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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
Neonatal CD71+ Erythroid Cells Do Not Modify Murine Sepsis Mortality.
Wynn JL, Scumpia PO, Stocks BT, Romano-Keeler J, Alrifai MW, Liu JH, Kim AS, Alford CE, Matta P, Weitkamp JH, Moore DJ
(2015) J Immunol 195: 1064-70
MeSH Terms: Adoptive Transfer, Animals, Antibodies, Antigens, CD, Bone Marrow Cells, CD11b Antigen, Endotoxins, Erythroid Cells, Female, Fetal Blood, Humans, Male, Mice, Mice, Inbred C57BL, Receptors, Transferrin, Reticulocytes, Sepsis, Spleen
Show Abstract · Added June 24, 2015
Sepsis is a major cause of neonatal mortality and morbidity worldwide. A recent report suggested that murine neonatal host defense against infection could be compromised by immunosuppressive CD71(+) erythroid splenocytes. We examined the impact of CD71(+) erythroid splenocytes on murine neonatal mortality to endotoxin challenge or polymicrobial sepsis and characterized circulating CD71(+) erythroid (CD235a(+)) cells in human neonates. Adoptive transfer or an Ab-mediated reduction in neonatal CD71(+) erythroid splenocytes did not alter murine neonatal survival to endotoxin challenge or polymicrobial sepsis challenge. Ex vivo immunosuppression of stimulated adult CD11b(+) cells was not limited to neonatal splenocytes; it also occurred with adult and neonatal bone marrow. Animals treated with anti-CD71 Ab showed reduced splenic bacterial load following bacterial challenge compared with isotype-treated mice. However, adoptive transfer of enriched CD71(+) erythroid splenocytes to CD71(+)-reduced animals did not reduce bacterial clearance. Human CD71(+)CD235a(+) cells were common among cord blood mononuclear cells and were shown to be reticulocytes. In summary, a lack of effect on murine survival to polymicrobial sepsis following adoptive transfer or diminution of CD71(+) erythroid splenocytes under these experimental conditions suggests that the impact of these cells on neonatal infection risk and progression may be limited. An unanticipated immune priming effect of anti-CD71 Ab treatment, rather than a reduction in immunosuppressive CD71(+) erythroid splenocytes, was likely responsible for the reported enhanced bacterial clearance. In humans, the well-described rapid decrease in circulating reticulocytes after birth suggests that they may have a limited role in reducing inflammation secondary to microbial colonization.
Copyright © 2015 by The American Association of Immunologists, Inc.
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18 MeSH Terms
Genome-wide DNA methylation in neonates exposed to maternal depression, anxiety, or SSRI medication during pregnancy.
Non AL, Binder AM, Kubzansky LD, Michels KB
(2014) Epigenetics 9: 964-72
MeSH Terms: Antidepressive Agents, Anxiety, Case-Control Studies, Cell Division, Cohort Studies, CpG Islands, DNA Methylation, Depression, Female, Fetal Blood, Gene Expression Regulation, Gene Ontology, Genome, Human, Humans, Infant, Newborn, Male, Pregnancy, Pregnancy Complications, Prenatal Exposure Delayed Effects, Protein Biosynthesis, Serotonin Uptake Inhibitors
Show Abstract · Added January 20, 2015
Despite the high prevalence of depression, anxiety, and use of antidepressant medications during pregnancy, there is much uncertainty around the impact of high levels of distress or antidepressant medications on the developing fetus. These intrauterine exposures may lead to epigenetic alterations to the DNA during this vulnerable time of fetal development, which may have important lifetime health consequences. In this study we investigated patterns of genome-wide DNA methylation using the Illumina Infinium Human Methylation450 BeadChip in the umbilical cord blood of neonates exposed to non-medicated maternal depression or anxiety (n = 13), or selective serotonin reuptake inhibitors (SSRIs) during pregnancy (n = 22), relative to unexposed neonates (n = 23). We identified 42 CpG sites with significantly different DNA methylation levels in neonates exposed to non-medicated depression or anxiety relative to controls. CpG site methylation was not significantly different in neonates exposed to SSRIs relative to the controls, after adjusting for multiple comparisons. In neonates exposed either to non-medicated maternal depression or SSRIs, the vast majority of CpG sites displayed lower DNA methylation relative to the controls, but differences were very small. A gene ontology analysis suggests significant clustering of the top genes associated with non-medicated maternal depression/anxiety, related to regulation of transcription, translation, and cell division processes (e.g., negative regulation of translation in response to oxidative stress, regulation of mRNA export from the nucleus, regulation of stem cell division). While the functional consequences of these findings are yet to be determined, these small DNA methylation differences may suggest a possible role for epigenetic processes in the development of neonates exposed to non-medicated maternal depression/anxiety.
