Antigen-driven selection in germinal centers as reflected by the shape characteristics of immunoglobulin gene lineage trees: A large-scale simulation study

Shahaf, Gitit; Barák, Michal; Zuckerman, Neta S.; Swerdlin, Naamah; Gorfine, Malka; Mehr, Ramit

doi:10.1016/j.jtbi.2008.08.005

Cited by 38 publications

(50 citation statements)

References 80 publications

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“…4,7 FL cells retain much of the normal GCB-cell phenotype, including apparent dependence upon T follicular helper (TFH) cells and follicular dendritic cells (FDCs). As long predicted, 23,24 recent work 25 has confirmed that normal GCB cells recycle between a light zone (LZ), in which TFH cells provide stimulation, and a dark zone (DZ) in which antigen-selected cells undergo a burst of proliferation and activation-induced cytidine deaminase-dependent somatic hypermutation. Cells stimulated in the LZ show high NF-kB activity, MYC 26,27 and miR-155 expression, 28 and decreased BCL6 functional activity.…”

Section: Discussionmentioning

confidence: 57%

Genome-wide copy-number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma

Bouska

McKeithan

Deffenbacher

et al. 2014

Blood

116

122

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• Chromosome copy-number alterations that may affect immune surveillance and the NF-kB and p53 pathways are more frequent in tFL than FL.• Abnormalities involving chromosomes 6 and X are predictive of overall survival in FL.Follicular lymphoma (FL), the second most common type of non-Hodgkin lymphoma in the western world, is characterized by the t(14;18) translocation, which is present in up to 90% of cases. We studied 277 lymphoma samples (198 FL and 79 transformed FL [tFL]) using a single-nucleotide polymorphism array to identify the secondary chromosomal abnormalities that drive the development of FL and its transformation to diffuse large B-cell lymphoma. Common recurrent chromosomal abnormalities in FL included gains of 2, 5, 7, 6p, 8, 12, 17q, 18, 21, and X and losses on 6q and 17p. We also observed many frequent small abnormalities, including losses of 1p36.33-p36.31, 6q23.3-q24.1, and 10q23.1-q25.1 and gains of 2p16.1-p15, 8q24.13-q24.3, and 12q12-q13.13, and identified candidate genes that may be driving this selection. Recurrent abnormalities more frequent in tFL samples included gains of 3q27.3-q28 and chromosome 11 and losses of 9p21.3 and 15q. Four abnormalities, gain of X or Xp and losses of 6q23.2-24.1 or 6q13-15, predicted overall survival. Abnormalities associated with transformation of the disease likely impair immune surveillance, activate the nuclear factor-kB pathway, and deregulate p53 and B-cell transcription

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Section: Discussionmentioning

confidence: 57%

Genome-wide copy-number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma

Bouska

McKeithan

Deffenbacher

et al. 2014

Blood

116

122

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“…A thorough statistical analysis correlating tree characteristics with dynamic parameters of the B-cell response such as mutation rate, using a computer simulation of the humoral immune response [52], has concluded that seven tree characteristics posses the highest correlation values with the biological parameters (Table 3).…”

Section: Data Used For the Lineage Tree And Mutation Analysesmentioning

confidence: 99%

“…Affinity k Selection k a) Correlation of tree variables with the dynamic parameters of the secondary B-cell response [52]: m denotes a direct correlation -as the value of dynamic parameter increases, the tree characteristic increases; k denotes an inverse correlation -as the value of the dynamic parameter increases, the value of the tree characteristic decreases. …”

Section: Dasn-min (Fork To Fork Distance -Min)mentioning

confidence: 99%

Ectopic GC in the thymus of myasthenia gravis patients show characteristics of normal GC

