Biomedical subjects

Gitit Shahaf

Publications and source records attributed to Gitit Shahaf.

7 recordsLinked to original sources

PubMed2006

Novel analysis of clonal diversification in blood B cell and bone marrow plasma cell clones in immunoglobulin light chain amyloidosis.

Immunoglobulin light chain amyloidosis (AL) is characterized by a limited clonal expansion of plasma cells and amyloid formation. Here, we report restriction in the diversity of VL gene usage with a dominance of clonally related B cells in the peripheral blood (PB) isotype-specific repertoire of AL patients. A rigorous quantification of lineage trees reveals presence of intraclonal variations in the PB clones compared to the bone marrow (BM) clones, which suggests a common precursor that is still subject to somatic mutation. When compared to normal BM and PB B cells, AL clones showed significant but incomplete impairment of antigenic selection, which could not be detected by conventional R and S mutation analysis. Therefore, graphical analysis of B cell lineage trees and mathematical quantification of tree properties provide novel insights into the process of B cell clonal evolution in AL.

Algorithms↗

PubMed2006

Quantitative analysis of clonal bone marrow CD19+ B cells: use of B cell lineage trees to delineate their role in the pathogenesis of light chain amyloidosis.

Light chain amyloidosis (AL) is a bone marrow (BM) plasma cell neoplasia with systemic deposition of Ig light chain amyloid fibrils. Here, we report the identification of clonal CD19 B cells in the BM and the use of a novel mathematical algorithm to generate B cell lineage trees of the clonal CD19 B cells and CD138 plasma cells from the BM of AL patients to delineate the relationship between these two clonal populations. The CD19+ clonal B cells in the BM of AL patients related to the clonal plasma cells represent a pre-plasma cell precursor population. The B cell lineage trees from AL patients also show significant differences in clonal diversification and antigenic selection compared to clones from normal, healthy controls. These data provide a robust example of the use of graphical quantification methods in delineating the role of neoplastic precursors in the pathogenesis of hematopoietic malignancies.

Algorithms↗

PubMed2005

B cell development in aging mice: lessons from mathematical modeling.

Previous studies have not completely clarified the precise defect that characterizes B cell development in aged animals. The question of which developmental mechanism is actually deficient in aging remains controversial. The goal of this study was to elucidate the effects of aging on bone marrow B cell population dynamics. We used mathematical modeling to predict the outcome of the different possible effects, and then compared these predictions to experimental data, to find the most plausible effects. Our model shows that the three main differences between B cell development in young and old mice are a decrease in the maximum number of cells in the pre-B compartment and increases in the rate of transition from cycling pre-B cells to resting pre-B cells and in the fractions of static cells included in the immature B cell subset.

Aging↗

PubMed2005

Immunoglobulin variable-region gene mutational lineage tree analysis: application to autoimmune diseases.

Lineage 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.

Arthritis, Rheumatoid↗

PubMed2004

Screening of alternative models for transitional B cell maturation.

Several functional and phenotypic B cell populations have been described in the spleen. These include the 'transitional' subsets, which are thought to be late differentiation intermediates of marrow-derived, mature follicular B cells. The exact progenitor-successor relationships of these transitional subsets, as well as whether a proliferative step is requisite for follicular B cell maturation, remain controversial. Moreover, whether late B cell differentiation might involve branched or asynchronous maturation pathways, thus allowing some cells to 'skip' one or more of these stages, has not been investigated. Herein we have used mathematical modeling to interrogate these possibilities. Using mathematical models that numerically simulate splenic B cell population dynamics, we have determined which alternative models of differentiation best fit existing in vivo labeling data. Our results indicate that follicular differentiation does not involve a proliferating splenic intermediate. Our results further suggest that some developing cells move directly from the immature marrow pool to more advanced semi-mature peripheral subsets without passing through the least mature subset in the spleen.

Animals↗

PubMed2003

Maximum likelihood estimator and likelihood ratio test in complex models: an application to B lymphocyte development.

In this paper we introduce a simple framework which provides a basis for estimating parameters and testing statistical hypotheses in complex models. The only assumption that is made in the model describing the process under study, is that the deviations of the observations from the model have a multivariate normal distribution. The application of the statistical techniques presented in this paper may have considerable utility in the analysis of a wide variety of complex biological and epidemiological models. To our knowledge, the model and methods described here have not previously been published in the area of theoretical immunology.

Animals↗

PubMed2003

Asynchronous differentiation models explain bone marrow labeling kinetics and predict reflux between the pre- and immature B cell pools.

B lymphopoiesis has historically been depicted as a unidirectional process, in which cohorts of developing cells transit through successive differentiative stages in an irreversible, synchronous manner. Here, we examine this view by combining kinetic analysis of developing B cell subsets in the bone marrow with mathematical modeling. Our bromo-deoxyuridine (BrdU) labeling data are incompatible with B cell development being a synchronous process, because labeling curves are non-linear. Moreover, we show that B cell development may not be completely unidirectional, because our results support the possibility of a phenotypic "reflux" among the immature to the pre-B cell subsets.

Animals↗