ORCID Profile
0000-0002-9952-7069
Current Organisations
University of Sheffield
,
Garvan Institute of Medical Research
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Community Child Health | Sociological Methodology and Research Methods | Aboriginal and Torres Strait Islander Health | Public Health and Health Services |
ANZSRC Socio-Economic Objective (SEO)
Related Links
Publications
Divergent human populations show extensive shared IGK rearrangements in peripheral blood B cells
Publisher: Springer Science and Business Media LLC
Date: 26-07-2011
DOI: 10.1007/S00251-011-0559-Z
Abstract: We have analysed the transcribed immunoglobulin kappa (IGK) repertoire of peripheral blood B cells from four in iduals from two genetically distinct populations, Papua New Guinean and Australian, using high-throughput DNA sequencing. The depth of sequencing data for each in idual averaged 5,548 high-quality IGK reads, and permitted genotyping of the inferred IGKV and IGKJ germline gene segments for each in idual. All in iduals were homozygous at each IGKJ locus and had highly similar inferred IGKV genotypes. Preferential gene usage was seen at both the IGKV and IGKJ loci, but only IGKV segment usage varied significantly between in iduals. Despite the differences in IGKV gene utilisation, the rearranged IGK repertoires showed extensive identity at the amino acid level. Public rearrangements (those shared by two or more in iduals) made up 60.2% of the total sequenced IGK rearrangements. The total ersity of IGK rearrangements of each in idual was estimated to range from just 340 to 549 unique amino acid sequences. Thus, the repertoire of unique expressed IGK rearrangements is dramatically less than previous theoretical estimates of IGK ersity, and the majority of expressed IGK rearrangements are likely to be extensively shared in in idual human beings.
Lymphoma Driver Mutations in the Pathogenic Evolution of an Iconic Human Autoantibody
Publisher: Elsevier BV
Date: 03-2020
Adjuvanted H5N1 influenza vaccine enhances both cross-reactive memory B cell and strain-specific naive B cell responses in humans
Publisher: Proceedings of the National Academy of Sciences
Date: 13-07-2020
Abstract: The development of a universal influenza vaccine is a major public health need globally, and identifying the optimal formulation will be an important first step for developing such a vaccine. Here we show that a two-dose immunization of humans with an inactivated, AS03-adjuvanted H5N1 avian influenza virus vaccine engaged both the preexisting memory and naive B cell compartments. Importantly, we show that the recruited memory B cells after first immunization were directed against conserved epitopes within the H5 HA stem region while the responses after the second immunization were mostly directed against strain-specific epitopes within the HA globular head. Taken together these findings have broad implications toward optimizing vaccination strategies for developing more effective vaccines against pandemic viruses.
Effects of Aging, Cytomegalovirus Infection, and EBV Infection on Human B Cell Repertoires
Publisher: The American Association of Immunologists
Date: 15-01-2014
Abstract: Elderly humans show decreased humoral immunity to pathogens and vaccines, yet the effects of aging on B cells are not fully known. Chronic viral infection by CMV is implicated as a driver of clonal T cell proliferations in some aging humans, but whether CMV or EBV infection contributes to alterations in the B cell repertoire with age is unclear. We have used high-throughput DNA sequencing of IGH gene rearrangements to study the BCR repertoires over two successive years in 27 in iduals ranging in age from 20 to 89 y. Some features of the B cell repertoire remain stable with age, but elderly subjects show increased numbers of B cells with long CDR3 regions, a trend toward accumulation of more highly mutated IgM and IgG Ig genes, and persistent clonal B cell populations in the blood. Seropositivity for CMV or EBV infection alters B cell repertoires, regardless of the in idual’s age: EBV infection correlates with the presence of persistent clonal B cell expansions, whereas CMV infection correlates with the proportion of highly mutated Ab genes. These findings isolate effects of aging from those of chronic viral infection on B cell repertoires and provide a baseline for understanding human B cell responses to vaccination or infectious stimuli.
Persistence and evolution of allergen-specific IgE repertoires during subcutaneous specific immunotherapy
Publisher: Elsevier BV
Date: 05-2016
A Temporal Model of Human IgE and IgG Antibody Function
Publisher: Frontiers Media SA
Date: 2013
Oral Health–related Beliefs, Behaviors, and Outcomes through the Life Course
Publisher: SAGE Publications
Date: 02-03-2016
Abstract: Complex associations exist among socioeconomic status (SES) in early life, beliefs about oral health care (held by in iduals and their parents), and oral health–related behaviors. The pathways to poor adult oral health are difficult to model and describe, especially due to a lack of longitudinal data. The study aim was to explore possible pathways of oral health from birth to adulthood (age 38 y). We hypothesized that higher socioeconomic position in childhood would predict favorable oral health beliefs in adolescence and early adulthood, which in turn would predict favorable self-care and dental attendance behaviors those would lead to lower dental caries experience and better self-reported oral health by age 38 y. A generalized structural equation modeling approach was used to investigate the relationship among oral health–related beliefs, behaviors in early adulthood, and dental health outcomes and quality of life in adulthood (age, 38 y), based on longitudinal data from a population-based birth cohort. The current investigation utilized prospectively collected data on early (up to 15 y) and adult (26 and 32 y) SES, oral health–related beliefs (15, 26, and 32 y), self-care behaviors (15, 28, and 32 y), oral health outcomes (e.g., number of carious and missing tooth surfaces), and oral health–related quality of life (38 y). Early SES and parental oral health–related beliefs were associated with the study members’ oral health–related beliefs, which in turn predicted toothbrushing and dental service use. Toothbrushing and dental service use were associated with the number of untreated carious and missing tooth surfaces in adulthood. The number of untreated carious and missing tooth surfaces were associated with oral health–related quality of life. Oral health toward the end of the fourth decade of life is associated with intergenerational factors and various aspects of people’s beliefs, SES, dental attendance, and self-care operating since the childhood years.
DJ Pairing during VDJ Recombination Shows Positional Biases That Vary among Individuals with Differing IGHD Locus Immunogenotypes
Publisher: The American Association of Immunologists
Date: 02-2016
Abstract: Human IgH ersity is influenced by biases in the pairing of IGHD and IGHJ genes, but these biases have not been described in detail. We used high-throughput sequencing of VDJ rearrangements to explore DJ pairing biases in 29 in iduals. It was possible to infer three contrasting IGHD-IGHJ haplotypes in nine of these in iduals, and two of these haplotypes include deletion polymorphisms involving multiple contiguous IGHD genes. Therefore, we were able to explore how the underlying genetic makeup of the H chain locus influences the formation of particular DJ pairs. Analysis of nonproductive rearrangements demonstrates that 3′ IGHD genes tend to pair preferentially with 5′ IGHJ genes, whereas 5′ IGHD genes pair preferentially with 3′ IGHJ genes the relationship between IGHD gene pairing frequencies and IGHD gene position is a near linear one for each IGHJ gene. However, striking differences are seen in in iduals who carry deletion polymorphisms in the D locus. The absence of different blocks of IGHD genes leads to increases in the utilization frequencies of just a handful of genes, and these genes have no clear positional relationships to the deleted genes. This suggests that pairing frequencies may be influenced by additional complex positional relationships that perhaps arise from chromatin structure. In contrast to IGHD gene usage, IGHJ gene usage is unaffected by the IGHD gene–deletion polymorphisms. Such an outcome would be expected if the recombinase complex associates with an IGHJ gene before associating with an IGHD gene partner.
