycopeptides bound to bnAb memory B cells and were able to be used to isolate a V3-glycan bnAb from an HIV-1-infected individual. In rhesus macaques, immunization with Man-V3 induced V3-glycan-targeted antibodies. Thus, the Man-V3 glycopeptide closely mimics an HIV-1 V3-glycan bnAb epitope and can be used to isolate V3-glycan bnAbs.
Copyright © 2017, American Association for the Advancement of Science.
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16 MeSH Terms
Advanced Intestinal Cancers often Maintain a Multi-Ancestral Architecture.
Zahm CD, Szulczewski JM, Leystra AA, Paul Olson TJ, Clipson L, Albrecht DM, Middlebrooks M, Thliveris AT, Matkowskyj KA, Washington MK, Newton MA, Eliceiri KW, Halberg RB
(2016) PLoS One 11: e0150170
MeSH Terms: Adenocarcinoma, Adenoma, Animals, Carcinoma in Situ, Cell Lineage, Cell Transformation, Neoplastic, Clone Cells, Disease Models, Animal, Disease Progression, Evolution, Molecular, Fatty Acid-Binding Proteins, Female, Gene Expression Regulation, Neoplastic, Genes, APC, Genes, Reporter, Integrases, Intestinal Mucosa, Intestinal Neoplasms, Luminescent Proteins, Male, Mice, Mice, Inbred C57BL, Models, Biological, Mosaicism, Neoplasm Invasiveness, Neoplastic Stem Cells, RNA, Untranslated, Rats, Transgenes, Tumor Microenvironment
Show Abstract · Added April 12, 2016
A widely accepted paradigm in the field of cancer biology is that solid tumors are uni-ancestral being derived from a single founder and its descendants. However, data have been steadily accruing that indicate early tumors in mice and humans can have a multi-ancestral origin in which an initiated primogenitor facilitates the transformation of neighboring co-genitors. We developed a new mouse model that permits the determination of clonal architecture of intestinal tumors in vivo and ex vivo, have validated this model, and then used it to assess the clonal architecture of adenomas, intramucosal carcinomas, and invasive adenocarcinomas of the intestine. The percentage of multi-ancestral tumors did not significantly change as tumors progressed from adenomas with low-grade dysplasia [40/65 (62%)], to adenomas with high-grade dysplasia [21/37 (57%)], to intramucosal carcinomas [10/23 (43%]), to invasive adenocarcinomas [13/19 (68%)], indicating that the clone arising from the primogenitor continues to coexist with clones arising from co-genitors. Moreover, neoplastic cells from distinct clones within a multi-ancestral adenocarcinoma have even been observed to simultaneously invade into the underlying musculature [2/15 (13%)]. Thus, intratumoral heterogeneity arising early in tumor formation persists throughout tumorigenesis.
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30 MeSH Terms
Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion.
Delong T, Wiles TA, Baker RL, Bradley B, Barbour G, Reisdorph R, Armstrong M, Powell RL, Reisdorph N, Kumar N, Elso CM, DeNicola M, Bottino R, Powers AC, Harlan DM, Kent SC, Mannering SI, Haskins K
(2016) Science 351: 711-4
MeSH Terms: Amino Acid Sequence, Animals, C-Peptide, CD4-Positive T-Lymphocytes, Clone Cells, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Epitopes, Immune Tolerance, Insulin-Secreting Cells, Mice, Mice, Inbred NOD, Molecular Sequence Data, Peptides
Show Abstract · Added July 16, 2016
T cell-mediated destruction of insulin-producing β cells in the pancreas causes type 1 diabetes (T1D). CD4 T cell responses play a central role in β cell destruction, but the identity of the epitopes recognized by pathogenic CD4 T cells remains unknown. We found that diabetes-inducing CD4 T cell clones isolated from nonobese diabetic mice recognize epitopes formed by covalent cross-linking of proinsulin peptides to other peptides present in β cell secretory granules. These hybrid insulin peptides (HIPs) are antigenic for CD4 T cells and can be detected by mass spectrometry in β cells. CD4 T cells from the residual pancreatic islets of two organ donors who had T1D also recognize HIPs. Autoreactive T cells targeting hybrid peptides may explain how immune tolerance is broken in T1D.
Copyright © 2016, American Association for the Advancement of Science.
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14 MeSH Terms
Cloning and variation of ground state intestinal stem cells.
