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Biomedical subjects

Giorgio Cattoretti

Publications and source records attributed to Giorgio Cattoretti.

13 recordsLinked to original sources
PubMed2003

The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma.

Mediastinal large B-cell lymphoma (MLBCL) is a recently identified subtype of diffuse large B-cell lymphoma (DLBCL) that characteristically presents as localized tumors in young female patients. Although MLBCL has distinctive pathologic features, it clinically resembles the nodular sclerosis subtype of classical Hodgkin lymphoma (cHL). To elucidate the molecular features of MLBCL, we compared the gene expression profiles of newly diagnosed MLBCL and DLBCL and developed a classifier of these diseases. MLBCLs had low levels of expression of multiple components of the B-cell receptor signaling cascade, a profile resembling that of Reed-Sternberg cells of cHL. Like cHLs, MLBCLs also had high levels of expression of the interleukin-13 (IL-13) receptor and downstream effectors of IL-13 signaling (Janus kinase-2 [JAK2] and signal transducer and activator of transcription-1 [STAT1]), tumor necrosis factor (TNF) family members, and TNF receptor-associated factor-1 (TRAF1). Increased expression of STAT1 and TRAF1 in MLBCL was confirmed by immunohistochemistry. Given the TRAF1 expression and known link to nuclear factor-kappa B (NF- kappa B), MLBCLs were also evaluated for nuclear translocation of c-REL protein. In almost all cases, c-REL was localized to the nucleus, consistent with activation of the NF-kappa B pathway. These studies identify a molecular link between MLBCL and cHL and a shared survival pathway.

Active Transport, Cell Nucleus↗
PubMed2003

Expression of the IRTA1 receptor identifies intraepithelial and subepithelial marginal zone B cells of the mucosa-associated lymphoid tissue (MALT).

IRTA1 (immunoglobulin superfamily receptor translocation-associated 1) is a novel surface B-cell receptor related to Fc receptors, inhibitory receptor superfamily (IRS), and cell adhesion molecule (CAM) family members and we mapped for the first time its distribution in human lymphoid tissues, using newly generated specific antibodies. IRTA1 was selectively and consistently expressed by a B-cell population located underneath and within the tonsil epithelium and dome epithelium of Peyer patches (regarded as the anatomic equivalents of marginal zone). Similarly, in mucosa-associated lymphoid tissue (MALT) lymphomas IRTA1 was mainly expressed by tumor cells involved in lympho-epithelial lesions. In contrast, no or a low number of IRTA1+ cells was usually observed in the marginal zone of mesenteric lymph nodes and spleen. Interestingly, monocytoid B cells in reactive lymph nodes were strongly IRTA1+. Tonsil IRTA1+ cells expressed the memory B-cell marker CD27 but not mantle cell-, germinal center-, and plasma cell-associated molecules. Polymerase chain reaction (PCR) analysis of single tonsil IRTA1+ cells showed they represent a mixed B-cell population carrying mostly mutated, but also unmutated, IgV genes. The immunohistochemical finding in the tonsil epithelial areas of aggregates of IRTA1+ B cells closely adjacent to plasma cells surrounding small vessels suggests antigen-triggered in situ proliferation/differentiation of memory IRTA1+ cells into plasma cells. Collectively, these results suggest a role of IRTA1 in the immune function of B cells within epithelia.

Antibodies, Monoclonal↗
PubMed2003

BCL6 controls the expression of the B7-1/CD80 costimulatory receptor in germinal center B cells.