Human transitional and IgMlow mature naïve B cells preserve permissive B‐cell receptors
Publisher: Wiley
Date: 04-06-2021
DOI: 10.1111/IMCB.12478
Abstract: The level of immunoglobulin M (IgM) displayed on the surface of peripheral blood B cells exhibits a broad dynamic range and has been associated with both development and selection. To determine whether IgM surface expression associates with distinct immunoglobulin heavy‐chain (IGH) repertoire properties, we performed deep IgM sequencing of peripheral blood transitional and mature naïve B cells in the upper and lower quartiles of surface IgM expression for 12 healthy donors. Mature naïve B cells within the lowest quartile for surface IgM expression displayed more erse IGH features including increased complementarity‐determining region 3 length, IGHJ6 segment usage and aromatic amino acids compared with mature naïve B cells with high surface IgM. There were no differences between IGH repertoires for transitional B cells with high or low surface IgM. These findings suggest that a selection checkpoint during progression of transitional to mature naïve B cells reduces the breadth of the IGH repertoire among high surface IgM B cells but that ersity is preserved in B cells expressing low levels of surface IgM.
Chapter 10: Oral Health-Related Quality of Life and Coronal Caries
Publisher: S. Karger AG
Date: 2023
DOI: 10.1159/000530614
Predicting Vaccine Responsiveness
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.CHOM.2015.02.015
Abstract: Vaccination has saved many lives and prevented needless suffering from disease, but it is not always effective. Immune responses are a highly "personalized" aspect of an in idual's biology, as they are subject to germline genetic influences but are embodied in cell populations that continuously s le the environment. Additionally, immunity is shaped by memory of prior infectious diseases and other antigenic exposures. Here, we review ex les of recent technical advances and insights into human vaccine responses that are helping to define the features associated with successful vaccination and that may enable a more predictive vaccinology in the future.
The methodological quality is insufficient in clinical practice guidelines in the context of COVID-19: systematic review
Publisher: Elsevier BV
Date: 07-2021
Ability To Develop Broadly Neutralizing HIV-1 Antibodies Is Not Restricted by the Germline Ig Gene Repertoire
Publisher: The American Association of Immunologists
Date: 05-2015
Abstract: The human Ig repertoire is vast, producing billions of unique Abs from a limited number of germline Ig genes. The IgH V region (IGHV) is central to Ag binding and consists of 48 functional genes. In this study, we analyzed whether HIV-1–infected in iduals who develop broadly neutralizing Abs show a distinctive germline IGHV profile. Using both 454 and Illumina technologies, we sequenced the IGHV repertoire of 28 HIV-infected South African women from the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 002 and 004 cohorts, 13 of whom developed broadly neutralizing Abs. Of the 259 IGHV alleles identified in this study, approximately half were not found in the International Immunogenetics Database (IMGT). This included 85 entirely novel alleles and 38 alleles that matched rearranged sequences in non-IMGT databases. Analysis of the rearranged H chain V region genes of mAbs isolated from seven of these women, as well as previously isolated broadly neutralizing Abs from other donors, provided evidence that at least eight novel or non-IMGT alleles contributed to functional Abs. Importantly, we found that, despite a wide range in the number of IGHV alleles in each in idual, including alleles used by known broadly neutralizing Abs, there were no significant differences in germline IGHV repertoires between in iduals who do and do not develop broadly neutralizing Abs. This study reports novel IGHV repertoires and highlights the importance of a fully comprehensive Ig database for germline gene usage prediction. Furthermore, these data suggest a lack of genetic bias in broadly neutralizing Ab development in HIV-1 infection, with positive implications for HIV vaccine design.
The Inference of Phased Haplotypes for the Immunoglobulin H Chain V Region Gene Loci by Analysis of VDJ Gene Rearrangements
Publisher: The American Association of Immunologists
Date: 02-2012
Abstract: The existence of many highly similar genes in the lymphocyte receptor gene loci makes them difficult to investigate, and the determination of phased “haplotypes” has been particularly problematic. However, V(D)J gene rearrangements provide an opportunity to infer the association of Ig genes along the chromosomes. The chromosomal distribution of H chain genes in an Ig genotype can be inferred through analysis of VDJ rearrangements in in iduals who are heterozygous at points within the IGH locus. We analyzed VDJ rearrangements from 44 in iduals for whom sufficient unique rearrangements were available to allow comprehensive genotyping. Nine in iduals were identified who were heterozygous at the IGHJ6 locus and for whom sufficient suitable VDJ rearrangements were available to allow comprehensive haplotyping. Each of the 18 resulting IGHV│IGHD│IGHJ haplotypes was unique. Apparent deletion polymorphisms were seen that involved as many as four contiguous, functional IGHV genes. Two deletion polymorphisms involving multiple contiguous IGHD genes were also inferred. Three previously unidentified gene duplications were detected, where two sequences recognized as allelic variants of a single gene were both inferred to be on a single chromosome. Phased genomic data brings clarity to the study of the contribution of each gene to the available repertoire of rearranged VDJ genes. Analysis of rearrangement frequencies suggests that particular genes may have substantially different yet predictable propensities for rearrangement within different haplotypes. Together with data highlighting the extent of haplotypic variation within the population, this suggests that there may be substantial variability in the available Ab repertoires of different in iduals.
Psychometric assessment of the short‐form Child Perceptions Questionnaire: an international collaborative study
Publisher: Wiley
Date: 08-2016
DOI: 10.1111/CDOE.12248
Abstract: To examine the factor structure and other psychometric characteristics of the most commonly used child oral-health-related quality-of-life (OHRQoL) measure (the 16-item short-form CPQ Secondary data analyses used subnational epidemiological s les of 11- to 14-year-olds in Australia (N = 372), New Zealand (three s les: 352, 202, 429), Brunei (423), Cambodia (244), Hong Kong (542), Malaysia (439), Thailand (220, 325), England (88, 374), Germany (1055), Mexico (335) and Brazil (404). Confirmatory factor analysis (CFA) was used to examine the factor structure of the CPQ Caries experience varied, with mean DMFT scores ranging from 0.5 in the Malaysian s le to 3.4 in one New Zealand s le. Even more variation was noted in the proportion reporting only fair or poor oral health this was highest in the Cambodian and Mexican s les and lowest in the German s le and one New Zealand s le. One in 10 reported that their oral health had a marked impact on their life overall. The CFA across all s les revealed two factors with eigenvalues greater than 1. The first involved all items in the oral symptoms and functional limitations subscales the second involved all emotional well-being and social well-being items. The first was designated the 'symptoms/function' subscale, and the second was designated the 'well-being' subscale. Cronbach's alpha scores were 0.72 and 0.84, respectively. The symptoms/function subscale contained more of the items with greater impact, with the item 'Food stuck in between your teeth' having greatest impact in the well-being subscale, the 'Felt shy or embarrassed' item had the greatest impact. Repeating the analyses by world region gave similar findings. The CPQ
The mouse antibody heavy chain repertoire is germline-focused and highly variable between inbred strains
Publisher: The Royal Society
Date: 05-09-2015
Abstract: The human and mouse antibody repertoires are formed by identical processes, but like all small animals, mice only have sufficient lymphocytes to express a small part of the potential antibody repertoire. In this study, we determined how the heavy chain repertoires of two mouse strains are generated. Analysis of IgM- and IgG-associated VDJ rearrangements generated by high-throughput sequencing confirmed the presence of 99 functional immunoglobulin heavy chain variable (IGHV) genes in the C57BL/6 genome, and inferred the presence of 164 IGHV genes in the BALB/c genome. Remarkably, only five IGHV sequences were common to both strains. Compared with humans, little N nucleotide addition was seen in the junctions of mouse VDJ genes. Germline human IgG-associated IGHV genes are rare, but many murine IgG-associated IGHV genes were unmutated. Together these results suggest that the expressed mouse repertoire is more germline-focused than the human repertoire. The apparently ergent germline repertoires of the mouse strains are discussed with reference to reports that inbred mouse strains carry blocks of genes derived from each of the three subspecies of the house mouse. We hypothesize that the germline genes of BALB/c and C57BL/6 mice may originally have evolved to generate distinct germline-focused antibody repertoires in the different mouse subspecies.
