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Freda K Stevenson - One of the best experts on this subject based on the ideXlab platform.
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Selective Expression of a VH1V Subfamily of Immunoglobulin Genes in Human CD5 +
2013Co-Authors: B Lymphocytes, Freda K Stevenson, Cord Blood, A Mageed, Lorna E Mackenzie, Bulend S Yuksel, Ii Fazel Shokri, Robert B. Maziak, Roy Jefferis, Peter M LydyardfAbstract:Human B lymphocytes expressing the CD5 surface antigen (CD5+ B cells) constitute a subset capable of producing polyspecific antibodies recognizing a variety of selfantigens. The repertoire of antibodies produced by CD5+ and CD5- B cells is different. However, it is not yet established whether this distribution is reflected in different Immunoglobulin Variable Region gene (IgV) use. Rearrangement of heavy chain IgV (IgV) genes represents one of the first identifiable stages in the maturation of B cells, and occurs in a developmentally ordered fashion. The repertoire of IgV gene expression is highly restricted during fetal life but diversifies progressively after birth. A high frequency of V gene use from the relatively small V IV gene family has previously been demonstrated in human fetal liver B cells. In the present study, 102 B cell lines established by Epstein-Barr Virus-transformation of separated CD5+ and CD5- cord blood B cells, were examined for the frequency of IgV expression using monoclonal antibodies to cross-reactive idiotypes (CRI). The results demonstrate a relatively high frequency of V IV gene use (30%) in B cells from cord blood. Furthermore, two mutually exclusive CRI associated with distinct subgroups of the V IV family are segregated in their association with either subset of B cells. One CRI is exclusively expressed in lines established from CD5 + B cells while the other is associated wit
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remarkable selective glycosylation of the Immunoglobulin Variable Region in follicular lymphoma
Molecular Immunology, 2008Co-Authors: Katy J Mccann, Christian H Ottensmeier, Alice Callard, Catherine M Radcliffe, David J Harvey, Raymond A Dwek, Pauline M Rudd, Brian J Sutton, Paul Hobby, Freda K StevensonAbstract:Follicular lymphoma (FL) generally expresses Immunoglobulin (Ig) with somatically mutated Variable (V) Region genes. Surprisingly, these almost always carry introduced motifs available for N-glycosylation (Asn-X-Ser/Thr). Introduced motifs are uncommon on normal B cells, but are on other germinal center (GC)-associated B-cell malignancies suggesting a site-specific role. They are not evident in mutated chronic lymphocytic leukemia (CLL) or myeloma. Recently, we found that the glycosylation sites are unusual in containing oligomannose glycans, which are apparently displayed on tumor cell surface IgM. This suggests a potential interaction with a mannose receptor in the GC. However, natural N-glycosylation sites exist in germline (GL) V Region genes, particularly the V4-34 gene expressed by normal B cells and by some malignancies, including CLL, potentially undermining the selective importance for FL. To compare oligosaccharide addition at the introduced and natural sites, we expressed V Region genes as single chain Fv (scFv) and analyzed the added glycans. In contrast to introduced sites, which were oligomannosylated, the natural GL motif in the V4-34 sequence had no added sugars. The remarkable selective glycosylation within the heavy chain V Region gene of FL apparently permits only limited processing to oligomannose at somatically mutated motifs, creating a feature exploitable by GC lymphomas.
