Immunoglobulin repertoire sequencing has successfully been applied to identify expanded antigen-activated B-cell clones that play a role in the pathogenesis of immune disorders. One challenge is the selection of the Ag-specific B cells from the measured repertoire for downstream analyses. A general feature of an immune response is the expansion of specific clones resulting in a set of subclones with common ancestry varying in abundance and in the number of acquired somatic mutations. The expanded subclones are expected to have BCR affinities for the Ag higher than the affinities of the naive B cells in the background population. For these reasons, several groups successfully proceeded or suggested selecting highly abundant subclones from the repertoire to obtain the Ag-specific B cells. Given the nature of affinity maturation one would expect that abundant subclones are of high affinity but since repertoire sequencing only provides information about abundancies, this can only be verified with additional experiments, which are very labor intensive. Moreover, this would also require knowledge of the Ag, which is often not available for clinical samples. Consequently, in general we do not know if the selected highly abundant subclone(s) are also the high(est) affinity subclones. Such knowledge would likely improve the selection of relevant subclones for further characterization and Ag screening. Therefore, to gain insight in the relation between subclone abundancy and affinity, we developed a computational model that simulates affinity maturation in a single GC while tracking individual subclones in terms of abundancy and affinity. We show that the model correctly captures the overall GC dynamics, and that the amount of expansion is qualitatively comparable to expansion observed from B cells isolated from human lymph nodes. Analysis of the fraction of high- and low-affinity subclones among the unexpanded and expanded subclones reveals a limited correlation between abundancy and affinity and shows that the low abundant subclones are of highest affinity. Thus, our model suggests that selecting highly abundant subclones from repertoire sequencing experiments would not always lead to the high(est) affinity B cells. Consequently, additional or alternative selection approaches need to be applied.
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http://dx.doi.org/10.3389/fimmu.2017.00221 | DOI Listing |
Harmful Algae
November 2024
Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki-Aza-Aoba, Aoba-ku, Sendai, Miyagi 980-8572, Japan.
Paralytic shellfish poisoning is caused by saxitoxin (STX), and its analogues (paralytic shellfish toxins (PSTs)) produced by marine dinoflagellates. SxtA and SxtG are the most essential enzymes in STX biosynthesis. Previous studies investigated the abundance and subcellular localization (i.
View Article and Find Full Text PDFJ Biol Chem
October 2024
Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA. Electronic address:
The ST6GAL1 sialyltransferase is overexpressed in multiple cancers, including pancreatic ductal adenocarcinoma (PDAC). ST6GAL1 adds an α2-6-linked sialic acid to N-glycosylated membrane receptors, which consequently modulates receptor structure and function. While many studies have investigated the effects of ST6GAL1 on cell phenotype, there is a dearth of knowledge regarding mechanisms that regulate ST6GAL1 expression.
View Article and Find Full Text PDFMalariaworld J
August 2024
Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX 75080-3021 USA.
Introduction: The cadherin G-protein coupled receptor BT-R in the mosquito is a single membrane-spanning α-helical (bitopic) protein that represents the most abundant and functionally diverse group of membrane proteins. Binding of the Cry4B toxin of subsp. (Bti) to BT-R triggers a Mg2+-dependent signalling pathway in the mosquito that involves stimulation of G protein α-subunit, which subsequently launches a coordinated signalling cascade involving Na/K-ATPase.
View Article and Find Full Text PDFNatl Sci Rev
May 2024
Cancer Institute, Department of Pathology, Peking University Shenzhen Hospital, Shenzhen Peking University-the Hong Kong University of Science and Technology (PKU-HKUST) Medical Center; Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518000, China.
Esophageal squamous cell carcinoma (ESCC) is a poor-prognostic cancer type with extensive intra- and inter-patient heterogeneity in both genomic variations and tumor microenvironment (TME). However, the patterns and drivers of spatial genomic and microenvironmental heterogeneity of ESCC remain largely unknown. Here, we generated a spatial multi-omic atlas by whole-exome, transcriptome, and methylome sequencing of 507 tumor samples from 103 patients.
View Article and Find Full Text PDFBiochem Biophys Rep
July 2024
Department of Thoracic Oncology, Hangzhou Cancer Hospital, Hangzhou, 310002, PR China.
Background: Approximately 50% of patients harbor the T790M mutation after developing first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance. Evidence has showed the major treatment failure is local relapses and limited metastases. Several studies have demonstrated the value of radiotherapy in metastatic non-small cell lung cancer (NSCLC) with the EGFR T790M mutation after the development of TKI resistance.
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