Shared B cell memory to coronaviruses and other pathogens varies in human age groups and tissues
Publisher: American Association for the Advancement of Science (AAAS)
Date: 14-05-2021
Abstract: It remains unclear whether B cell repertoires against coronaviruses and other pathogens differ between adults and children and how important these distinctions are. Yang et al. analyzed blood s les from young children and adults, as well as tissues from deceased organ donors, characterizing the B cell receptor (BCR) repertoires specific to six common pathogens and two viruses that they had not seen before: Ebola virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Children had higher frequencies of B cells with convergent BCR heavy chains against previously encountered pathogens and higher frequencies of class-switched convergent B cell clones against SARS-CoV-2 and related coronaviruses. These findings suggest that encounters with coronaviruses in early life may produce cross-reactive memory B cell populations that contribute to ergent COVID-19 susceptibilities. Science , this issue p. 738
Immunizations with diverse sarbecovirus receptor-binding domains elicit SARS-CoV-2 neutralizing antibodies against a conserved site of vulnerability
Publisher: Elsevier BV
Date: 12-2021
High-throughput targeted long-read single cell sequencing reveals the clonal and transcriptional landscape of lymphocytes
Publisher: Cold Spring Harbor Laboratory
Date: 24-09-2018
DOI: 10.1101/424945
Abstract: High-throughput single-cell RNA-Sequencing is a powerful technique for gene expression profiling of complex and heterogeneous cellular populations such as the immune system. However, these methods only provide short-read sequence from one end of a cDNA template, making them poorly suited to the investigation of gene-regulatory events such as mRNA splicing, adaptive immune responses or somatic genome evolution. To address this challenge, we have developed a method that combines targeted long-read sequencing with short-read based transcriptome profiling of barcoded single cell libraries generated by droplet-based partitioning. We use Repertoire And Gene Expression sequencing (RAGE-seq) to accurately characterize full-length T cell (TCR) and B cell (BCR) receptor sequences and transcriptional profiles of more than 7,138 lymphocytes s led from the primary tumour and draining lymph node of a breast cancer patient. With this method we show that somatic mutation, alternate splicing and clonal evolution of T and B lymphocytes can be tracked across these tissue compartments. Our results demonstrate that RAGE-Seq is an accessible and cost-effective method for high-throughput deep single cell profiling, applicable to a wide range of biological challenges.
Aberrant B cell repertoire selection associated with HIV neutralizing antibody breadth
Publisher: Springer Science and Business Media LLC
Date: 20-01-2020
High-throughput targeted long-read single cell sequencing reveals the clonal and transcriptional landscape of lymphocytes
Publisher: Springer Science and Business Media LLC
Date: 17-02-2019
DOI: 10.1038/S41467-019-11049-4
Abstract: High-throughput single-cell RNA sequencing is a powerful technique but only generates short reads from one end of a cDNA template, limiting the reconstruction of highly erse sequences such as antigen receptors. To overcome this limitation, we combined targeted capture and long-read sequencing of T-cell-receptor (TCR) and B-cell-receptor (BCR) mRNA transcripts with short-read transcriptome profiling of barcoded single-cell libraries generated by droplet-based partitioning. We show that Repertoire and Gene Expression by Sequencing (RAGE-Seq) can generate accurate full-length antigen receptor sequences at nucleotide resolution, infer B-cell clonal evolution and identify alternatively spliced BCR transcripts. We apply RAGE-Seq to 7138 cells s led from the primary tumor and draining lymph node of a breast cancer patient to track transcriptome profiles of expanded lymphocyte clones across tissues. Our results demonstrate that RAGE-Seq is a powerful method for tracking the clonal evolution from large numbers of lymphocytes applicable to the study of immunity, autoimmunity and cancer.
Molecular Profiling and Clonal Tracking of Secreted Rheumatoid Factors in Primary Sjogren's Syndrome
Publisher: Wiley
Date: 03-08-2018
DOI: 10.1002/ART.40539
Abstract: Rheumatoid factors (RFs) are associated with systemic disease in primary Sjögren's syndrome (SS) and may be pathogenic as mixed cryoglobulins. Current detection methods cannot resolve RFs at a molecular level. This study was undertaken to perform the first proteomic and transcriptomic analysis of secreted and membrane-bound IgM-RF in primary SS and identify unique heavy-chain peptide signatures for RF clonotype tracking. Purified heavy chains of serum RFs from 15 patients with primary SS were subjected to de novo mass spectrometric sequencing. The circulating B cell Ig repertoire was determined by massively parallel sequencing of IGH RNA from matched peripheral blood mononuclear cells (n = 7). RF-specific heavy-chain third complementarity-determining region (CDR3) peptides were identified by searching RF heavy-chain peptide sequences against the corresponding IGH RNA sequence libraries. Heavy-chain CDR3 peptides were used as biomarkers to track serum RF clonotypes using quantitative multiple reaction monitoring. Serum RFs were clonally restricted and composed of shared sets of IgM heavy-chain variable region (Ig V Cryoprecipitable RF clonotypes linked to vasculitis in primary SS have different molecular profiles than nonprecipitating RFs, suggesting different underlying mechanisms of production. The combined omics workflow presented herein provides molecular biomarkers for tracking and removal of pathogenic RF clones.
IgE Sequences in Individuals Living in an Area of Endemic Parasitism Show Little Mutational Evidence of Antigen Selection
Publisher: Wiley
Date: 25-03-2011
DOI: 10.1111/J.1365-3083.2011.02525.X
Abstract: Patterns of somatic mutation in IgE genes from allergic in iduals have been a focus of study for many years, but IgE sequences have never been reported from parasitized in iduals. To study the role of antigen selection in the evolution of the anti-parasite response, we therefore generated 118 IgE sequences from donors living in Papua New Guinea (PNG), an area of endemic parasitism. For comparison, we also generated IgG1, IgG2, IgG3 and IgG4 sequences from these donors, as well as IgG1 sequences from Australian donors. IgE sequences had, on average, 23.0 mutations. PNG IgG sequences had average mutation levels that varied from 17.7 (IgG3) to 27.1 (IgG4). Mean mutation levels correlated significantly with the position of their genes in the constant region gene locus (IgG3 < IgG1 < IgG2 < IgG4). Interestingly, given the heavy, life-long antigen burden experienced by PNG villagers, average mutation levels in IgG sequences were little different to that seen in Australian IgG1 sequences (19.2). Patterns of mutation provide clear evidence of antigen selection in many IgG sequences. The percentage of IgG sequences that showed significant accumulations of replacement mutations in the complementarity determining regions ranged from 22% of IgG3 sequences to 39% of IgG2 sequences. By contrast, only 12% of IgE sequences had such evidence of antigen selection, and this was significantly less than in PNG IgG1, IgG2 and IgG4 subclass sequences (P < 0.01). The anti-parasite IgE response therefore has the reduced evidence of antigen selection that has previously been reported in studies of IgE sequences from allergic in iduals.
