Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.

Inflammation and cancer

12 Pathology and Microbiology, and 13 Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumours. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumours of DLBCL patients, apparently reflecting the variation in tumour proliferation rate, host response and differentiation state of the tumour. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal centre B cells ('germinal centre B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal centre B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumours on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer.

/pdf/distinct-types-of-diffuse-large-b-cell-lymphoma-identified-508avrqemv.pdf

Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling

Effector functions in the immune system are carried out by a variety of cell types, and as our understanding of the complexity of the system expands, the number of recognized subdivisions of cell types also continues to increase. B lymphocytes, producing antibody, were initially distinguished from T lymphocytes, which provide help for B cells (1, 2). The T-cell population was further divided when surface markers allowed separation of helper cells from cytotoxic cells (3). Although there were persistent reports of heterogeneity in the helper T-cell compartment (reviewed below), only relatively recently were distinct types of helper cells resolved. In this review we describe the differences between two types of cloned helper T cells, defined primarily by differences in the pattern of lymphokines ynthesized, and we also discuss the different functions of the two types of cells and their lymphokines. Patterns of lymphokine synthesis are convenient and explicit markers to describe T-cell subclass differences, and evidence increases that many of the functions of helper T cells are predicted by the functions of the lymphokines that they synthesize after activation by antigen and presenting cells. The separation of many mouse helper T-cell clones into these two distinct types is now well established, but their origin in normal T-cell populations is still not clear. Further divisions of helper T cells may have to be recognized before a complete picture of helper T-cell function can be obtained.

TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties.

Autophagy in the Pathogenesis of Disease

Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health.

/pdf/autophagy-fights-disease-through-cellular-self-digestion-5i6zc9bv8a.pdf

Autophagy fights disease through cellular self-digestion

Background
Polymorphisms of the Plant homeodomain finger protein 11 (PHF11) are strongly associated with high serum IgE levels and clinical severity of atopic patients. However, the precise mechanism has not been fully elucidated. We investigated the role of Phf11 in class switch recombination (CSR) to IgE by activated B cells.

Methods
We generated Phf11 transgenic (Lckd-Phf11-Tg) mice that express the exogenous murine Phf11 in lymphocytes under the control of distal Lck promoter. We examined IL-4-induced CSR to IgE in activated Lckd-Phf11-Tg B cells in vitro. We analyzed production of ovalbumin (OVA)-specific IgE and nose-scratching symptoms in Lckd-Phf11-Tg mice using an OVA-induced allergic rhinitis model.

Results
The exogenous Phf11 promoted CSR to IgG1 and IgE in activated B cells with an increase in germ line transcript (GLT) γ1 and GLT e expression. The exogenous Phf11 augmented transcriptional activity of the GLT γ1 and GLT e promoters through permissive histone modifications and binding of NF-κB and STAT6. Furthermore, the exogenous Phf11 bound to the GLT e promoter with increased binding of NF-κB. Silencing of the endogenous Phf11 reduced the frequency of CSR to IgE and GLT e expression, but not to IgG1 or GLT γ1 expression, in activated B cells. In an allergic rhinitis model, Lckd-Phf11-Tg mice showed a significant increase in the production of OVA-specific IgE and the frequency of nose scratching.

Conclusion
Phf11 accelerates CSR to IgE in activated B cells by increasing the transcriptional activity of GLT e promoter and contributes to the exacerbation of allergic responses. These findings provide a novel therapeutic target for allergic diseases.

Plant homeodomain finger protein 11 promotes class switch recombination to IgE in murine activated B cells.

The cellular consequences in the suppression of IgG antibody formation initiated by an antigen-specific suppressor T cell factor (TsF) were investigated. The initial step of the suppression is the production of TsF by Lyt-2+,3+ T cells (Tsi) which activates Lyt-1+,2+,3+ acceptor T cells in the nylon wool-adherent T cell population. The activated Lyt-1+,2+,3+ T cells further generate a new effector-suppressor T cell (Tse) that belongs to the Lyt-2+,3+ T cell subset in the culture of nylon-adherent T cells with antigen. The Tse thus induced directly suppresses the responses mounted by B cells and nylon column-purified helper T cells in the absence of TsF. The origin of Tse was further examined by utilizing Lyt congeneic mice. The result indicates that Lyt-1+,2+,3+ acceptor T cells themselves do not differentiate into Lyt-2+,3+ Tse with losing Lyt-1 phenotype but facilitate the transduction of Tse from a preexisting precursor pool. These cellular interactions strongly suggest that Lyt-1+,2+,3+ T cells play a decisive role in an amplification of immunoregulation.

Transduction of Effector-Suppressor T Cells by an Antigen-Specific Suppressor T Cell Factor and Lyt-1+,2+,3+ T Cells

. Evidence was presented that at least two loci are selectively expressed on different subsets of T cells, but not on B cells. These represent antigen-specific T cell factors, one enhancing and the other suppressing the antibody response, coded for by genes in I-A and I-J subregions, respectively. An antiserum A.TH anti-A.TL after extensive absorption with B cells still had an ability to absorb both T cell factors despite having no cytotoxic activity for splenic B cells. On the contrary, the same antiserum after a single absorption with nylon wool column-purified T cells completely lost its ability to absorb the T cell factors, while being able to kill B cells to the same extent as the unabsorbed antiserum. The results indicate that there are at least two loci in I-A and I-J subregions which code for biologically active molecules on T cells but not on B cells.

Takeshi Tokuhisa

Papers

Plant homeodomain finger protein 11 promotes class switch recombination to IgE in murine activated B cells.

Transduction of Effector-Suppressor T Cells by an Antigen-Specific Suppressor T Cell Factor and Lyt-1+,2+,3+ T Cells

Two loci selectively expressed on functionally different t cells

Overexpression of the c-fos gene perturbs functional maturation of M1 cells into macrophages.

Antigen-specific suppressive and enhancing T-cell factors determined by distinct loci in the I region of H-2 complex☆☆☆