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acquisition of potential n glycosylation sites in the Immunoglobulin Variable Region by somatic mutation is a distinctive feature of follicular lymphoma
Blood, 2002Co-Authors: Delin Zhu, Helen Mccarthy, Christian H Ottensmeier, Peter Johnson, Terry J Hamblin, Freda K StevensonAbstract:Most patients with follicular lymphoma (FL) have somatically mutated V genes with intraclonal variation, consistent with location in the germinal center site. Using our own and published sequences, we have investigated the frequency of potential N-glycosylation sites introduced into functional VH genes as a consequence of somatic mutation. FL cells were compared with normal memory B cells or plasma cells matched for similar levels of mutation. Strikingly, novel sites were detected in 55 of 70 (79%) patients with FL, compared to 7 of 75 (9%) in the normal B-cell population (P
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cd38 expression and Immunoglobulin Variable Region mutations are independent prognostic Variables in chronic lymphocytic leukemia but cd38 expression may vary during the course of the disease
Blood, 2002Co-Authors: Terry J Hamblin, Freda K Stevenson, Jenny A Orchard, Rachel E Ibbotson, Zadie Davis, Peter Thomas, David OscierAbstract:Although the presence or absence of somatic mutations in the Immunoglobulin Variable Region ( IgVH ) genes in chronic lymphocytic leukemia (B-CLL) identifies subtypes with very different prognoses, the assay is technically complex and unavailable to most laboratories. CD38 expression has been suggested as a surrogate marker for the 2 subtypes. IgVH mutations and CD38 expression in 145 patients with B-CLL with a long follow-up were compared. The 2 assays gave discordant results in 41 patients (28.3%). Multivariate analysis demonstrated that Binet stage, IgVH mutations and CD38 were independent prognostic indicators. Median survival time in patients whose cells had unmutated IgVH genes and expressed CD38 was 8 years; in those with mutated IgVH genes not expressing CD38, it was 26 years. For those with discordant results, median survival time was 15 years. Thus, although CD38 expression does not identify the same 2 subsets as IgVH mutations in CLL, it is an independent risk factor that can be used with IgVH mutations and clinical stage to select patients with B-CLL with the worst prognoses. Using cryopreserved cells taken at intervals during the course of the disease, however, changes of CD38 expression over time were demonstrated in 10 of 41 patients. Causes of the variation of CD38 expression require further study. Additional prospective studies are required for comparing CD38 expression with other prognostic factors and for taking sequential measurements during the course of the disease.
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insight into burkitt s lymphoma from Immunoglobulin Variable Region gene analysis
Leukemia & Lymphoma, 1998Co-Authors: Caroline J Chapman, D H Wright, Freda K StevensonAbstract:Analysis of usage of V(H) and V(L) genes, and the degree and pattern of somatic mutation, has been used to investigate the cell of origin and clonal history in cases of Burkitt's lymphoma (BL). Tumor cell lines and biopsy material from patients with endemic, sporadic and AIDS-associated BL have been compared. V(H) genes were most commonly derived from the V(H)3 (52%) and V(H)4 (39%) families. This shows a similar gene usage of the V(H)3 family to that seen in the normal peripheral blood repertoire (55%), but a biased usage of the V(H)4 family (22% in normal). There was no restriction in V(L) gene usage. This overall distribution was similar in all subsets of BL. In all categories, there was significant somatic mutation in both V(H) and V(L) sequences. There was no evidence for accumulation of mutations in cell lines cultured in vitro indicating that all mutations in BL-derived cell lines have accumulated in vivo. The mean percentage level of mutation +/- standard deviation was greater in endemic BL (V(H) = 7.7 +/- 4.0, V(L) = 5.3 +/- 2.2) and AIDS-associated BL (V(H) = 7.5 +/- 3.6, V(L) = 3.9 +/- 1.9) than in sporadic BL (V(H) = 4.0 +/- 2.5, V(L) = 2.2 +/- 1.2). The pattern of somatic hypermutation was similar in V(H) and V(L) sequences of the different types of BL although the light chain genes were less mutated. Mutational patterns in the V(H) genes did not reveal a conventional role for antigen in selection of tumor cell sequences in 23/25 V(H) genes analysed. In contrast, patterns in V(L) sequences were consistent with a role for antigen in 8/13 sBL +/- eBL cases and 8/17 cases overall. The presence of EBV did not seem to influence the quantity or pattern of somatic mutations. Evidence for intraclonal variation was seen in uncloned cell lines from cases of eBL and AIDS-associated BL and confirmed in biopsy material in some, but not all cases of eBL, sBL and AIDS-associated BL examined. These common features indicate that the B-cells involved in all types of BL are derived from cells that have traversed the germinal centre, and that the somatic mutation mechanism may still be operative following neoplastic transformation. Overall, in 10/30 cases, there was evidence of significant clustering of replacement amino acids, in CDRs, particularly in V(L), indicating that the B-cell of origin is likely to have been selected by antigen.