iHMMune-align: hidden Markov model-based alignment and identification of germline genes in rearranged immunoglobulin gene sequences
Publisher: Oxford University Press (OUP)
Date: 26-04-2007
DOI: 10.1093/BIOINFORMATICS/BTM147
Abstract: Motivation: Immunoglobulin heavy chain (IGH) genes in mature B lymphocytes are the result of recombination of IGHV, IGHD and IGHJ germline genes, followed by somatic mutation. The correct identification of the germline genes that make up a variable VH domain is essential to our understanding of the process of antibody ersity generation as well as to clinical investigations of some leukaemias and lymphomas. Results: We have developed iHMMune-align, an alignment program that uses a hidden Markov model (HMM) to model the processes involved in human IGH gene rearrangement and maturation. The performance of iHMMune-align was compared to that of other immunoglobulin gene alignment utilities using both clonally related and randomly selected IGH sequences. This evaluation suggests that iHMMune-align provides a more accurate identification of component germline genes than other currently available IGH gene characterization programs. Availability: iHMMune-align cross-platform Java executable and web interface are freely available to academic users and can be accessed at www.emi.unsw.edu.au/~ihmmune/ Contact: bgaeta@cse.unsw.edu.au
A bibliometric analysis of Community Dentistry and Oral Epidemiology: Fifty years of publications
Publisher: Wiley
Date: 05-10-2023
DOI: 10.1111/CDOE.12910
Does Autonomic Arousal Distinguish Good and Bad Decisions?
Publisher: Hogrefe Publishing Group
Date: 2008
DOI: 10.1027/0269-8803.22.3.141
Abstract: The somatic marker hypothesis (SMH) proposes that physiological feedback to the brain influences cognitive appraisal and human decisions, however, the strength of evidence in support of the SMH is equivocal. We examined the validity of the SMH by measuring physiological arousal in a population of healthy in iduals playing the Iowa Gambling Task (IGT), which is a computerized card game designed to assess real-life decisions. We also examined the influence of reinforcer type on IGT performance and physiological reactivity. Skin conductance level (SCL) reactivity was measured in 41 participants performing the IGT using either facsimile or real money. Participants were categorized as normal (i.e., nonimpaired) or impaired on the basis of their IGT performance, and differences in performance and physiological reactivity between groups were examined. No differences in SCL were found between normal and impaired groups. However, greater SCL rises were borderline significant when anticipating choices from bad decks compared with good decks, and a significantly greater SCL rise followed a reward from a bad deck. The effect of reinforcer type also revealed marginally greater performance when using facsimile money. This was corroborated physiologically by Deck × Reinforcer Type interactions, showing a marginally significant tendency for a greater SCL rise when anticipating a choice from a bad deck using facsimile but not real money, and a significantly greater SCL rise following a reward from a bad deck when using facsimile but not real money. Findings constrain the SMH, suggesting that autonomic activity may discriminate between good and bad decks (i.e., good vs. bad decision-making) by reflecting the magnitude of gains and losses, but is independent of long-term consequences and does not discriminate between overall good and bad performance (i.e., normal vs. impaired decision-makers).
A comparison of immunoglobulin IGHV , IGHD and IGHJ genes in wild‐derived and classical inbred mouse strains
Publisher: Wiley
Date: 06-10-2019
DOI: 10.1111/IMCB.12288
Abstract: The genomes of classical inbred mouse strains include genes derived from all three major subspecies of the house mouse, Mus musculus. We recently posited that genetic ersity in the immunoglobulin heavy chain (IGH) gene loci of C57BL/6 and BALB/c mice reflects differences in subspecies origin. To investigate this hypothesis, we conducted high-throughput sequencing of IGH gene rearrangements to document IGH variable (IGHV), joining (IGHJ) and ersity (IGHD) genes in four inbred wild-derived mouse strains (CAST/EiJ, LEWES/EiJ, MSM/MsJ and PWD/PhJ) and a single disease model strain (NOD/ShiLtJ), collectively representing genetic backgrounds of several major mouse subspecies. A total of 341 germline IGHV sequences were inferred in the wild-derived strains, including 247 not curated in the international ImMunoGeneTics information system. By contrast, 83/84 inferred NOD IGHV genes had previously been observed in C57BL/6 mice. Variability among the strains examined was observed for only a single IGHJ gene, involving a description of a novel allele. By contrast, unexpected variation was found in the IGHD gene loci, with four previously unreported IGHD gene sequences being documented. Very few IGHV sequences of C57BL/6 and BALB/c mice were shared with strains representing major subspecies, suggesting that their IGH loci may be complex mosaics of genes of disparate origins. This suggests a similar level of ersity is likely present in the IGH loci of other classical inbred strains. This must now be documented if we are to properly understand interstrain variation in models of antibody-mediated disease.
Next-Generation Sequencing of Antibody Display Repertoires
Publisher: Frontiers Media SA
Date: 02-02-2018
Gender inequities in dental research publications: Findings from 20 years
Publisher: Wiley
Date: 22-12-2022
DOI: 10.1111/CDOE.12831
Abstract: The first steps towards gender equity in science are measuring the magnitude of inequity and increasing awareness of the problem. To describe trends in gender disparities in first and last authorship in the most cited dental publications and general dental literature over a 20‐year period. Articles and bibliometric data were retrieved from the Scopus database for the period 1996 to 2015. Two groups of 1000 articles each were retrieved: a random s le and another s le of top‐cited articles for each year. The gender of the first and last author of each publication was manually identified. When this was not possible, we used an online software platform ( genderize.io/ ). Descriptive analyses identified the proportion of women first and last authors in both s les, stratifying by dental discipline and geographic region. Trends were ascertained by frequency metrics across years. Gender disparity was observed in both first and last authorship, with a larger gap being observed in the top‐cited s le. Women led 28.4% and 20.3% of articles in the random and top‐cited s les, respectively. A similar pattern was observed for the last authorship group (22.1% and 16.1%, respectively). An increasing trend in the proportion of articles led by women over time was observed in both s les. This increase was larger in the top‐cited s le (from 15.0% in 1996–2000 to 25.1% in 2015) than in the random s le (from 26.3% in 1996–2000 to 33.2% in 2011). Clear gender disparities in dental research publications in the last 20 years were identified in both general and top‐cited manuscripts, across dental disciplines, across countries, across first and last authorship, and over time. It is paramount that actions are taken to attract, retain and promote women in science, as well as to monitor and ensure progress towards gender equity.
