Stromal Cell-Derived Factor-1 as a Chemoattractant for Follicular Center Lymphoma B Cells

Corcione, Anna; Ottonello, Luciano; Tortolina, Giuseppe; Facchetti, Paola; Airoldi, Irma; Guglielmino, Roberta; Dadati, Patrizia; Truini, Mauro; Sozzani, Silvano; Dallegri, Franco; Pistoia, Vito

doi:10.1093/jnci/92.8.628

Cited by 94 publications

(69 citation statements)

References 49 publications

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“…[16][17][18][19]21,30 Studies showing that FL cells colonize non-neoplastic germinal centers and that non-neoplastic germinal centers can serve as a niche for FL cells are further supported by the concept of "in situ" FL, which represents infiltration of pre-existing non-neoplastic germinal centers by FL cells, rather than de novo formation of malignant germinal centers. 17,[31][32][33] Our conclusion that FL originates in the LN is consistent with the hypothesis of a possible dormant FL tumor stem cell harboring an unmutated, rearranged IgV H/L gene as part of the t(14;18)(q32;q21) translocation, which is possibly exposed to the somatic hypermutation machinery by passing the germinal centers of LN, acquiring additional point mutations and progressing to clinically overt FL. 34,35 In the FL population of the first patient, we detected a putative naïve LN clone with an unmutated IgV H gene and consequently identified it as the founder clone of this FL.…”

Section: Discussionsupporting

confidence: 87%

Somatic hypermutation analysis in follicular lymphoma provides evidence suggesting bidirectional cell migration between lymph node and bone marrow during disease progression and relapse

et al. 2013

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ABSTRACTdeveloped algorithm to describe clonal hierarchy and migration patterns more thoroughly. Methods Patients, histology, and immunohistochemistryThis study comprised three patients with synchronous LN and BM infiltration by FL at presentation. Biopsies were performed during the diagnostic and staging procedures. The selection criteria were the diagnosis of FL according to the fourth edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.1 Clinical information was obtained from the patients' medical records. Material was collected from patients after their informed consent in accordance with the Declaration of Helsinki. The study was approved by the responsible institutional ethic boards. Further details are provided in the Online Supplementary Methods. Sequence analysis of IgV H genes and definition of mutational patternsDNA from the IgV H gene segments was extracted and amplified as described elsewhere. 23,24 Cloning, sequencing, and the mutational analysis of the obtained segments are described in detail in the Online Supplementary Methods. Delineation of tumor cell evolution by construction of pedigreesFor each patient and each compartment (LN and BM separately), the mutational patterns of IgV H gene segments were arranged in an ascending order of mutations to illustrate the mutational hierarchy of intraclonal sequence heterogeneity. Consequently, mutational patterns of early clones with few mutations had to be included in successor clones. When direct transition of one mutation pattern into that of successor clones with higher mutation loads was not observable, hypothetical predecessor clones (HPC) were introduced to retrace the evolution of sequenced clones back to the determined initial V H DJ H gene rearrangement (wild-type sequence). Accordingly, compartment-specific pedigrees were constructed. Thereafter, a third "summary-pedigree" comprising all sequenced clones was constructed, to evaluate the possibility of inter-compartmental exchange between LN and BM. Generation of hypothetical predecessor clones and delineation of migration probabilityFor each sequenced FL population (i.e. LN, BM, and LN and BM together) the pool of possible HPC was derived from mutations shared by at least two sequenced clones. To select the most appropriate predecessor clones from the abundance of generated HPC, the probability measurement was introduced (Figure 1). Only HPC with the highest probability measurement values were introduced until the evolution of sequenced clones could be retraced to the "wild-type sequence". Already established clone groups could not be disrupted by HPC with lower probability measurement values. These calculations resulted in a LN, a BM and an inter-compartment pedigree. If HPC of the inter-compartment pedigree displayed a higher probability measurement value than the corresponding LN or BM counterparts, inter-compartment migration was considered. The LN or BM allocation of these inter-compartment HPC was directed by the LN or BM affiliation of the majority of ev...