Terry J Hamblin - One of the best experts on this subject based on the ideXlab platform.
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determination of how many Immunoglobulin Variable Region heavy chain mutations are allowable in unmutated chronic lymphocytic leukaemia long term follow up of patients with different percentages of mutations
British Journal of Haematology, 2008Co-Authors: Terry J Hamblin, Zadie Davis, David OscierAbstract:The choice of 98% sequence homology for Immunoglobulin heavy chains to distinguish between mutated and unmutated versions of chronic lymphocytic leukaemia (CLL) was arbitrary and was chosen to account for supposed polymorphisms. Some authors chose 97% or even 95%. This study examined survival curves for cohorts of patients with varying degrees of sequence homology. All patients with 98% homology.
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acquisition of potential n glycosylation sites in the Immunoglobulin Variable Region by somatic mutation is a distinctive feature of follicular lymphoma
Blood, 2002Co-Authors: Delin Zhu, Helen Mccarthy, Christian H Ottensmeier, Peter Johnson, Terry J Hamblin, Freda K StevensonAbstract:Most patients with follicular lymphoma (FL) have somatically mutated V genes with intraclonal variation, consistent with location in the germinal center site. Using our own and published sequences, we have investigated the frequency of potential N-glycosylation sites introduced into functional VH genes as a consequence of somatic mutation. FL cells were compared with normal memory B cells or plasma cells matched for similar levels of mutation. Strikingly, novel sites were detected in 55 of 70 (79%) patients with FL, compared to 7 of 75 (9%) in the normal B-cell population (P
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cd38 expression and Immunoglobulin Variable Region mutations are independent prognostic Variables in chronic lymphocytic leukemia but cd38 expression may vary during the course of the disease
Blood, 2002Co-Authors: Terry J Hamblin, Freda K Stevenson, Jenny A Orchard, Rachel E Ibbotson, Zadie Davis, Peter Thomas, David OscierAbstract:Although the presence or absence of somatic mutations in the Immunoglobulin Variable Region ( IgVH ) genes in chronic lymphocytic leukemia (B-CLL) identifies subtypes with very different prognoses, the assay is technically complex and unavailable to most laboratories. CD38 expression has been suggested as a surrogate marker for the 2 subtypes. IgVH mutations and CD38 expression in 145 patients with B-CLL with a long follow-up were compared. The 2 assays gave discordant results in 41 patients (28.3%). Multivariate analysis demonstrated that Binet stage, IgVH mutations and CD38 were independent prognostic indicators. Median survival time in patients whose cells had unmutated IgVH genes and expressed CD38 was 8 years; in those with mutated IgVH genes not expressing CD38, it was 26 years. For those with discordant results, median survival time was 15 years. Thus, although CD38 expression does not identify the same 2 subsets as IgVH mutations in CLL, it is an independent risk factor that can be used with IgVH mutations and clinical stage to select patients with B-CLL with the worst prognoses. Using cryopreserved cells taken at intervals during the course of the disease, however, changes of CD38 expression over time were demonstrated in 10 of 41 patients. Causes of the variation of CD38 expression require further study. Additional prospective studies are required for comparing CD38 expression with other prognostic factors and for taking sequential measurements during the course of the disease.
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insight into the origin and clonal history of b cell tumors as revealed by analysis of Immunoglobulin Variable Region genes
Immunological Reviews, 1998Co-Authors: Freda K Stevenson, David Oscier, Delin Zhu, Christian H Ottensmeier, Caroline J Chapman, Surinder S Sahota, Terry J HamblinAbstract:Recombination of VH, DH and JH genes is a unique first step in normal B-cell development. Subsequent differentiation to a mature plasma cell is accompanied by further events in the Ig genes, including VL-JL joining, somatic hypermutation and isotype switching. Chromosomal changes leading to B-cell tumors can occur at many points in this sequence, and may be partly a consequence of the genetic mobility and mutability permitted in order to generate a diverse antibody repertoire. V genes of neoplastic B cells may reflect the point of maturation reached by the B cell of origin, prior to transformation. Analysis of tumors therefore provides useful information on V-gene patterns in normal B cells, and may add another dimension to classification of B-cell tumors. Transformation may also preserve cell populations normally destined to die by apoptosis. Tumor cells arrested in the site where somatic hypermutation and isotype switch are occurring can still be subject to these processes, and could be influenced by persisting antigen. However, mutation is silenced at the point of exit to the periphery, leading to fixed mutational patterns in tumors of mature B cells. V-gene analysis provides an invaluable tool for understanding the genesis of neoplastic change. It also has a clear clinical relevance in tracking tumor cells, measuring residual disease, and finally in offering the opportunity of developing vaccines for treatment.