Influenza vaccine–induced human bone marrow plasma cells decline within a year after vaccination
Publisher: American Association for the Advancement of Science (AAAS)
Date: 09-10-2020
Abstract: The seasonal flu shot is currently recommended each year because the influenza viral strains in circulation are continuously changing and because the antibody responses produced by the vaccine decline over time. In a human study of healthy volunteers, Davis et al. tracked antibody responses after flu vaccination. They investigated whether the vaccine led to the generation of antibody-secreting plasma cells in the bone marrow, a lymphoid organ that supports the survival of these cells for years. Although vaccination did generate influenza-specific cells, most were short-lived and lost within 1 year. The fact that a small number did persist over 1 year raises prospects that the longevity of flu vaccines can be improved and provides key information for the development of universal vaccines against influenza. Science , this issue p. 237
Human B Cell Clonal Expansion and Convergent Antibody Responses to SARS-CoV-2
Publisher: Elsevier BV
Date: 10-2020
Genetic variation in the immunoglobulin heavy chain locus shapes the human antibody repertoire
Publisher: Springer Science and Business Media LLC
Date: 21-07-2023
DOI: 10.1038/S41467-023-40070-X
Abstract: Variation in the antibody response has been linked to differential outcomes in disease, and suboptimal vaccine and therapeutic responsiveness, the determinants of which have not been fully elucidated. Countering models that presume antibodies are generated largely by stochastic processes, we demonstrate that polymorphisms within the immunoglobulin heavy chain locus (IGH) impact the naive and antigen-experienced antibody repertoire, indicating that genetics predisposes in iduals to mount qualitatively and quantitatively different antibody responses. We pair recently developed long-read genomic sequencing methods with antibody repertoire profiling to comprehensively resolve IGH genetic variation, including novel structural variants, single nucleotide variants, and genes and alleles. We show that IGH germline variants determine the presence and frequency of antibody genes in the expressed repertoire, including those enriched in functional elements linked to V(D)J recombination, and overlapping disease-associated variants. These results illuminate the power of leveraging IGH genetics to better understand the regulation, function, and dynamics of the antibody response in disease.
Do people trust dentists? Development of the Dentist Trust Scale
Publisher: Wiley
Date: 07-06-2017
DOI: 10.1111/ADJ.12514
Abstract: This study aimed to adapt a measure of trust in physicians to trust in dentists and to assess the reliability and validity of the measure. Questionnaire data were collected from a simple random s le of 596 Australian adults. The 11-item General Trust in Physicians Scale was modified to apply to dentists. The Dentist Trust Scale (DTS) had good internal consistency (α = 0.92) and exploratory factor analysis revealed a single-factor solution. Lower DTS scores were associated with less trust in the dentist last visited, having previously changed dentists due to unhappiness with the care received, currently having dental pain, usual visiting frequency, dental avoidance, and with past experiences of discomfort, gagging, fainting, embarrassment and personal problems with the dentist. The majority of people appear to exhibit trust in dentists. The DTS shows promising reliability and validity evidence.
Convergent Antibody Signatures in Human Dengue
Publisher: Elsevier BV
Date: 06-2013
The reported germline repertoire of human immunoglobulin kappa chain genes is relatively complete and accurate
Publisher: Springer Science and Business Media LLC
Date: 20-08-2008
DOI: 10.1007/S00251-008-0325-Z
Abstract: We describe a bioinformatic analysis of germline and rearranged immunoglobulin kappa chain (IGK) gene sequences, performed in order to assess the completeness and reliability of the reported IGK repertoire. In contrast to the reported heavy-chain gene repertoire, which includes many dubious sequences, only five IGK variable gene (IGKV) alleles appear to have been reported in error. There was, however, insufficient evidence to justify removing these IGKV genes from the germline repertoire. Bioinformatic analysis of apparent mismatches between reported germline genes and 1,863 expressed IGK sequences suggested the existence of two unreported IGKV polymorphisms. Genomic screening of 12 in iduals led to the confirmation of both of these polymorphisms, IGKV1-16*02 and IGKV2-30*02. We also show that in contrast to the heavy chain, the IGK repertoire is dominated by sequences that use just a handful of kappa variable (IGKV) and junction (IGKJ) gene pairs. There is also little modification of IGKV and IGKJ genes by the processes of exonuclease removal and N nucleotide addition. The expressed IGK repertoire therefore lacks ersity and the junction region is particularly constrained. Remarkably, the analysis of a dataset of 435 relatively unmutated rearranged kappa genes showed that ten amino acid sequences account for almost 10% of the rearrangements, with identical sequences being derived from as many as seven independent sources. Such dominant sequences are likely to have important roles in the operation of the humoral immune response.
Single B-cell deconvolution of peanut-specific antibody responses in allergic patients
Publisher: Elsevier BV
Date: 2016
The Shape of the Lymphocyte Receptor Repertoire: Lessons from the B Cell Receptor
Publisher: Frontiers Media SA
Date: 2013
Exonuclease activity and P nucleotide addition in the generation of the expressed immunoglobulin repertoire
Publisher: Springer Science and Business Media LLC
Date: 2004
Comment on “A Database of Human Immune Receptor Alleles Recovered from Population Sequencing Data”
Publisher: The American Association of Immunologists
Date: 05-2017
Modeling human adaptive immune responses with tonsil organoids
Publisher: Springer Science and Business Media LLC
Date: 2021
High-fat diet induces systemic B-cell repertoire changes associated with insulin resistance
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1038/MI.2017.25
Abstract: The development of obesity-associated insulin resistance is associated with B-lymphocyte accumulation in visceral adipose tissue (VAT) and is prevented by B-cell ablation. To characterize potentially pathogenic B-cell repertoires in this disorder, we performed high-throughput immunoglobulin (Ig) sequencing from multiple tissues of mice fed high-fat diet (HFD) and regular diet (RD). HFD significantly changed the biochemical properties of Ig heavy-chain complementarity-determining region-3 (CDRH3) sequences, selecting for IgA antibodies with shorter and more hydrophobic CDRH3 in multiple tissues. A set of convergent antibodies of highly similar sequences found in the VAT of HFD mice but not RD mice showed significant somatic mutation, suggesting a response shared between mice to a common antigen or antigens. These findings indicate that a simple high-fat dietary intervention has a major impact on mouse B-cell repertoires, particularly in adipose tissues.
Clinical status in adolescents: is its impact on oral health-related quality of life influenced by psychological characteristics?
Publisher: Wiley
Date: 28-03-2013
DOI: 10.1111/EOS.12034
Abstract: The objective of this study was to examine, using structural equation modelling, the relationships among clinical characteristics (such as caries experience and malocclusion), oral health-related quality of life (OHRQoL), and psychological characteristics (mental health, self-esteem, somatisation, and social perception of body image) in adolescents in New Zealand. Adolescents were examined for malocclusion using the Dental Aesthetic Index (DAI) and for dental caries. Among the 353 (58.8%) 12- and 13-yr-old adolescents who took part in this cross-sectional study, the overall mean ± SD decayed, missing, or filled surfaces (DMFS) value was 1.6 ± 3.0, with slightly more than 50% of being caries-free the mean ± SD DAI was 31.5 ± 7.6, with one-quarter of subjects having a 'handicapping' malocclusion. The structural equation modelling analysis showed that the structural model was a good fit to the data. As hypothesized, the DAI score significantly predicted OHRQoL. There was no direct relationship between caries experience (DMFS) and OHRQoL, but there was an indirect effect of DMFS on OHRQoL mediated through psychological characteristics. The amount of OHRQoL variance accounted for in the model was substantial, at 62%. It appears that investigating OHRQoL in adolescents is not straightforward while malocclusion directly affects OHRQoL, the influence of dental caries experience is less direct.
Use of IGHJ and IGHD gene mutations in analysis of immunoglobulin sequences for the prognosis of chronic lymphocytic leukemia
Publisher: Elsevier BV
Date: 09-2007
DOI: 10.1016/J.LEUKRES.2006.10.013
Abstract: The level of somatic point mutation in immunoglobulin genes is an important prognostic indicator for patients with chronic lymphocytic leukemia (CLL). Mutation analysis presently focuses solely upon the heavy chain IGHV gene, however mutation is a stochastic process that also targets IGHD and IGHJ genes. Here, we evaluate the completeness and reliability of the reported IGHJ gene repertoire, and demonstrate the likely consequences of the inclusion of IGHD and IGHJ mutations in CLL analysis, using a dataset of 607 sequences. Inclusion of these mutations would lead to the re-classification of many sequences, which should significantly improve the prognostic value of mutation analysis.