The BCL6 proto-oncogene encodes a transcriptional repressor required for the development of germinal centers (GCs) and implicated in the pathogenesis of GC-derived B cell lymphoma. Understanding the precise role of BCL6 in normal GC formation and in lymphomagenesis depends on the identification of genes that are direct targets of its transcriptional repression. Here we report that BCL6 directly controls the expression of B7-1/CD80, a costimulatory receptor involved in B-T cell interactions critical for the development of T cell-mediated antibody responses. Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor. Our results show that BCL6 prevents CD40-induced expression of CD80 by binding its promoter region in vivo and suppressing its transcriptional activation by NF-kappaB. Consistent with a physiologic role for BCL6 in suppressing CD80, the expression of these two genes is mutually exclusive in B cells, and BCL6-defective mice show increased expression of CD80 in B cells. The results suggest that BCL6 may directly control the ability of B cell to interact with T cells during normal GC development. In addition, these findings imply that T-B cell interactions may be disrupted in B cell lymphoma expressing deregulated BCL6 genes.

Antigens, CD↗
PubMed2003

Transcriptional analysis of the B cell germinal center reaction.

The germinal center (GC) reaction is crucial for T cell-dependent immune responses and is targeted by B cell lymphomagenesis. Here we analyzed the transcriptional changes that occur in B cells during GC transit (naive B cells --> centroblasts --> centrocytes --> memory B cells) by gene expression profiling. Naive B cells, characterized by the expression of cell cycle-inhibitory and antiapoptotic genes, become centroblasts by inducing an atypical proliferation program lacking c-Myc expression, switching to a proapoptotic program, and down-regulating cytokine, chemokine, and adhesion receptors. The transition from GC to memory cells is characterized by a return to a phenotype similar to that of naive cells except for an apoptotic program primed for both death and survival and for changes in the expression of cell surface receptors including IL-2 receptor beta. These results provide insights into the dynamics of the GC reaction and represent the basis for the analysis of B cell malignancies.

Apoptosis↗
PubMed2003

Molecular cloning of IBP, a SWAP-70 homologous GEF, which is highly expressed in the immune system.

Rho GTPases play a fundamental role in a variety of biological processes ranging from the reorganization of the actin cytoskeleton to the regulation of cell proliferation. The activation of Rho GTPases is regulated by guanine nucleotide exchange factors (GEFs) belonging to the Dbl family of proteins. The hallmark of this large family of GEFs is the presence of a tandem DH-PH module in which a pleckstrin-homology (PH) domain is located at the C-terminus of a Dbl-homology (DH) domain. Recent studies have demonstrated that SWAP-70 constitutes a novel class of Rac-GEF, in which the PH domain is located at the N-terminus, rather than the C terminus, of the DH domain. Here we report the molecular cloning of human IBP (IRF-4 binding protein), a new member of this novel family of GEFs. The IBP gene maps to human chromosome 6p21.31 centromeric to the MHC locus. Isolation of the murine IBP cDNA reveals a very high degree of homology with the human IBP cDNA suggesting that IBP is evolutionarily conserved. The 5' portion of the murine IBP cDNA is furthermore identical to the Def-6 cDNA fragment, which was identified in the course of a search for genes differentially expressed in the murine hematopoietic system. IBP is broadly expressed in the immune system and can be detected in both T and B cell compartments in contrast to SWAP-70 whose expression is primarily restricted to B cells. Taken together these findings indicate that IBP is a novel type of GEF, which participates in the activation of Rho GTPases in lymphoid tissues.

Amino Acid Sequence↗
PubMed2003

Gene expression dynamics during germinal center transit in B cells.

The germinal center (GC) reaction in T cell dependent antibody responses is crucial for the generation of B cell memory and plays a critical role in B cell lymphomagenesis. To gain insight into the physiology of this reaction, we identified the transcriptional changes that occur in B cells during the GC-transit (naïve B cells --> CD77(+) centroblasts (CBs) --> CD77(-) centrocytes (CCs) --> memory B cells) by DNA microarray experiments and the subsequent data analysis employing unsupervised and supervised hierarchical clustering. The naïve B cell is characterized by a nonproliferative, anti-apoptotic phenotype and the expression of various chemokine and cytokine receptors. The transition from naïve B cells to CBs is associated with (1) the up-regulation of genes associated with cellular proliferation, DNA-repair, and chromatin remodeling; (2) the acquisition of a pro-apoptotic phenotype; (3) the down-regulation of cytokine, chemokine, and adhesion receptors expressed in the naïve cells; and (4) the expression of a distinct adhesion repertoire. The CB and the CC revealed surprisingly few gene expression differences, suggesting that the CC is heterogeneous in its cellular composition. The CB/CC to memory B cell transition shows a general reversion to the profile characteristic for the naïve B cells, with the exception of the up-regulation of several surface receptors, including CD27, CD80, and IL-2Rbeta, and the simultaneous expression of both anti- and pro-apoptotic genes. These gene expression profiles of the normal B cell subpopulations are being used to identify the signals occurring during GC development, the cellular derivation of various types of B cell malignancies, and the genes deregulated in GC-derived tumors.

