48 research outputs found
Ig gene diversification and selection in follicular lymphoma, diffuse large B cell lymphoma and primary central nervous system lymphoma revealed by lineage tree and mutation analyses
No full textFollicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL) and primary central nervous system lymphoma are B cell malignancies. FL and DLBCL have a germinal center origin. We have applied mutational analyses and a novel algorithm for quantifying shape properties of mutational lineage trees to investigate the nature of the diversification, somatic hypermutation and selection processes that affect B cell clones in these malignancies and reveal whether they differ from normal responses. Lineage tree analysis demonstrated higher diversification and mutations per cell in the lymphoma clones. This was caused solely by the longer diversification times of the malignant clones, as their recent diversification processes were similar to those of normal responses, implying similar mutation frequencies. Since previous analyses of antigen-driven selection were shown to yield false positives, we performed a corrected analysis of replacement and silent mutation patterns, which revealed selection against replacement mutations in the framework regions, responsible for the structural integrity of the B cell receptor, but not for positive selection for replacements in the complementary determining regions. Most replacements, however, were neutral or conservative, suggesting that if at all selection operates in these malignancies it is for structural B cell receptor integrity but not for antigen binding
Kinetic modeling reveals a common death niche for newly formed and mature B cells.
No full textB lymphocytes are subject to elimination following strong BCR ligation in the absence of appropriate second signals, and this mechanism mediates substantial cell losses during late differentiation steps in the bone marrow and periphery. Mature B cells may also be eliminated through this mechanism as well as through normal turnover, but the population containing mature cells destined for elimination has not been identified. Herein, we asked whether the transitional 3 (T3) subset, which contains most newly formed cells undergoing anergic death, could also include mature B cells destined for elimination.To interrogate this hypothesis and its implications, we applied mathematical models to previously generated in vivo labeling data. Our analyses reveal that the death rate of T3 B cells is far higher than the death rates of all other splenic B cell subpopulations. Further, the model, in which the T3 pool includes both newly formed and mature primary B cells destined for apoptotic death, shows that this cell loss may account for nearly all mature B cell turnover.This finding has implications for the mechanism of normal mature B cell turnover
Immunoglobulin variable-region gene mutational lineage tree analysis: application to autoimmune diseases
No full textLineage trees have frequently been drawn to illustrate diversification, via somatic hypermutation (SHM), of immunoglobulin variable-region (IGV) genes. In order to extract more information from IGV sequences, we developed a novel mathematical method for analyzing the graphical properties of IgV gene lineage trees, allowing quantification of the differences between the dynamics of SHM and antigen-driven selection in different lymphoid tissues, species, and disease situations. Here, we investigated trees generated from published IGV sequence data from B cell clones participating in autoimmune responses in patients with Myasthenia Gravis (MG), Rheumatoid Arthritis (RA), and Sjögren's Syndrome (SS). At present, as no standards exist for cell sampling and sequence extraction methods, data obtained by different research groups from two studies of the same disease often vary considerably. Nevertheless, based on comparisons of data groups within individual studies, we show here that lineage trees from different individual patients are often similar and can be grouped together, as can trees from two different tissues in the same patient, and even from IgG- and IgA-expressing B cell clones. Additionally, lineage trees from most studies reflect the chronic character of autoimmune diseases
Abstract CT108: Tumor treating fields (TTFields) in combination with Lomustine (CCNU) in the EF-14 phase III clinical study: A safety analysis
No full textBrdU labeling kinetics.
No full text<p>These kinetics were obtained by a simulation of the spleen population model <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009497#pone.0009497-Mehr1" target="_blank">[25]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009497#pone.0009497-Shahaf1" target="_blank">[26]</a> with the parameter set that gave the best fit to the data <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009497#pone.0009497-Allman3" target="_blank">[28]</a>. Parameter values are given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009497#pone-0009497-t002" target="_blank">Table 2</a>. Simulation results (dashed lines) are presented along with the experimental results (symbols with error bars).</p
Parameter ranges that result from the simulation.
No full texta<p>Rates are per 6 hours.</p>b<p>Models that obey our parameter choice criteria and fit the experimental data.</p
Cell numbers versus time in a simulation of the spleen population model.
No full text<p>These numbers were obtained by a simulation with the parameters set that gave the best fit to the data. Parameter values are given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009497#pone-0009497-t002" target="_blank">Table 2</a>. The steady-state numbers are: T1/2: 1.17×10<sup>6</sup> cells, T3: 1.43×10<sup>6</sup> cells, and Mature FO: 2.51×10<sup>6</sup> cells.</p