IgE-associated IGHV genes from venom and peanut allergic individuals lack mutational evidence of antigen selection
Publisher: Public Library of Science (PLoS)
Date: 25-02-2014
Flexible, Fast and Accurate Sequence Alignment Profiling on GPGPU with PaSWAS
Publisher: Public Library of Science (PLoS)
Date: 04-2015
Genomic screening by 454 pyrosequencing identifies a new human IGHV gene and sixteen other new IGHV allelic variants
Publisher: Springer Science and Business Media LLC
Date: 20-01-2011
DOI: 10.1007/S00251-010-0510-8
Abstract: Complete and accurate knowledge of the genes and allelic variants of the human immunoglobulin gene loci is critical for studies of B cell repertoire development and somatic point mutation, but evidence from studies of VDJ rearrangements suggests that our knowledge of the available immunoglobulin gene repertoire is far from complete. The reported repertoire has changed little over the last 15 years. This is, in part, a consequence of the inefficiencies involved in searching for new members of large, multigenic gene families by cloning and sequencing. The advent of high-throughput sequencing provides a new avenue by which the germline repertoire can be explored. In this report, we describe pyrosequencing studies of the heavy chain IGHV1, IGHV3 and IGHV4 gene subgroups in ten Papua New Guineans. Thousands of 454 reads aligned with complete identity to 51 previously reported functional IGHV genes and allelic variants. A new gene, IGHV3-NL1*01, was identified, which differs from the nearest previously reported gene by 15 nucleotides. Sixteen new IGHV alleles were also identified, 15 of which varied from previously reported functional IGHV genes by between one and four nucleotides, while one sequence appears to be a functional variant of the pseudogene IGHV3-25. BLAST searches suggest that at least six of these new genes are carried within the relatively well-studied populations of North America, Europe or Asia. This study substantially expands the known immunoglobulin gene repertoire and demonstrates that genetic variation of immunoglobulin genes can now be efficiently explored in different human populations using high-throughput pyrosequencing.
On being the right size: antibody repertoire formation in the mouse and human
Publisher: Springer Science and Business Media LLC
Date: 19-12-2017
DOI: 10.1007/S00251-017-1049-8
Abstract: The immune systems of all mammals include populations of B cells producing antibodies with incredibly erse specificities. Repertoire ersity has been described as the "miracle of immunology," and it was long thought to be the result of essentially stochastic processes. Recently, however, analysis of high throughput gene sequencing data has shown that hard-wired biases in these processes result in antibody repertoires that are broadly predictable. The repertoires of mice and humans are both predictable, but they are strikingly different. In this review, features of the naïve antibody repertoires of the two species are contrasted. We show that the mouse repertoire includes a conspicuous population of public clonotypes that are shared by different in iduals of an inbred strain. These clonotypes are the result of gene rearrangements that involve little gene processing. By skewing repertoire formation toward such sequences, which probably target commonly encountered pathogens, it may be that the relatively small mouse repertoire is appropriate and effective despite its size. Species like the mouse face challenges that are a direct consequence of their small body sizes and the limitations this places on the antibody arsenal-particularly early in ontogeny. We propose that it is the differences in the naïve repertoires of mice and humans, and the differences in the ways these repertoires are used, which ensure that the very different biological needs of the two species are met. The processes that contribute to repertoire formation may appear to be stochastic, but in both species, evolution has left little to chance.
Broadening Horizons: New Antibodies Against Influenza
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.CELL.2016.07.023
Abstract: Seasonal influenza vaccine formulation efforts struggle to keep up with viral antigenic variation. Two studies now report engineered or naturally occurring human antibodies targeting the influenza hemagglutinin (HA) stem, with exceptional neutralizing breadth (Joyce et al., 2016 Kallewaard et al., 2016). Antibodies with similar structural features are elicited in multiple subjects, suggesting that modified vaccine regimens could provide broad protection.
A comparison of immunoglobulin IGHV, IGHD and IGHJ genes in wild-derived and classical inbred mouse strains
Publisher: Cold Spring Harbor Laboratory
Date: 08-05-2019
DOI: 10.1101/631754
Abstract: The genomes of classical inbred mouse strains include genes derived from all three major subspecies of the house mouse, Mus musculus . We recently posited that genetic ersity in the immunoglobulin heavy chain (IGH) gene loci of C57BL/6 and BALB/c mice reflect differences in subspecies origin. To investigate this hypothesis, we conducted high-throughput sequencing of IGH gene rearrangements to document IGH variable (IGHV), joining (IGHJ), and ersity (IGHD) genes in four inbred wild-derived mouse strains (CAST/EiJ, LEWES/EiJ, MSM/MsJ, and PWD/PhJ), and a single disease model strain (NOD/ShiLtJ), collectively representing genetic backgrounds of several major mouse subspecies. A total of 341 germline IGHV sequences were inferred in the wild-derived strains, including 247 not curated in the International Immunogenetics Information System. In contrast, 83/84 inferred NOD IGHV genes had previously been observed in C57BL/6 mice. Variability among the strains examined was observed for only a single IGHJ gene, involving a description of a novel allele. In contrast, unexpected variation was found in the IGHD gene loci, with four previously unreported IGHD gene sequences being documented. Very few IGHV sequences of C57BL/6 and BALB/c mice were shared with strains representing major subspecies, suggesting that their IGH loci may be complex mosaics of genes of disparate origins. This suggests a similar level of ersity is likely present in the IGH loci of other classical inbred strains. This must now be documented if we are to properly understand inter-strain variation in models of antibody-mediated disease.
Improvement of immune dysregulation and health-related quality of life in individuals with long COVID at 24-months following SARS-CoV-2 infection
Publisher: Cold Spring Harbor Laboratory
Date: 28-08-2023
DOI: 10.1101/2023.08.27.23294704
Abstract: This study investigated the humoral and cellular immune responses in in iduals with long COVID (LC) compared to age and gender matched recovered COVID-19 controls (MC) over 24-months. LC participants showed elevated spike and nucleocapsid IgG levels, higher neutralizing capacity, and increased spike- and nucleocapsid-specific CD4+ T cells, PD-1, and TIM-3 expression on CD4+ and CD8+ T cells at 3- and 8-months, but these differences did not persist at 24-months. Some LC participants had detectable IFN-γ and IFN-β, that was attributed to reinfection and antigen re-exposure. Single-cell RNA sequencing at 24-month timepoint revealed similar immune cell proportions and reconstitution of naïve T and B cell subsets in LC. No significant differences in exhaustion scores or antigen-specific T cell clones were observed. These findings suggest resolution of immune activation in LC and return to comparable immune responses between LC and MC over time. Improvement in self-reported health-related quality of life at 24-months was also evident in the majority of LC (62%). PTX3, CRP levels and platelet count were associated with improvements in health-related quality of life.