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Section: Discussionsupporting

confidence: 87%

Somatic hypermutation analysis in follicular lymphoma provides evidence suggesting bidirectional cell migration between lymph node and bone marrow during disease progression and relapse

et al. 2013

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“…A similar observation has been reported for CXCR4 and CD40 on GC cells. CD40 pretreatment of these cells led to an increased migration upon stimulation with the CXCR4 ligand stromal-derived factor 1 (13). Apparently, exposure to CD40-activating agents is crucial for the induction of a functional response of certain GPCRs such as CB2 or CXCR4.…”

Section: Figurementioning

confidence: 98%

Distinct Expression Profiles of the Peripheral Cannabinoid Receptor in Lymphoid Tissues Depending on Receptor Activation Status

Rayman¹,

Lam

Laman

et al. 2004

The Journal of Immunology

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Using two distinct anti-CB2 receptor Abs, we investigated the expression patterns of the peripheral cannabinoid receptor CB2 in human secondary lymphoid organs. Immunohistochemical analysis using an N-terminal specific anti-CB2 Ab revealed high protein expression in the germinal centers (GCs) of secondary follicles. A C-terminal specific anti-CB2 Ab, which only recognizes a nonphosphorylated inactive receptor, showed positivity in the mantle zones (MZs) and marginal zones (MGZs) of the secondary follicles where resting cells reside, and in the primary follicles. In contrast, no positivity was observed in GCs using the C-terminal Ab, suggesting that active CB2 receptors are mainly present on cells in the GCs. Dual immunohistochemical analysis revealed that B lymphocytes express the CB2 protein abundantly. In contrast to B cells in the MZ or MGZ, CB2-expressing cells in the GCs coexpress the costimulatory membrane protein CD40, which is mainly expressed in the GCs and at very low levels in the MZs and MGZs and the proliferation marker Ki-67. Using the human Raji B cell line as a model, we demonstrate in a transwell assay that moderate migration occurs upon stimulation of the CB2 receptor with the endocannabinoid 2-arachidonoylglycerol, which is enhanced by CD40 costimulation. Our findings, that GC-related cells express active CB2 and that CB2-dependent migration requires CD40 costimulation, suggest that CB2 is involved in B cell activation.

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“…Chemotaxis was investigated using 5-mm pore-size transwell plates (Costar) as described previously (28). Five hundred thousand cells were dispensed in the upper chamber, whereas chemokines or medium alone was added to the lower chamber.…”

Section: Chemotaxismentioning

confidence: 99%

Binding of HLA-G to ITIM-Bearing Ig-like Transcript 2 Receptor Suppresses B Cell Responses

Naji

Menier

Morandi

et al. 2014

The Journal of Immunology

145

123

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Inhibition of B cells constitutes a rational approach for treating B cell–mediated disorders. We demonstrate in this article that the engagement of the surface Ig-like transcript 2 (ILT2) inhibitory receptor with its preferential ligand HLA-G is critical to inhibit B cell functions. Indeed, ILT2–HLA-G interaction impedes both naive and memory B cell functions in vitro and in vivo. Particularly, HLA-G inhibits B cell proliferation, differentiation, and Ig secretion in both T cell–dependent and –independent models of B cell activation. HLA-G mediates phenotypic and functional downregulation of CXCR4 and CXCR5 chemokine receptors on germinal center B cells. In-depth analysis of the molecular mechanisms mediated by ILT2–HLA-G interaction showed a G0/G1 cell cycle arrest through dephosphorylation of AKT, GSK-3β, c-Raf, and Foxo proteins. Crucially, we provide in vivo evidence that HLA-G acts as a negative B cell regulator in modulating B cell Ab secretion in a xenograft mouse model. This B cell regulatory mechanism involving ILT2–HLA-G interaction brings important insight to design future B cell–targeted therapies aimed at reducing inappropriate immune reaction in allotransplantation and autoimmune diseases.

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Stromal Cell-Derived Factor-1 as a Chemoattractant for Follicular Center Lymphoma B Cells

Cited by 94 publications

References 49 publications

Somatic hypermutation analysis in follicular lymphoma provides evidence suggesting bidirectional cell migration between lymph node and bone marrow during disease progression and relapse

Somatic hypermutation analysis in follicular lymphoma provides evidence suggesting bidirectional cell migration between lymph node and bone marrow during disease progression and relapse

Distinct Expression Profiles of the Peripheral Cannabinoid Receptor in Lymphoid Tissues Depending on Receptor Activation Status

Binding of HLA-G to ITIM-Bearing Ig-like Transcript 2 Receptor Suppresses B Cell Responses

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