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differential usage of an autoantibody associated vh gene vh4 21 by human b cell tumors
Leukemia & Lymphoma, 1995Co-Authors: Freda K Stevenson, Caroline J Chapman, M B Spellerberg, Terry J HamblinAbstract:Selection of Immunoglobulin Variable Region genes for recombination in B cells takes place from among those VH and VL gene segments available in the unrearranged germ line repertoire. In the case of neoplastic B cells, there is apparent deviation in the use of V-genes from that expected on a random basis, both for VH and for VL. Also, the preferred V-genes, and their patterns of mutation, differ among the various categories of B-cell tumor possibly reflecting the distinct origins and clonal histories on the individual tumor cells. This review focuses on a single VH gene, VH4-21, which is a member of the VH4 family, and which appears selectively to encode Immunoglobulins with autoantibody activity, particularly anti-red cell antibodies. The pattern of usage of this VH gene by B-cell tumors demonstrates clear asymmetry among different tumor types. Also, the mutations detected in this relatively non-polymorphic gene indicate that antigen, possibly autoantigen, may influence the behavior of the tumor cell.
Fazel Shokri - One of the best experts on this subject based on the ideXlab platform.
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Immunoglobulin heavy chain Variable Region gene usage and mutational status of the leukemic b cells in iranian patients with chronic lymphocytic leukemia
Cancer Science, 2009Co-Authors: Mohammad Hojjatfarsangi, Mahmood Jedditehrani, Seyed Mohsen Razavi, Fazel Shokri, Ramazan Ali Sharifian, Hakan Mellstedt, Hodjatallah RabbaniAbstract:The mutational status of the Immunoglobulin Variable Region heavy chain genes (IGHV) is an important prognostic marker in chronic lymphocytic leukemia (CLL). The data accumulated in the literature has largely been derived from studies conducted on Caucasian Western populations. Little is known about Asian CLL patients. In this study the IGHV genes usage and somatic hypermutation status have been investigated in 87 Iranian CLL patients. Based on a cut-off of 98% nucleotide sequence homology, 64.4% and 35.6% of the patients expressed mutated and unmutated IGHV genes, respectively, with most non-progressive patients being in the mutated group (35/44 vs 19/40; P = 0.009). Progression-free survival (PFS) and time to first treatment (TTFT) were significantly higher in our mutated and non-progressive patients compared to unmutated and progressive subtypes, respectively. The most frequently used IGHV gene was IGHV3-7 (12.6%) followed by IGHV3-30 (11.4%), IGHV3-48 (9.2%), IGHV4-39 (6.9%), and IGHV1-8 (6.9%) genes, which taken together comprised nearly half of the IGHV genes expressed in the Iranian CLL patients. Of the IGHV genes, IGHV3-7 was significantly over-represented in non-progressive compared to progressive CLL patients (P = 0.036), whereas IGHV1-69 and IGHV1-2 were expressed at a higher frequency in unmutated compared to mutated CLL patients (P < 0.03). Comparison of IGHV gene usage in our patients with that of Western CLL patients revealed significant differences in expression of IGHV1-69, IGHV3-7, IGHV3-21, and IGHV4-34 genes. Analysis of the IGHV third complementary determining Region (HCDR3) sequences revealed a high frequency use of certain HCDR3 motifs, such as YYYGMDV, in our samples. These findings imply contribution of antigen selection and Regional (ethnic/geographic) parameters in the leukomogenesis of CLL.