Evolution and development of methodologies in social and behavioural science research in relation to oral health
Publisher: Wiley
Date: 02-2023
DOI: 10.1111/CDOE.12821
Abstract: The aim of this introductory paper is to provide an overview of key methodological developments in social and behavioural research in oral health. In the first section, we provide a brief historical perspective on research in the field. In the second section, we outline key methodological issues and introduce the seven papers in the theme. Conceptual models can contextualize research findings and address the ‘why’ and ‘how’ instead of ‘what’ and ‘how many’. Many models exist, albeit they need to be evaluated (and adapted) for use in oral health research and in specific settings. The increasing availability of big data can facilitate this with data linkage. Through data linkage, it is possible to explore and understand in a broader capacity the array of factors that influence oral health outcomes and how oral health can influences other factors. With advances in statistical approaches, it is feasible to consider casual inferences and to quantify these effects. There is a need for not only in idual efforts to embrace causal inference research but also systematic and structural changes in the field to yield substantial results. The value of qualitative research in co‐producing knowledge with and from human participants in addressing ‘the how’ and ‘the why’ factors is also key. There have been calls to employ more sophisticated qualitative methods together with mixed methods approaches as ways of helping to address the complex or Wicked Problems in population oral health. In the final section, we outline possible future methodological directions in social and behavioural oral health research including participatory approaches and the development of core outcome sets. Our overriding goal in the paper is to facilitate a critical debate in relation to methodological issues which can be used to improve understanding and generate knowledge in population oral health and that this, in turn, will help inform oral health policy and practices.
Individual Variation in the Germline Ig Gene Repertoire Inferred from Variable Region Gene Rearrangements
Publisher: The American Association of Immunologists
Date: 15-06-2010
Abstract: In idual variation in the Ig germline gene repertoire leads to in idual differences in the combinatorial ersity of the Ab repertoire, but the study of such variation has been problematic. The application of high-throughput DNA sequencing to the study of rearranged Ig genes now makes this possible. The sequencing of thousands of VDJ rearrangements from an in idual, either from genomic DNA or expressed mRNA, should allow their germline IGHV, IGHD, and IGHJ repertoires to be inferred. In addition, where previously mere glimpses of ersity could be gained from sequencing studies, new large data sets should allow the rearrangement frequency of different genes and alleles to be seen with clarity. We analyzed the DNA of 108,210 human IgH chain rearrangements from 12 in iduals and determined their in idual IGH genotypes. The number of reportedly functional IGHV genes and allelic variants ranged from 45 to 60, principally because of variable levels of gene heterozygosity, and included 14 previously unreported IGHV polymorphisms. New polymorphisms of the IGHD3-16 and IGHJ6 genes were also seen. At heterozygous loci, remarkably different rearrangement frequencies were seen for the various IGHV alleles, and these frequencies were consistent between in iduals. The specific alleles that make up an in idual's Ig genotype may therefore be critical in shaping the combinatorial repertoire. The extent of genotypic variation between in iduals is highlighted by an in idual with aplastic anemia who appears to lack six contiguous IGHD genes on both chromosomes. These deletions significantly alter the potential expressed IGH repertoire, and possibly immune function, in this in idual.
Shaping of infant B cell receptor repertoires by environmental factors and infectious disease
Publisher: American Association for the Advancement of Science (AAAS)
Date: 27-02-2019
DOI: 10.1126/SCITRANSLMED.AAT2004
Abstract: Distinct environmental exposures are associated with the maturation of antibody types in early childhood.
Laboratory and Data Analysis Methods for Characterization of Human B Cell Repertoires by High-Throughput DNA Sequencing
Publisher: Springer New York
Date: 2015
DOI: 10.1007/978-1-4939-2963-4_17
Abstract: High-throughput DNA sequencing techniques have greatly accelerated the pace of research into the repertoires of antibody and T cell receptor gene rearrangements that confer antigen specificity to adaptive immune responses. Studies of aging-related changes in human B cell repertoires have benefited from the ability to detect and quantify thousands to millions of B cell clones in human s les, and study the mutational lineages and isotype switching relationships within each clonal lineage. Correlation of repertoire analysis with antibody gene data from antigen-specific B cells is poised to give much greater insight into clinically relevant B cell responses and memory storage. Here, we describe strategies for preparing and analyzing human antibody gene libraries for studying B cell repertoires.
Human Responses to Influenza Vaccination Show Seroconversion Signatures and Convergent Antibody Rearrangements
Publisher: Elsevier BV
Date: 07-2014
Primary caregivers' perceptions of factors influencing preschool children's oral health: social practices perspective
Publisher: BMJ
Date: 04-2023
DOI: 10.1136/BMJOPEN-2022-068444
Abstract: The role of primary caregivers in setting the foundation for a child’s oral health throughout life is well recognised. Due to the dominant behaviour-based approach, research to date has mainly focused on exploring in idual primary caregivers’ oral health knowledge and behaviours. A social science approach involving social practice theories moves beyond in idual attitudes, behaviour and choices to offer a better understanding of the ways in which collective activity relates to health. This qualitative metasynthesis will involve an interpretive synthesis of data found in published qualitative literature from developed countries. The aim of the metasynthesis is to identify social practices in families from published qualitative research with caregivers on preschool children’s oral health. This is a protocol for qualitative metasynthesis. The following databases will be used: MEDLINE, EMBASE, Global Health and Dentistry & Oral Sciences Source (DOSS) using the web-based database search platform Ovid, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Scopus. The research team has determined search strategies by using relevant key terms. Qualitative studies published in English language on family factors related to preschool children (aged 0–5 years) from developed countries (2022 United Nations classification) will be included. Qualitative data analysis will involve thematic analysis of the reported factors influencing oral health of preschool children, from the perspective of social practice theory. Researchers will use NVivo software for organising and managing the data. No ethics approval is required, as this study does not involve human subjects. Findings will be disseminated through professional networks, conference presentations and submission to a peer-reviewed journal.
Defining antigen-specific plasmablast and memory B cell subsets in human blood after viral infection or vaccination
Publisher: Springer Science and Business Media LLC
Date: 15-08-2016
DOI: 10.1038/NI.3533
Identifying highly mutated IGHD genes in the junctions of rearranged human immunoglobulin heavy chain genes
Publisher: Elsevier BV
Date: 07-2007
DOI: 10.1016/J.JIM.2007.04.011
Abstract: The reliable identification of IGHD genes within human immunoglobulin heavy chains is challenging with up to one third of rearrangements having no identifiable IGHD gene. The short, mutated IGHD genes are generally assumed to be indistinguishable from the N-REGIONS of non-template encoded nucleotides that surround them. In this study we have characterised N-REGIONS, demonstrating the importance of nucleotide composition biases in the addition process, including the formation of homopolymer tracts. We then use a simulation approach to determine the likelihood of misidentification of highly mutated IGHD genes among the JUNCTION nucleotides. These likelihoods provide general rules for the identification of mutated D-REGIONs, and suggest that longer D-REGIONs (>25 nucleotides) with as many as ten mutations can be identified with a low risk of error. Shorter D-REGIONs (>16 nucleotides) with as many as four mutations are also identifiable. The reliability of different alignments is dependent upon the junction length (combined N-REGIONs and D-REGION). Data is presented that can guide the alignment of sequences with junction lengths from 5 to 50 nucleotides, including explicit selection between two D-REGION possibilities. The use of such a statistically-based approach to the alignment of IGHD genes will improve the reliability of the partitioning of immunoglobulin sequences, and this in turn will facilitate the study of the many processes that contribute to the ersity of the immunoglobulin repertoire.