B-Lymphocytes↗
PubMed2003

Identification of Hodgkin and Reed-Sternberg cell-specific genes by gene expression profiling.

Hodgkin lymphoma (HL) is a malignancy of unknown pathogenesis. The malignant Hodgkin and Reed/Sternberg (HRS) cells derive from germinal center B cells (or rarely, T cells) but have a heterogeneous and largely uncharacterized phenotype. Using microarrays, we compared the gene expression profile of four HL cell lines with profiles of the main B cell subsets and B cell non-HLs to find out whether HRS cells, despite their described heterogeneity, show a distinct gene expression, to study their relationship to other normal and malignant B cells, and to identify genes aberrantly or overexpressed by HRS cells. The HL lines indeed clustered as a distinct entity, irrespective of their B or T cell derivation, and their gene expression was most similar to that of EBV-transformed B cells and cell lines derived from diffuse large cell lymphomas showing features of in vitro-activated B cells. Twenty-seven genes, most of which were previously unknown to be expressed by HRS cells, showed aberrant expression specifically in these cells, e.g., the transcription factors GATA-3, ABF1, EAR3, and Nrf3. For five genes, expression in primary HRS cells was confirmed. The newly identified HL-specific genes may play important roles in the pathogenesis of HL, potentially represent novel diagnostic markers, and can be considered for therapeutic targeting.

B-Lymphocytes↗
PubMed2002

The Tnfrh1 (Tnfrsf23) gene is weakly imprinted in several organs and expressed at the trophoblast-decidua interface.

BACKGROUND: The Tnfrh1 gene (gene symbol Tnfrsf23) is located near one end of a megabase-scale imprinted region on mouse distal chromosome 7, about 350 kb distant from the nearest known imprinting control element. Within 20 kb of Tnfrh1 is a related gene called Tnfrh2 (Tnfrsf22) These duplicated genes encode putative decoy receptors in the tumor necrosis factor (TNF) receptor family. Although other genes in this chromosomal region show conserved synteny with genes on human Chr11p15.5, there are no obvious human orthologues of Tnfrh1 or Tnfrh2. RESULTS: We analyzed Tnfrh1 for evidence of parental imprinting, and characterized its tissue-specific expression. Tnfrh1 mRNA is detectable in multiple adult and fetal tissues, with highest expression in placenta, where in situ hybridization reveals a distinctive population of Tnfrh1-positive cells in maternal decidua, directly beneath the trophoblast giant cells. In offspring of interspecific mouse crosses, Tnfrh1 shows a consistent parent-of-origin-dependent allelic expression bias, with relative repression, but not silencing, of the paternal allele in several organs including fetal liver and adult spleen. CONCLUSIONS: Genes preferentially expressed in the placenta are predicted to evolve rapidly, and Tnfrh1 appears to be an example of this phenomenon. In view of its strong expression in cells at the fetal-maternal boundary, Tnfrh1 warrants further study as a gene that might modulate immune or trophic interactions between the invasive placental trophoblast and the maternal decidua. The preferential expression of Tnfrh1 from the maternal allele indicates weak functional imprinting of this locus in some tissues.

Alleles↗
PubMed2002

IRTAs: a new family of immunoglobulinlike receptors differentially expressed in B cells.