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21 MeSH Terms
Comparison of pre-cryopreserved and post-thaw-and-wash-nucleated cell count on major outcomes following unrelated cord blood transplant in children.
McManus MP, Wang L, Calder C, Manes B, Evans M, Bruce K, Ho RH, Domm J, Frangoul H
(2012) Pediatr Transplant 16: 438-42
MeSH Terms: Adolescent, Blood Specimen Collection, Cell Count, Child, Child, Preschool, Cord Blood Stem Cell Transplantation, Cryopreservation, Female, Fetal Blood, Follow-Up Studies, Humans, Infant, Leukemia, Myeloid, Acute, Male, Multivariate Analysis, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Proportional Hazards Models, Prospective Studies, Treatment Outcome
Show Abstract · Added March 5, 2014
Engraftment and OS after umbilical CBT is highly dependent on the TNC. The contribution of the wash step to cell loss and ultimately the dose of cells available for transplant is not well described. To investigate the amount of cell loss after washing and its impact on major outcomes compared to pre-cryopreserved TNC, we analyzed data from patients prospectively enrolled on a National Heart, Lung and Blood Institute sponsored cord blood transplant study between 1999 and 2003. There were 310 patients ≤18 yr of age with malignant (N = 218) or non-malignant (N = 92) disease enrolled on this trial. Only single CBU were used. All CBU were thawed and washed using an identical process. The median TNC after thawing and washing (PTW) was 5.43 × 10(7) /kg (79% recovery of cells). The cumulative incidence of neutrophil engraftment was significantly higher in patients receiving a PTW TNC ≥2.5 × 10(7) /kg (p = 0.01). The cumulative incidence of TRM was higher among patients receiving post-thaw-and-wash TNC <2.5 × 10(7) /kg (p = 0.039). In conclusion, receiving a PTW TNC of <2.5 × 10(7) /kg resulted in worse neutrophil engraftment and increased transplant-related mortality compared to a PTW TNC of ≥2.5 × 10(7) /kg.
© 2012 John Wiley & Sons A/S.
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19 MeSH Terms
Attitudes of pregnant women towards collection of biological specimens during pregnancy and at birth.
Nechuta S, Mudd LM, Elliott MR, Lepkowski JM, Paneth N, Michigan Alliance for the National Children's Study
(2012) Paediatr Perinat Epidemiol 26: 272-5
MeSH Terms: Adult, Attitude to Health, Biomedical Research, Blood Banks, Cross-Sectional Studies, Female, Fetal Blood, Humans, Michigan, Parity, Placenta, Pregnancy, Pregnant Women, Specimen Handling, Young Adult
Show Abstract · Added September 9, 2015
Epidemiological investigations of maternal and child health may involve the collection of biological specimens, including cord blood and the placenta; however, the attitudes of pregnant women towards participation in the collection of biological specimens have been studied rarely. We evaluated attitudes towards collection and storage of biological specimens, and determined whether attitudes differed by maternal characteristics, in a cross-sectional study of pregnant women residing in Kent County, Michigan. Women were interviewed at their first visit for prenatal care between April and October 2006 (n = 311). Willingness to participate was highest for maternal blood collection (72%), followed by storage of biological specimens (68%), placenta collection (64%), and cord blood collection (63%). About one-quarter of women (25-28% by procedure) would not participate even if compensated. Hispanic ethnicity was associated with unwillingness to participate in maternal blood collection (OR = 2.16 [95% CI 1.15, 4.04]). Primiparity was associated with unwillingness to participate in cord blood collection (OR = 1.72 [95% CI 1.23, 2.42]). Among women willing to participate, Hispanic women were less likely to require compensation; while higher educated, married and primiparous women were more likely to require compensation. In conclusion, while many pregnant women were willing to participate in biological specimen collection, some women were more resistant, in particular Hispanic and primiparous women. Targeting these groups of women for enhanced recruitment efforts may improve overall participation rates and the representativeness of participants in future studies of maternal and child health.