Activated PI3Kδ breaches multiple B cell tolerance checkpoints and causes autoantibody production
Publisher: Rockefeller University Press
Date: 16-12-2019
DOI: 10.1084/JEM.20191336
Abstract: Antibody-mediated autoimmune diseases are a major health burden. However, our understanding of how self-reactive B cells escape self-tolerance checkpoints to secrete pathogenic autoantibodies remains incomplete. Here, we demonstrate that patients with monogenic immune dysregulation caused by gain-of-function mutations in PIK3CD, encoding the p110δ catalytic subunit of phosphoinositide 3-kinase (PI3K), have highly penetrant secretion of autoreactive IgM antibodies. In mice with the corresponding heterozygous Pik3cd activating mutation, self-reactive B cells exhibit a cell-autonomous subversion of their response to self-antigen: instead of becoming tolerized and repressed from secreting autoantibody, Pik3cd gain-of-function B cells are activated by self-antigen to form plasmablasts that secrete high titers of germline-encoded IgM autoantibody and hypermutating germinal center B cells. However, within the germinal center, peripheral tolerance was still enforced, and there was selection against B cells with high affinity for self-antigen. These data show that the strength of PI3K signaling is a key regulator of pregerminal center B cell self-tolerance and thus represents a druggable pathway to treat antibody-mediated autoimmunity.
Benchmarking the performance of human antibody gene alignment utilities using a 454 sequence dataset
Publisher: Oxford University Press (OUP)
Date: 29-10-2010
DOI: 10.1093/BIOINFORMATICS/BTQ604
Abstract: Motivation: Immunoglobulin heavy chain genes are formed by recombination of genes randomly selected from sets of IGHV, IGHD and IGHJ genes. Utilities have been developed to identify genes that contribute to observed VDJ rearrangements, but in the absence of datasets of known rearrangements, the evaluation of these utilities is problematic. We have analyzed thousands of VDJ rearrangements from an in idual (S22) whose IGHV, IGHD and IGHJ genotype can be inferred from the dataset. Knowledge of this genotype means that the Stanford_S22 dataset can serve to benchmark the performance of IGH alignment utilities. Results: We evaluated the performance of seven utilities. Failure to partition a sequence into genes present in the S22 genome was considered an error, and error rates for different utilities ranged from 7.1% to 13.7%. Availability: Supplementary data includes the S22 genotypes and alignments. The Stanford_S22 dataset and an evaluation tool is available at www.emi.unsw.edu.au/~ihmmune/IGHUtilityEval/. Contact: katherine.jackson@unsw.edu.au Supplementary information: Supplementary data are available at Bioinformatics online.
Inferred Allelic Variants of Immunoglobulin Receptor Genes: A System for Their Evaluation, Documentation, and Naming
Publisher: Frontiers Media SA
Date: 18-03-2019
HIV-1 Envelope gp41 Antibodies Can Originate from Terminal Ileum B Cells that Share Cross-Reactivity with Commensal Bacteria
Publisher: Elsevier BV
Date: 08-2014
Human T-bet governs the generation of a distinct subset of CD11c high CD21 low B cells
Publisher: American Association for the Advancement of Science (AAAS)
Date: 04-07-0004
DOI: 10.1126/SCIIMMUNOL.ABQ3277
Abstract: High-level expression of the transcription factor T-bet characterizes a phenotypically distinct murine B cell population known as “age-associated B cells” (ABCs). T-bet–deficient mice have reduced ABCs and impaired humoral immunity. We describe a patient with inherited T-bet deficiency and largely normal humoral immunity including intact somatic hypermutation, affinity maturation and memory B cell formation in vivo, and B cell differentiation into Ig-producing plasmablasts in vitro. Nevertheless, the patient exhibited skewed class switching to IgG1, IgG4, and IgE, along with reduced IgG2, both in vivo and in vitro. Moreover, T-bet was required for the in vivo and in vitro development of a distinct subset of human B cells characterized by reduced expression of CD21 and the concomitantly high expression of CD19, CD20, CD11c, FCRL5, and T-bet, a phenotype that shares many features with murine ABCs. Mechanistically, human T-bet governed CD21 lo CD11c hi B cell differentiation by controlling the chromatin accessibility of lineage-defining genes in these cells: FAS , IL21R , SEC61B , DUSP4 , DAPP1 , SOX5 , CD79B , and CXCR4 . Thus, human T-bet is largely redundant for long-lived protective humoral immunity but is essential for the development of a distinct subset of human CD11c hi CD21 lo B cells.
Human immunoglobulin classes and subclasses show variability in VDJ gene mutation levels
Publisher: Wiley
Date: 10-06-2014
DOI: 10.1038/ICB.2014.44
Abstract: Somatic point mutations provide glimpses into B-cell histories, and mutation numbers generally correlate with antibody affinity. We recently proposed a model of human isotype function, based in part on mutation analysis, in which the dominant pathway of isotype switching involves B cells moving sequentially through the four immunoglobulin (Ig) G subclasses. This should result in predictable differences in affinity between isotypes, and this helps explain how different isotypes work together. The model built on analysis of rearranged immunoglobulin heavy chain sequences lified from Papua New Guinean villagers, which showed highly significant differences in the mean number of V-REGION mutations in sequences, associated with the different IgG subclasses. To determine whether this relationship between mutation levels and isotypes is a more general phenomenon, the present study was conducted in healthy, urban residents of Sydney, Australia. VDJ sequences were generated from eight in iduals, using 454 pyrosequencing, from cells expressing all isotypes except IgD and IgE. This resulted in 35 118 unique, productive VDJ sequences for the study. The data confirm that VDJ genes associated with progressively more 3' Ig heavy chain gamma (IGHG) constant region genes show increasing levels of point mutation. Mean V-REGION mutations in IgA1 and IgA2 sequences were similar. Patterns of mutations also differed between isotypes. Despite their association with T-independent responses, IgG2 sequences showed significantly more mutational evidence of antigen selection than other IgG isotypes. Antigen selection was also significantly higher in IgA2 than in IgA1 sequences, raising the possibility of a preferential switch pathway from IGHG2 to IGHA2.
Many human immunoglobulin heavy‐chain IGHV gene polymorphisms have been reported in error
Publisher: Wiley
Date: 27-11-2007
Abstract: The identification of the genes that make up rearranged immunoglobulin genes is critical to many studies. For ex le, the enumeration of mutations in immunoglobulin genes is important for the prognosis of chronic lymphocytic leukemia, and this requires the accurate identification of the germline genes from which a particular sequence is derived. The immunoglobulin heavy-chain variable (IGHV) gene repertoire is generally considered to be highly polymorphic. In this report, we describe a bioinformatic analysis of germline and rearranged immunoglobulin gene sequences which casts doubt on the existence of a substantial proportion of reported germline polymorphisms. We report a five-level classification system for IGHV genes, which indicates the likelihood that the genes have been reported accurately. The classification scheme also reflects the likelihood that germline genes could be incorrectly identified in mutated VDJ rearrangements, because of similarities to other alleles. Of the 226 IGHV alleles that have previously been reported, our analysis suggests that 104 of these alleles almost certainly include sequence errors, and should be removed from the available repertoire. The analysis also highlights the presence of common mismatches, with respect to the germline, in many rearranged heavy-chain sequences, suggesting the existence of twelve previously unreported alleles. Sequencing of IGHV genes from six in iduals in this study confirmed the existence of three of these alleles, which we designate IGHV3-49*04, IGHV3-49*05 and IGHV4-39*07. We therefore present a revised repertoire of expressed IGHV genes, which should substantially improve the accuracy of immunoglobulin gene analysis.
Related Organisations
University Of Sheffield
Location: United Kingdom of Great Britain and Northern Ireland
Stanford University School Of Medicine
Location: United States of America
Related Funding Activities
Discovery Projects - Grant ID: DP210101166
Start Date: 04-2021
End Date: 04-2025
Amount: $660,000.00
Funder: Australian Research Council
View Funded Activity