The IRTA1 and IRTA2 genes encode immunoglobulinlike cell surface receptors expressed in B cells and involved in chromosome 1q21 translocations in B-cell malignancy. We have now characterized and comparatively analyzed the structure and expression pattern of the entire family of IRTA genes, which includes 5 members contiguously located on chromosome 1q21. The IRTA messenger RNAs are expressed predominantly in the B-cell lineage within discrete B-cell compartments: IRTA1 is specific to the marginal zone, IRTA2 and IRTA3 are found in the germinal center light zone and in intraepithelial and interfollicular regions, and IRTA4 and IRTA5 are expressed predominantly in the mantle zone. All IRTA genes code for transmembrane receptors that are closely related to Fc receptors in their most amino-terminal extracellular domains and that possess cytoplasmic domains containing ITIM (immunotyrosine inhibition motifs)- and, possibly, ITAM (immunotyrosine activation motifs)-like motifs. These structural features suggest that the IRTA receptors may play a role in regulating activation of normal B cells and possibly in the development of neoplasia.

Amino Acid Sequence↗
PubMed2002

Glycosylphosphatidylinositol-linked proteins are required for maintenance of a normal peripheral lymphoid compartment but not for lymphocyte development.

Surface proteins tethered to the membrane through a glycosylphosphatidylinositol (GPI) anchor are deficient in the blood cells of patients with paroxysmal nocturnal hemoglobinuria (PNH) as result of a somatic mutation, in a hematopoietic stem cell, of the X-linked phosphatidylinositolglycan complementation group A (PIG-A) gene. In PNH patients, compared to the large numbers of GPI-deficient myeloid cells, the proportion of GPI-deficient lymphocytes tends to be low, and therefore the impact of GPI deficiency on immune function has been unclear. We have obtained complementation by Pig-a(-) embryonic stem (ES) cells of Rag(-/-) blastocysts, and we show that Pig-a(-) ES cells are able to reconstitute the T cell and B cell compartments of Rag(-/-) mice. Although these mice were immunologically competent, by comparison with appropriate controls we detected several abnormalities: (1) increased levels of IgG; (2) high frequency/titers of anti-nuclear antibodies; (3) markedly reduced delayed hypersensitivity; and (4) impaired activation-induced lymphocyte death in vitro. In some cases, aging Pig-a(-)/Rag(-/-) chimeric mice developed lymphadenopathy and polyclonal T cell and B cell expansion. Thus, GPI-linked proteins are not required for lymphocyte development but they are required for normal lymphocyte function and for maintaining normal peripheral lymphoid homeostasis.

Aging↗
PubMed2002

The dynamic expression pattern of B lymphocyte induced maturation protein-1 (Blimp-1) during mouse embryonic development.

We have analyzed the spatial and temporal patterns of B lymphocyte-induced maturation protein-1 (Blimp-1) expression during mouse embryonic development. Blimp-1 expression is induced early in the anterior definitive endoderm, mesoderm of head process, and prechordal plate. In ectoderm-derived tissues at later stages, Blimp-1 expression is found in the primitive photoreceptors of neural retina, in differentiated epithelial cells of epidermis, tongue, oral and nasal cavities, and in the precursors of internal root sheaths of hair follicles. In mesoderm-derived tissues, Blimp-1 expression is observed in splanchnopleure, a subset of somatopleure-derived cells in limb buds, and myotomes of somites. Blimp-1 is also expressed in mesenchyme of developing hand plates, digits, branchial arches, nasal processes, and external genitalia. Blimp-1 is present in mesenchyme-derived chondroblasts, supporting cells of taste buds, and papilla of teeth, hair follicles and taste buds. In endoderm-derived tissues, Blimp-1 expression in the foregut region is restricted to a subset of epithelial cells at the headfold stage while expression in the endodermal epithelium of midgut and hindgut persists from the headfold stage to birth. Finally, Blimp-1 is expressed in the migrating primordial germ cells.

Animals↗