© 2012 Blackwell Publishing Ltd.
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15 MeSH Terms
The quality of privately banked cord blood.
Frangoul H, Domm J
(2011) Pediatr Blood Cancer 57: 1248
MeSH Terms: Anemia, Aplastic, Blood Banks, Fetal Blood, Hematopoietic Stem Cell Transplantation, Humans, Privatization
Added March 27, 2014
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6 MeSH Terms
Maternal and cord blood hormone levels in the United States and China and the intrauterine origin of breast cancer.
Lagiou P, Samoli E, Okulicz W, Xu B, Lagiou A, Lipworth L, Georgila C, Vatten L, Adami HO, Trichopoulos D, Hsieh CC
(2011) Ann Oncol 22: 1102-8
MeSH Terms: Adiponectin, Adult, Breast Neoplasms, China, Female, Fetal Blood, Gonadal Steroid Hormones, Hormones, Humans, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor Binding Proteins, Insulin-Like Growth Factor I, Pregnancy, Prolactin, Sex Hormone-Binding Globulin, Statistics, Nonparametric, United States, Young Adult
Show Abstract · Added March 1, 2014
BACKGROUND - Breast cancer is less common in China than in the United States and perinatal characteristics predict breast cancer risk in the offspring. We determined levels of pregnancy hormones in Boston and Shanghai to identify those possibly involved in the intrauterine origin of breast cancer.
PARTICIPANTS AND METHODS - We compared maternal and cord blood levels of estradiol, estriol, testosterone, progesterone, prolactin, insulin-like growth factors (IGF) 1 and 2, insulin-like growth factor-binding protein 3, adiponectin and sex hormone-binding globulin (SHBG) in 241 Caucasian and 295 Chinese women.
RESULTS - In both centers, hormone levels at the 16th were predictive of those at the 27th gestational week, but there was little correlation between maternal and cord blood levels. In cord blood, we found significantly (P < 0.01) higher levels of estradiol (44.2%), testosterone (54.5%), IGF-2 (22.7%) and strikingly SHBG (104.6%) in Shanghai women, whereas the opposite was true for IGF-1 (-36.8%).
CONCLUSIONS - Taking into account the current understanding of the plausible biological role of the examined endocrine factors, those likely to be involved in the intrauterine origin of breast cancer are SHBG and IGF-2, with higher cord blood levels among Chinese, and IGF-1, with higher cord blood levels among Caucasian women.
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18 MeSH Terms
Transforming growth factor beta is a major regulator of human neonatal immune responses following respiratory syncytial virus infection.