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differential expression of rheumatoid factor associated cross reactive idiotypes in iranian seropositive and seronegative patients with rheumatoid arthritis
Iranian biomedical journal, 2007Co-Authors: Ghasem Mosayebi, Mageed A Rizgar, Soheila Gharagozloo, Fazel ShokriAbstract:Introduction: High levels of rheumatoid factors (RF) are detectable in serum of the majority of patients with rheumatoid arthritis (RA), but 5-10% of patients remain seronegative (SN). Despite clinical and genetic similarities between these two subsets of RA, it has been proposed that they may be regarded as distinct clinical entities. Methods: In the present study a panel of monoclonal antibodies (mAb) recognizing RFassociated cross-reactive idiotypes (CRI) linked to the VH1 (G8), VH4 (LC1), VK3b (17-109) and a mAb recognizing the VK3 subgroup (C7) of Immunoglobulin Variable Region (IgV) gene products were used to quantitate the level of expression of these gene products in serum and synovial fluid of 35 seropositive (SP) and 8 SN RA patients by capture ELISA. Results: While the concentration and relative proportion of the IgV are recognized by the mAb G8, 17-109 and C7 were significantly higher in serum and synovial fluid of the SP RA, compared to the SN-RA patients (G8, p = 0.009; 17-109, p = 0.0001; C7, p = 0.001). The CRI recognized by the mAb LC1 was highly represented in serum and synovial fluid of the SN-RA patients. There have been no significant differences in the level of expression of these IgV gene products (other than the product recognized by C7 mAb in SP patients) between serum and synovial fluid of either group of patients. Conclusion: Our results suggest that the expressed repertoire of Ig VH and VK genes in these two subsets of RA is differentially regulated and may be influenced by selective mechanisms leading to positive or negative
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analysis of the Immunoglobulin heavy chain Variable Region gene expression in iranian patients with chronic lymphocytic leukemia
Leukemia & Lymphoma, 2007Co-Authors: Hojjat M Farsangi, Mahmood Jedditehrani, Ramezanali Sharifian, Seyed Mohsen Razavi, Jalal Khoshnoodi, Hodjatallah Rabbani, Fazel ShokriAbstract:B-cell chronic lymphocytic leukemia (B-CLL) results from clonal expansion of phenotypically mature but functionally immature B-lymphocytes. The incidence of this type of leukemia is low in Asian countries, whereas it is the most frequent type of leukemia in the West. Previous investigations mainly conducted in Western populations have demonstrated non-random rearrangement of certain Immunoglobulin Variable Region heavy (VH) and/or light (VL) chain genes in different groups of B-CLL patients. Little is known about the profile of VH gene expression in Asian patients. In the present study, we determined the frequency of VH gene family usage in 59 Iranian patients with B-CLL. VH gene family of patients was determined by reverse transcriptase-polymerase chain reaction using VH1-VH7 family specific primers. The most frequently expressed VH gene family was found to be VH3 (45.8%) followed by VH4 (32.2%), VH1 (18.6%), VH5 (1.7%) and VH6 (1.7%), with no expression of VH2 and VH7 gene families. The results indicate a lower representation of the VH1 and VH2 gene families and a higher representation of the VH4 gene family in Iranian B-CLL patients compared to Western patients, suggesting involvement of ethnic and/or environmental factors in B-CLL disease initiation.
Ramit Mehr - One of the best experts on this subject based on the ideXlab platform.
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somatic hypermutation and antigen driven selection of b cells are altered in autoimmune diseases
Journal of Autoimmunity, 2010Co-Authors: Neta S Zuckerman, Michal Barak, Hanna Edelman, Deborah K Dunnwalters, Helena Hazanov, Shira Hess, Hadas Shcolnik, Ramit MehrAbstract:B cells have been found to play a critical role in the pathogenesis of several autoimmune (AI) diseases. A common feature amongst many AI diseases is the formation of ectopic germinal centers (GC) within the afflicted tissue or organ, in which activated B cells expand and undergo somatic hypermutation (SHM) and antigen-driven selection on their Immunoglobulin Variable Region (IgV) genes. However, it is not yet clear whether these processes occurring in ectopic GCs are identical to those in normal GCs. The analysis of IgV mutations has aided in revealing many aspects concerning B cell expansion, mutation and selection in GC reactions. We have applied several mutation analysis methods, based on lineage tree construction, to a large set of data, containing IgV productive and non-productive heavy and light chain sequences from several different tissues, to examine three of the most profoundly studied AI diseases - Rheumatoid Arthritis (RA), Multiple Sclerosis (MS) and Sjogren's Syndrome (SS). We have found that RA and MS sequences exhibited normal mutation spectra and targeting motifs, but a stricter selection compared to normal controls, which was more apparent in RA. SS sequence analysis results deviated from normal controls in both mutation spectra and indications of selection, also showing differences between light and heavy chain IgV and between different tissues. The differences revealed between AI diseases and normal control mutation patterns may result from the different microenvironmental influences to which ectopic GCs are exposed, relative to those in normal secondary lymphoid tissues.
