The pool of peripheral B lymphocytes is established through an ordered set of molecular events initiated in the bone marrow with the assembly on the surface of the cells of a functional, non-autoimmune, B cell antigen receptor (BCR) complex. Expression and signaling through the BCR is essential for developing B cells to differentiate respectively into follicular, marginal zone or B-1 B cells, each of these subsets displaying a specific effector function. Basal signaling through the BCR is required for survival of resting mature B cells, which in turn become rapidly activated and undergo proliferation upon BCR-mediated antigen recognition. Signals arising from BCR engagement leading to B cell proliferation, survival and differentiation are commonly integrated by others initiated from receptors such as BAFF-R, CD40 and the family of Toll-like receptors recognizing a variety of microbial antigens.The germinal center reaction
Upon recognition of foreign antigens through the BCR, in the presence of T-cell help, B cells are recruited into germinal centers (GCs) formed in spleen and lymph nodes during T-cell dependent antibody responses. During the GC reaction, B cells undergo an initial phase of proliferation followed by cell-cycle arrest and selection based on the affinity of the BCR for the cognate antigen. The establishment of a productive antibody response to a foreign antigen depends on the selection within the GC of a limited pool of B cells expressing high affinity antigen receptors generated in situ through the process of immunoglobulin (Ig) somatic mutation. GC B cells also undergo replacement of the constant region of the Ig heavy chains through the process of Ig class-switch recombination, thereby changing the effector functions of the BCR. Finally, high-affinity, isotype-switched, B cells exit the GC to become long-lived memory B cells or antibody-producing plasma cells.The germinal center origin of B cell lymphomas
The majority of human B cell malignancies arise from mature B cells recruited into the GC reaction. GC B cell lymphomas are classified on the basis of histological appearance and molecular features as Hodgkin and non-Hodgkin B cell lymphomas. The latter group includes several tumor types such as Burkitt lymphoma (BL), follicular lymphoma (FL), diffuse-large B cell lymphomas (DLBCL) and lymphomas affecting mucosa-associated lymphoid tissues (MALT). Despite the common GC B-cell origin, Hodgkin and the different forms of non-Hodgkin B cell lymphomas differ from each other by the involvement of different oncogenic pathways driving the tumorigenic process.Conditional gene targeting as a tool to study germinal center B cell biology
To study gene function in GC B cells we employ the Cre/loxP recombination system to generate conditional gene-targeted mice. Specifically, transgenic animals are generated from embryonic stem cells manipulated in vitro through DNA homologous recombination. Experimental mice obtained with this procedure carry, on the one hand, a transgene coding for the Cre recombinase expressed in a cell-type and stage-specific manner (e.g. GC B cells) and, on the other, the gene of interest flanked by loxP sites. In this way, Cre-mediated recombination leads to inducible loss of gene function in a cell-type and stage-specific manner. We employ the Cre/loxP recombination system also to induce in vivo activation of gene expression (e.g. proto-oncogenes) in a cell-type, stage-specific and temporal manner. To study gene function in GC B cells we dispose of Cϒ1-cre knock-in mice, allowing efficient Cre-mediated recombination in GC and post-GC B cells.
Our group has three long-term goals:
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