Wang X, Yamamoto Y, Wilson LH, Zhang T, Howitt BE, Farrow MA, Kern F, Ning G, Hong Y, Khor CC, Chevalier B, Bertrand D, Wu L, Nagarajan N, Sylvester FA, Hyams JS, Devers T, Bronson R, Lacy DB, Ho KY, Crum CP, McKeon F, Xian W
(2015) Nature 522: 173-8
MeSH Terms: Bacterial Toxins, Cell Differentiation, Cell Lineage, Cells, Cultured, Clone Cells, Clostridium difficile, Colon, Enterocolitis, Pseudomembranous, Epigenesis, Genetic, Epithelium, Fetus, Genomic Instability, Humans, Intestine, Small, Intestines, Organoids, Stem Cells
Show Abstract · Added September 28, 2015
Stem cells of the gastrointestinal tract, pancreas, liver and other columnar epithelia collectively resist cloning in their elemental states. Here we demonstrate the cloning and propagation of highly clonogenic, 'ground state' stem cells of the human intestine and colon. We show that derived stem-cell pedigrees sustain limited copy number and sequence variation despite extensive serial passaging and display exquisitely precise, cell-autonomous commitment to epithelial differentiation consistent with their origins along the intestinal tract. This developmentally patterned and epigenetically maintained commitment of stem cells is likely to enforce the functional specificity of the adult intestinal tract. Using clonally derived colonic epithelia, we show that toxins A or B of the enteric pathogen Clostridium difficile recapitulate the salient features of pseudomembranous colitis. The stability of the epigenetic commitment programs of these stem cells, coupled with their unlimited replicative expansion and maintained clonogenicity, suggests certain advantages for their use in disease modelling and regenerative medicine.
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17 MeSH Terms
Quantifying heterogeneity and dynamics of clonal fitness in response to perturbation.
Frick PL, Paudel BB, Tyson DR, Quaranta V
(2015) J Cell Physiol 230: 1403-12
MeSH Terms: Cell Culture Techniques, Cell Line, Cell Proliferation, Clone Cells, Cycloheximide, Gene Expression Regulation, Genetic Fitness, Humans, Protein Synthesis Inhibitors
Show Abstract · Added February 19, 2015
The dynamics of heterogeneous clonal lineages within a cell population, in aggregate, shape both normal and pathological biological processes. Studies of clonality typically relate the fitness of clones to their relative abundance, thus requiring long-term experiments and limiting conclusions about the heterogeneity of clonal fitness in response to perturbation. We present, for the first time, a method that enables a dynamic, global picture of clonal fitness within a mammalian cell population. This novel assay allows facile comparison of the structure of clonal fitness in a cell population across many perturbations. By utilizing high-throughput imaging, our methodology provides ample statistical power to define clonal fitness dynamically and to visualize the structure of perturbation-induced clonal fitness within a cell population. We envision that this technique will be a powerful tool to investigate heterogeneity in biological processes involving cell proliferation, including development and drug response.
© 2015 Wiley Periodicals, Inc.
2 Communities
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9 MeSH Terms
Bone morphogenetic protein type I receptor antagonists decrease growth and induce cell death of lung cancer cell lines.
Langenfeld E, Hong CC, Lanke G, Langenfeld J
(2013) PLoS One 8: e61256
MeSH Terms: Bone Morphogenetic Protein 2, Bone Morphogenetic Protein Receptors, Type I, Bronchi, Cell Death, Cell Line, Tumor, Cell Proliferation, Cell Survival, Clone Cells, Endothelial Cells, Epithelial Cells, Gene Knockdown Techniques, Humans, Inhibitor of Differentiation Proteins, Lung Neoplasms, Pyrazoles, Pyrimidines, Signal Transduction, Smad Proteins
Show Abstract · Added September 20, 2013
Bone morphogenetic proteins (BMPs) are highly conserved morphogens that are essential for normal development. BMP-2 is highly expressed in the majority of non-small cell lung carcinomas (NSCLC) but not in normal lung tissue or benign lung tumors. The effects of the BMP signaling cascade on the growth and survival of cancer cells is poorly understood. We show that BMP signaling is basally active in lung cancer cell lines, which can be effectively inhibited with selective antagonists of the BMP type I receptors. Lung cancer cell lines express alk2, alk3, and alk6 and inhibition of a single BMP receptor was not sufficient to decrease signaling. Inhibition of more than one type I receptor was required to decrease BMP signaling in lung cancer cell lines. BMP receptor antagonists and silencing of BMP type I receptors with siRNA induced cell death, inhibited cell growth, and caused a significant decrease in the expression of inhibitor of differentiation (Id1, Id2, and Id3) family members, which are known to regulate cell growth and survival in many types of cancers. BMP receptor antagonists also decreased clonogenic cell growth. Knockdown of Id3 significantly decreased cell growth and induced cell death of lung cancer cells. H1299 cells stably overexpressing Id3 were resistant to growth suppression and induction of cell death induced by the BMP antagonist DMH2. These studies suggest that BMP signaling promotes cell growth and survival of lung cancer cells, which is mediated through its regulation of Id family members. Selective antagonists of the BMP type I receptors represents a potential means to pharmacologically treat NSCLC and other carcinomas with an activated BMP signaling cascade.
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18 MeSH Terms
Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma.