et al. 2010

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Young patients with myasthenia gravis (MG) frequently have ectopic GC in their thymus. We investigated these ectopic GC by microdissection of GC B cells and analysis of their Ig gene characteristics, in comparison to normal GC. CDR3 length distribution, a measure of clonal variability, and Ig gene family usage were similar in MG and normal tonsil samples. Lineage tree analysis demonstrated similar diversification and mutations per cell compared with normal control trees. Mutations were observed in the framework regions, responsible for the structural integrity of the BCR; however, these mutations were mostly conservative or neutral, confirming that a functional BCR is conserved in MG. In the CDR, responsible for Ag binding, selection against replacement mutations was revealed. This may indicate that the MG clones analyzed are already highly Ag-specific, and therefore potential affinity-reducing replacement mutations in the CDR3 are not propagated, due to Ag-driven selection. Somatic hypermutation (SHM) targeting motifs and aa substitution preferences in MG were similar to those of normal controls. Overall, these results suggest that B cells in the ectopic GC in MG appear to undergo normal diversification and selection, in spite of the chronic nature and different environment of the response.Key words: GC . Ig . myasthenia gravis . Somatic hypermutation . Thymus IntroductionMyasthenia gravis (MG) is an autoimmune condition characterized by muscle weakness, which fluctuates over time. Transmission at the neuromuscular junction is impaired due to autoantibodies (autoAb), which bind to the nicotinic acetylcholine receptors (AChR) in 80-85% of patients and, to musclespecific tyrosine kinase in about 5% of patients [1].Studies so far have focused on pro-inflammatory cytokines, which were shown to induce increased thymic expression of the auto-Ag AChR and presentation to autoreactive T cells [2]. However, emerging data have renewed interest in the importance of B cells in the pathophysiology of neurological autoimmune disorders, such as MG. The establishment of a large B-cell compartment in the thymus of MG patients may be partly attributable to the observed increase in the expression of APRIL and BAFF, which are known B-cell survival enhancing factors [3].The generation of high-affinity AChR autoAb requires activated CD41 T cells to interact with B cells resulting in hypermutation of initially low-affinity anti-AChR Ab [1]. AChR-specific CD4 1 T cells are present in both the blood and the thymus of MG Ã These authors contributed equally to this work. patients. The Ab response is polyclonal and predominantly composed of different IgG subclasses [4]. Though the presence of AChR autoAb is indicative of MG, the titer does not always correspond to severity [4]. It has been observed that patients seronegative for AChR autoAb may in fact possess thymic B cells that do secrete AChR autoAb [5]. These are sometimes low-affinity AChR autoAb which cannot always be detected in solution-phase assays, but can be detected using more...

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“…The same phenomenon was present in LC sequences from four out of six CPS. In many cases, a large number of mutations were observed between clonally related sequences, thus demonstrating the presence of long-lasting Ag-driven stimulation (30). Neither the CDR3 lengths nor the number of positively charged residues in the CDR3 resulted in significantly differences between CPS and PBLs (Table II).…”

Section: Ag-driven Evolution Of B Cells In Coronary Plaquesmentioning

confidence: 99%

Antigen-Driven Evolution of B Lymphocytes in Coronary Atherosclerotic Plaques

Burioni

Canducci

Saita

et al. 2009

The Journal of Immunology

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Recent data indicated that adaptive immunity is involved in the process of atherogenesis. Oligoclonal recruitment of T lymphocytes has been described in coronary plaques of patients with acute coronary syndrome. However, the nature of immune response remains to be determined. In the present study, we examined the Ab response in six coronary plaques obtained by endoluminal directional atherectomy. The IgG1/κ-coding gene repertoires of B lymphocytes present in circulating blood and in coronary plaques were cloned and analyzed. In all of the six plaques, we observed 1) a skewed usage of heavy and light IgG1/κ Ab-coding genes, 2) an oligoclonal distribution of VK, JK, and VH, DH, and JH genes with overrepresentation of some rarely used IgG genes, and 3) the unequivocal signs of Ag-driven clonal expansion and evolution of B cells. The data document for the first time the presence of a local Ag-driven clonal evolution of B cells in human atherosclerotic plaques.

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Antigen-driven selection in germinal centers as reflected by the shape characteristics of immunoglobulin gene lineage trees: A large-scale simulation study

Cited by 38 publications

References 80 publications

Genome-wide copy-number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma

Genome-wide copy-number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma

Ectopic GC in the thymus of myasthenia gravis patients show characteristics of normal GC

Antigen-Driven Evolution of B Lymphocytes in Coronary Atherosclerotic Plaques

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