Germinal Center Founder Cells Display Propensity for Apoptosis before Onset of Somatic Mutation

B lymphocytes undergo affinity maturation of their antigen receptors within germinal centers. These anatomical structures develop in secondary lymphoid organs from the clonal expansion of a few antigen-specific founder B cells, whose isolation and characterization are reported here. Human germinal center founder cells express the naive B cell markers surface IgM and IgD as well as the germinal center B cell markers CD10 and CD38. They express low levels of Bcl-2, high levels of Fas, and undergo rapid apoptosis in culture. The smaller nonproliferating sIgM+IgD+CD38+ B cells displayed a lower level of somatic mutation in their immunoglobulin variable region genes compared with the large proliferating ones. Unmutated sIgM+IgD+CD38+ tonsillar B cells may thus represent germinal center founder cells in which the program for apoptotic cell death is triggered before the onset of somatic mutation, allowing the selection of the germline antibody repertoire at an early stage

The Normal Counterpart of IgD Myeloma Cells in Germinal Center Displays Extensively Mutated IgVH Gene, Cμ–Cδ Switch, and λ Light Chain Expression

Human myeloma are incurable hematologic cancers of immunoglobulin-secreting plasma cells in bone marrow. Although malignant plasma cells can be almost eradicated from the patient's bone marrow by chemotherapy, drug-resistant myeloma precursor cells persist in an apparently cryptic compartment. Controversy exists as to whether myeloma precursor cells are hematopoietic stem cells, pre–B cells, germinal center (GC) B cells, circulating memory cells, or plasma blasts. This situation reflects what has been a general problem in cancer research for years: how to compare a tumor with its normal counterpart. Although several studies have demonstrated somatically mutated immunoglobulin variable region genes in multiple myeloma, it is unclear if myeloma cells are derived from GCs or post-GC memory B cells. Immunoglobulin (Ig)D-secreting myeloma have two unique immunoglobulin features, including a biased λ light chain expression and a Cμ–Cδ isotype switch. Using surface markers, we have previously isolated a population of surface IgM−IgD+CD38+ GC B cells that carry the most impressive somatic mutation in their IgV genes. Here we show that this population of GC B cells displays the two molecular features of IgD-secreting myeloma cells: a biased λ light chain expression and a Cμ–Cδ isotype switch. The demonstration of these peculiar GC B cells to differentiate into IgD-secreting plasma cells but not memory B cells both in vivo and in vitro suggests that IgD-secreting plasma and myeloma cells are derived from GCs

Prognostic value of the expression of C-Chemokine Receptor 6 and 7 and their ligands in non-metastatic breast cancer

<p>Abstract</p> <p>Background</p> <p>Chemokines and chemokine receptors are major actors of leukocytes trafficking and some have been shown to play an important role in cancer metastasis. Chemokines CCL19, CCL20 and CCL21 and their receptors CCR6 and CCR7, were assessed as potential biomarkers of metastatic dissemination in primary breast cancer.</p> <p>Methods</p> <p>Biomarker expression levels were evaluated using immunohistochemistry on paraffin-embedded tissue sections of breast cancer (n = 207).</p> <p>Results</p> <p>CCR6 was expressed by tumor cells in 35% of cases. CCR7 was expressed by spindle shaped stromal cells in 43% of cases but not by tumor cells in this series. CCL19 was the only chemokine found expressed in a significant number of breast cancers and was expressed by both tumor cells and dendritic cells (DC). CCR6, CCL19 and CCR7 expression correlated with histologic features of aggressive disease. CCR6 expression was associated with shorter relapse-free survival (RFS) in univariate and but not in multivariate analysis (p = 0.0316 and 0.055 respectively), and was not associated with shorter overall survival (OS). Expression of CCR7 was not significantly associated with shorter RFS or OS. The presence of CCL19-expressing DC was associated with shorter RFS in univariate and multivariate analysis (p = 0.042 and 0.020 respectively) but not with shorter OS.</p> <p>Conclusion</p> <p>These results suggest a contribution of CCR6 expression on tumor cells and CCL19-expressing DC in breast cancer dissemination. In our series, unlike what was previously published, CCR7 was exclusively expressed on stromal cells and was not associated with survival.</p

Activation des cellules dendritiques humaines par les Toll-Like Receptors (propriétés fonctionnelles de hTLR8, récepteur antiviral des cellules myéloïdes)

Les cellules dendritiques (DC) matures jouent un rôle clé dans l'orientation des réponses immunitaires adaptatives. La maturation des DC peut être déclenchée par l'engagement de leurs Toll-Like Receptors (TLR), qui reconnaissent une grande variété de motifs moléculaires caractéristiques des micro-organismes pathogènes ou de signaux de danger. Les différentes populations de DC générées in vitro, les cellules de Langerhans de l'épiderme et les DC dermiques ont des profils d'expression des TLR caractéristiques, qui déterminent en grande partie leur sensibilité et leur réponse aux éléments pathogènes. TLR8 est un récepteur de l'ARN simple brin viral, dont l'expression chez l'homme est restreinte aux DC d'origine myéloïde. Afin d'éviter la reconnaissance de l'ARN de l'hôte, TLR8 est confiné dans des compartiments intracellulaires. Suite à l'engagement de TLR8, un signal intracellulaire est transmis, conduisant notamment à l'activation des facteurs de transcription NF-kB, dont dépend la synthèse de cytokines et chimiokines proinflammatoires. Le domaine cytoplasmique de TLR8 contient des motifs essentiels à la transmission du signal. Un de ces motifs pourrait être impliqué dans le recrutement des protéines de la famille Src. En effet, ces tyrosine-kinases participent à l'activation de la voie NF-kB par TLR8, et pourraient aussi être impliquées dans certaines maladies auto-immunesLYON1-BU.Sciences (692662101) / SudocSudocFranceF