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igtree creating Immunoglobulin Variable Region gene lineage trees
Journal of Immunological Methods, 2008Co-Authors: Michal Barak, Neta S Zuckerman, Hanna Edelman, Ron Unger, Ramit MehrAbstract:Abstract Lineage trees describe the microevolution of cells within an organism. They have been useful in the study of B cell affinity maturation, which is based on somatic hypermutation of Immunoglobulin genes in germinal centers and selection of the resulting mutants. Our aim was to create and implement an algorithm that can generate lineage trees from Immunoglobulin Variable Region gene sequences. The IgTree © program implements the algorithm we developed, and generates lineage trees. Original sequences found in experiments are assigned to either leaves or internal nodes of the tree. Each tree node represents a single mutation separating the sequences. The mutations that separate the sequences from each other can be point mutations, deletions or insertions. The program can deal with gaps and find potential reversion mutations. The program also enumerates mutation frequencies and sequence motifs around each mutation, on a per-tree basis. The algorithm has proven useful in several studies of Immunoglobulin Variable Region gene mutations.
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lineage tree analysis of Immunoglobulin Variable Region gene mutations in autoimmune diseases chronic activation normal selection
Cellular Immunology, 2006Co-Authors: Avital Steimanshimony, Michal Barak, Neta S Zuckerman, Hanna Edelman, Gitit Shahaf, Deborah K Dunnwalters, David I Stott, Roshini S Abraham, Anat Hutzler, Ramit MehrAbstract:Autoimmune diseases show high diversity in the affected organs, clinical manifestations and disease dynamics. Yet they all share common features, such as the ectopic germinal centers found in many affected tissues. Lineage trees depict the diversification, via somatic hypermutation (SHM), of Immunoglobulin Variable-Region (IGV) genes. We previously developed an algorithm for quantifying the graphical properties of IGV gene lineage trees, allowing evaluation of the dynamical interplay between SHM and antigen-driven selection in different lymphoid tissues, species, and disease situations. Here, we apply this method to ectopic GC B cell clones from patients with Myasthenia Gravis, Rheumatoid Arthritis, and Sjogren’s Syndrome, using data scaling to minimize the effects of the large variability due to methodological differences between groups. Autoimmune trees were found to be significantly larger relative to normal controls. In contrast, comparison of the measurements for tree branching indicated that similar selection pressure operates on autoimmune and normal control clones.
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Immunoglobulin Variable Region gene mutational lineage tree analysis application to autoimmune diseases
Autoimmunity Reviews, 2006Co-Authors: Avital Steimanshimony, Michal Barak, Hanna Edelman, Gitit Shahaf, Deborah K Dunnwalters, David I Stott, Roshini S Abraham, Ramit MehrAbstract: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 Sjogren'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.
David Oscier - One of the best experts on this subject based on the ideXlab platform.
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determination of how many Immunoglobulin Variable Region heavy chain mutations are allowable in unmutated chronic lymphocytic leukaemia long term follow up of patients with different percentages of mutations
British Journal of Haematology, 2008Co-Authors: Terry J Hamblin, Zadie Davis, David OscierAbstract:The choice of 98% sequence homology for Immunoglobulin heavy chains to distinguish between mutated and unmutated versions of chronic lymphocytic leukaemia (CLL) was arbitrary and was chosen to account for supposed polymorphisms. Some authors chose 97% or even 95%. This study examined survival curves for cohorts of patients with varying degrees of sequence homology. All patients with 98% homology.