Green MR, Gentles AJ, Nair RV, Irish JM, Kihira S, Liu CL, Kela I, Hopmans ES, Myklebust JH, Ji H, Plevritis SK, Levy R, Alizadeh AA
(2013) Blood 121: 1604-11
MeSH Terms: Clonal Evolution, Clone Cells, DNA, Neoplasm, Disease Progression, Exome, Gene Frequency, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Immunophenotyping, Lymphoma, Follicular, Mutation, Mutation Rate, Polymerase Chain Reaction, Recurrence
Show Abstract · Added February 15, 2013
Follicular lymphoma (FL) is currently incurable using conventional chemotherapy or immunotherapy regimes, compelling new strategies. Advances in high-throughput sequencing technologies that can reveal oncogenic pathways have stimulated interest in tailoring therapies toward actionable somatic mutations. However, for mutation-directed therapies to be most effective, the mutations must be uniformly present in evolved tumor cells as well as in the self-renewing tumor-cell precursors. Here, we show striking intratumoral clonal diversity within FL tumors in the representation of mutations in the majority of genes as revealed by whole exome sequencing of subpopulations. This diversity captures a clonal hierarchy, resolved using immunoglobulin somatic mutations and IGH-BCL2 translocations as a frame of reference and by comparing diagnosis and relapse tumor pairs, allowing us to distinguish early versus late genetic eventsduring lymphomagenesis. We provide evidence that IGH-BCL2 translocations and CREBBP mutations are early events, whereas MLL2 and TNFRSF14 mutations probably represent late events during disease evolution. These observations provide insight into which of the genetic lesions represent suitable candidates for targeted therapies.
1 Communities
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15 MeSH Terms
Epitope-specific human influenza antibody repertoires diversify by B cell intraclonal sequence divergence and interclonal convergence.
Krause JC, Tsibane T, Tumpey TM, Huffman CJ, Briney BS, Smith SA, Basler CF, Crowe JE
(2011) J Immunol 187: 3704-11
MeSH Terms: Amino Acid Sequence, Animals, Antibodies, Monoclonal, Antibody Specificity, Antigens, Viral, B-Lymphocytes, Cell Lineage, Clone Cells, Epitopes, B-Lymphocyte, Female, Genes, Immunoglobulin, Hemagglutinin Glycoproteins, Influenza Virus, Humans, Influenza A Virus, H1N1 Subtype, Mice, Mice, Inbred BALB C, Molecular Sequence Data, Reverse Transcriptase Polymerase Chain Reaction
Show Abstract · Added August 6, 2012
We generated from a single blood sample five independent human mAbs that recognized the Sa antigenic site on the head of influenza hemagglutinin and exhibited inhibitory activity against a broad panel of H1N1 strains. All five Abs used the V(H)3-7 and J(H)6 gene segments, but at least four independent clones were identified by junctional analysis. High-throughput sequence analysis of circulating B cells revealed that each of the independent clones were members of complex phylogenetic lineages that had diversified widely using a pattern of progressive diversification through somatic mutation. Unexpectedly, B cells encoding multiple diverging lineages of these clones, including many containing very few mutations in the Ab genes, persisted in the circulation. Conversely, we noted frequent instances of amino acid sequence convergence in the Ag combining sites exhibited by members of independent clones, suggesting a strong selection for optimal binding sites. We suggest that maintenance in circulation of a wide diversity of somatic variants of dominant clones may facilitate recognition of drift variant virus epitopes that occur in rapidly mutating virus Ags, such as influenza hemagglutinin. In fact, these Ab clones recognize an epitope that acquired three glycosylation sites mediating escape from previously isolated human Abs.
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18 MeSH Terms
Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations.
Payne BA, Wilson IJ, Hateley CA, Horvath R, Santibanez-Koref M, Samuels DC, Price DA, Chinnery PF
(2011) Nat Genet 43: 806-10
MeSH Terms: Adult, Aging, Anti-Retroviral Agents, Clone Cells, DNA, Mitochondrial, Female, HIV, HIV Infections, Humans, Male, Middle Aged, Mitochondria, Mitochondrial Diseases, Mutation
Show Abstract · Added December 12, 2013
There is emerging evidence that people with successfully treated HIV infection age prematurely, leading to progressive multi-organ disease, but the reasons for this are not known. Here we show that patients treated with commonly used nucleoside analog anti-retroviral drugs progressively accumulate somatic mitochondrial DNA (mtDNA) mutations, mirroring those seen much later in life caused by normal aging. Ultra-deep re-sequencing by synthesis, combined with single-cell analyses, suggests that the increase in somatic mutation is not caused by increased mutagenesis but might instead be caused by accelerated mtDNA turnover. This leads to the clonal expansion of preexisting age-related somatic mtDNA mutations and a biochemical defect that can affect up to 10% of cells. These observations add weight to the role of somatic mtDNA mutations in the aging process and raise the specter of progressive iatrogenic mitochondrial genetic disease emerging over the next decade.
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14 MeSH Terms