Thornburg NJ, Shepherd B, Crowe JE
(2010) J Virol 84: 12895-902
MeSH Terms: Adult, Biomarkers, Tumor, Blotting, Western, Carcinoma, Squamous Cell, Cell Differentiation, Child, Dendritic Cells, Fetal Blood, Flow Cytometry, Gene Expression Profiling, Humans, Interferon-gamma, Interleukin-2, Interleukin-4, Interleukin-6, Laryngeal Neoplasms, Oligonucleotide Array Sequence Analysis, RNA, Messenger, Respiratory Syncytial Virus Infections, Respiratory Syncytial Viruses, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes, Transforming Growth Factor beta, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha
Show Abstract · Added August 6, 2012
Respiratory syncytial virus (RSV) is a major cause of morbidity and mortality. Previous studies have suggested that T-cell responses may contribute to RSV immunopathology, which could be driven by dendritic cells (DCs). DCs are productively infected by RSV, and during RSV infections, there is an increase of DCs in the lungs with a decrease in the blood. Pediatric populations are particularly susceptible to severe RSV infections; however, DC responses to RSV from pediatric populations have not been examined. In this study, primary isolated DCs from cord blood and adult peripheral blood were compared after RSV infection. Transcriptional profiling and biological network analysis identified transforming growth factor beta (TGF-β) and associated signaling molecules as differentially regulated in the two age groups. TGF-β1 was decreased in RSV-infected adult-blood DCs but increased in RSV-infected cord blood DCs. Coculture of adult RSV-infected DCs with autologous T cells induced secretion of gamma interferon (IFN-γ), interleukin 12p70 (IL-12p70), IL-2, and tumor necrosis factor alpha (TNF-α). Conversely, coculture of cord RSV-infected DCs and autologous T cells induced secretion of IL-4, IL-6, IL-1β, and IL-17. Addition of purified TGF-β1 to adult DC-T-cell cocultures reduced secretion of IFN-γ, IL-12p70, IL-2, and TNF-α, while addition of a TGF-β chemical inhibitor to cord DC-T-cell cocultures increased secretion of IL-12p70. These data suggest that TGF-β acts as a major regulator of RSV DC-T-cell responses, which could contribute to immunopathology during infancy.
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25 MeSH Terms
Dioxin-like PCBs and endometriosis.
Bruner-Tran KL, Osteen KG
(2010) Syst Biol Reprod Med 56: 132-46
MeSH Terms: Adult, Dioxins, Endometriosis, Endometrium, Environmental Exposure, Environmental Pollutants, Female, Fetal Blood, Humans, Polychlorinated Biphenyls, Pregnancy, Prenatal Exposure Delayed Effects, United States
Show Abstract · Added May 29, 2014
A recent survey in the United States identified 287 different chemicals in human cord blood, demonstrating the significant exposure of women and their children to a wide array of environmental toxicants. While reducing contamination and exposure should be an international priority, it is equally appropriate to develop an understanding of the health consequences of increasing world-wide industrialization. Endometriosis, a disease of the female reproductive tract, has emerged as a disease potentially related to environmental exposures. While a number of population-based studies have suggested that a woman's exposure to dioxin-like polychlorinated biphenyls may affect her risk of developing this disease, other studies have failed to find such evidence. In the current manuscript, we will review the limited data regarding polychlorinated biphenyl congeners and endometriosis with a focus on dioxin-like toxicants. We will also discuss the potential importance of early life exposures to these toxicants on the subsequent development of endometriosis.
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13 MeSH Terms
Pathogenic mitochondrial DNA mutations are common in the general population.
Elliott HR, Samuels DC, Eden JA, Relton CL, Chinnery PF
(2008) Am J Hum Genet 83: 254-60
MeSH Terms: Cohort Studies, DNA Mutational Analysis, DNA, Mitochondrial, Female, Fetal Blood, Genetics, Population, Genotype, Haplotypes, Heterozygote, Humans, Mitochondrial Diseases, Models, Genetic, Models, Statistical, Mutation, Prevalence
Show Abstract · Added December 12, 2013
Mitochondrial DNA (mtDNA) mutations are a major cause of genetic disease, but their prevalence in the general population is not known. We determined the frequency of ten mitochondrial point mutations in 3168 neonatal-cord-blood samples from sequential live births, analyzing matched maternal-blood samples to estimate the de novo mutation rate. mtDNA mutations were detected in 15 offspring (0.54%, 95% CI = 0.30-0.89%). Of these live births, 0.00107% (95% CI = 0.00087-0.0127) harbored a mutation not detected in the mother's blood, providing an estimate of the de novo mutation rate. The most common mutation was m.3243A-->G. m.14484T-->C was only found on sub-branches of mtDNA haplogroup J. In conclusion, at least one in 200 healthy humans harbors a pathogenic mtDNA mutation that potentially causes disease in the offspring of female carriers. The exclusive detection of m.14484T-->C on haplogroup J implicates the background mtDNA haplotype in mutagenesis. These findings emphasize the importance of developing new approaches to prevent transmission.
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15 MeSH Terms