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splenic marginal zone lymphoma
Blood Reviews, 2005Co-Authors: David Oscier, Roger G Owen, S A JohnsonAbstract:Splenic marginal zone lymphoma (SMZL) is an indolent B cell malignancy usually involving spleen, bone marrow and blood. The disease presents as an incidental finding or with symptoms of splenic enlargement or anaemia. Diagnosis is based on a combination of lymphocyte morphology, immunophenotype and marrow and /or splenic histology. There is no genetic abnormality specific for SMZL, but deletions of chromosome 7q are the commonest abnormality and are found in 30-50% of cases. SMZL cells may have either mutated or unmutated Immunoglobulin Variable Region genes and probably arise from different subsets of splenic marginal zone B cells. Prognostic factors are poorly defined and only loss or mutation of the p53 gene is consistently associated with a poor outcome. Therapeutic options include splenectomy, splenic irradiation, alkylating agents, purine analogues or anti CD20 antibody. The median survival is 10-13 years and most disease-related deaths are associated with transformation to diffuse large cell lymphoma.
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cd38 expression and Immunoglobulin Variable Region mutations are independent prognostic Variables in chronic lymphocytic leukemia but cd38 expression may vary during the course of the disease
Blood, 2002Co-Authors: Terry J Hamblin, Freda K Stevenson, Jenny A Orchard, Rachel E Ibbotson, Zadie Davis, Peter Thomas, David OscierAbstract:Although the presence or absence of somatic mutations in the Immunoglobulin Variable Region ( IgVH ) genes in chronic lymphocytic leukemia (B-CLL) identifies subtypes with very different prognoses, the assay is technically complex and unavailable to most laboratories. CD38 expression has been suggested as a surrogate marker for the 2 subtypes. IgVH mutations and CD38 expression in 145 patients with B-CLL with a long follow-up were compared. The 2 assays gave discordant results in 41 patients (28.3%). Multivariate analysis demonstrated that Binet stage, IgVH mutations and CD38 were independent prognostic indicators. Median survival time in patients whose cells had unmutated IgVH genes and expressed CD38 was 8 years; in those with mutated IgVH genes not expressing CD38, it was 26 years. For those with discordant results, median survival time was 15 years. Thus, although CD38 expression does not identify the same 2 subsets as IgVH mutations in CLL, it is an independent risk factor that can be used with IgVH mutations and clinical stage to select patients with B-CLL with the worst prognoses. Using cryopreserved cells taken at intervals during the course of the disease, however, changes of CD38 expression over time were demonstrated in 10 of 41 patients. Causes of the variation of CD38 expression require further study. Additional prospective studies are required for comparing CD38 expression with other prognostic factors and for taking sequential measurements during the course of the disease.
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insight into the origin and clonal history of b cell tumors as revealed by analysis of Immunoglobulin Variable Region genes
Immunological Reviews, 1998Co-Authors: Freda K Stevenson, David Oscier, Delin Zhu, Christian H Ottensmeier, Caroline J Chapman, Surinder S Sahota, Terry J HamblinAbstract:Recombination of VH, DH and JH genes is a unique first step in normal B-cell development. Subsequent differentiation to a mature plasma cell is accompanied by further events in the Ig genes, including VL-JL joining, somatic hypermutation and isotype switching. Chromosomal changes leading to B-cell tumors can occur at many points in this sequence, and may be partly a consequence of the genetic mobility and mutability permitted in order to generate a diverse antibody repertoire. V genes of neoplastic B cells may reflect the point of maturation reached by the B cell of origin, prior to transformation. Analysis of tumors therefore provides useful information on V-gene patterns in normal B cells, and may add another dimension to classification of B-cell tumors. Transformation may also preserve cell populations normally destined to die by apoptosis. Tumor cells arrested in the site where somatic hypermutation and isotype switch are occurring can still be subject to these processes, and could be influenced by persisting antigen. However, mutation is silenced at the point of exit to the periphery, leading to fixed mutational patterns in tumors of mature B cells. V-gene analysis provides an invaluable tool for understanding the genesis of neoplastic change. It also has a clear clinical relevance in tracking tumor cells, measuring residual disease, and finally in offering the opportunity of developing vaccines for treatment.
