Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is curable in less than 50% of patients. Prognostic models based on pre-treatment characteristics, such as the International Prognostic Index (IPI), are currently used to predict outcome in DLBCL. However, clinical outcome models identify neither the molecular basis of clinical heterogeneity, nor specific therapeutic targets. We analyzed the expression of 6,817 genes in diagnostic tumor specimens from DLBCL patients who received cyclophosphamide, adriamycin, vincristine and prednisone (CHOP)-based chemotherapy, and applied a supervised learning prediction method to identify cured versus fatal or refractory disease. The algorithm classified two categories of pa- tients with very different five-year overall survival rates (70% versus 12%). The model also ef- fectively delineated patients within specific IPI risk categories who were likely to be cured or to die of their disease. Genes implicated in DLBCL outcome included some that regulate responses to B-cell-receptor signaling, critical serine/threonine phosphorylation pathways and apoptosis. Our data indicate that supervised learning classification techniques can predict outcome in DLBCL and identify rational targets for intervention. © 2002 Nature Publishing Group http://medicine.nature.com

/pdf/diffuse-large-b-cell-lymphoma-outcome-prediction-by-gene-2dnd8dxnlx.pdf

Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning

A functional immune system requires the selection of T lymphocytes expressing receptors that are major histocompatibility complex restricted but tolerant to self-antigens. This selection occurs predominantly in the thymus, where lymphocyte precursors first assemble a surface receptor. In this review we summarize the current state of the field regarding the natural ligands and molecular factors required for positive and negative selection and discuss a model for how these disparate outcomes can be signaled via the same receptor. We also discuss emerging data on the selection of regulatory T cells. Such cells require a high-affinity interaction with self-antigens, yet differentiate into regulatory cells instead of being eliminated.

Positive and Negative Selection of T Cells

https://www.pure.ed.ac.uk/ws/files/8117651/The_anti_inflammatory_and_immunosuppressive_effects_of_glucocorticoids_recent_developments_and_mechanistic_insights.pdf

The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights

Oxygenated derivatives of cholesterol (oxysterols) present a remarkably diverse profile of biological activities, including effects on sphingolipid metabolism, platelet aggregation, apoptosis, and ...

Oxysterols: modulators of cholesterol metabolism and other processes.

A reciprocal regulation exists between the central nervous and immune systems through which the CNS signals the immune system via hormonal and neuronal pathways and the immune system signals the CNS through cytokines. The primary hormonal pathway by which the CNS regulates the immune system is the hypothalamic-pituitary-adrenal axis, through the hormones of the neuroendocrine stress response. The sympathetic nervous system regulates the function of the immune system primarily via adrenergic neurotransmitters released through neuronal routes. Neuroendocrine regulation of immune function is essential for survival during stress or infection and to modulate immune responses in inflammatory disease. Glucocorticoids are the main effector end point of this neuroendocrine system and, through the glucocorticoid receptor, have multiple effects on immune cells and molecules. This review focuses on the regulation of the immune response via the neuroendocrine system. Particular details are presented on the effects of interruptions of this regulatory loop at multiple levels in predisposition and expression of immune diseases and on mechanisms of glucocorticoid effects on immune cells and molecules.

Neuroendocrine Regulation of Immunity

Previous data have suggested that glucocorticoids (GCs) are involved in the differentiation of thymocytes into mature T cells. In this report we demonstrate that the mouse thymic epithelial cells (TEC) express the cytochrome P450 hydroxylases Cyp11A1, Cyp21, and Cyp11B1. These enzymes, in combination with 3beta-hydroxysteroid dehydrogenase (3betaHSD), convert cholesterol into corticosterone, the major GC in rodents. In addition, when TEC were cocultured with 'reporter cells' containing the glucocorticoid receptor (GR) and a GR-dependent reporter gene, a specific induction of reporter gene activity was observed. Induction of reporter gene activity was blocked when the TEC and reporter cells were incubated in the presence of the Cyp11B1 inhibitor metyrapone or the 3betaHSD inhibitor trilostane, as well as by the GR antagonist RU486. Coculturing of TEC with thymocytes induced apoptosis in the latter, which was partially blocked by the enzyme inhibitors and RU486. We conclude that TEC secrete a GC hormone activity and suggest a paracrine role for this in thymocyte development.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fasebj.13.8.893

Paracrine glucocorticoid activity produced by mouse thymic epithelial cells

SPECIFIC AIMSThe aim of the present study was to investigate a direct effect of normal concentrations of endogenous glucocorticoids (GCs) under regular nonstressed conditions on thymocyte and T cell homeostasis independent of secondary systemic effects of GCs. This was achieved by generating transgenic mice with an altered GC sensitivity restricted to the T cell lineage.PRINCIPAL FINDINGS1. Increased GC sensitivity in the T cell lineage causes a reduction in thymocyte pool sizeTransgenic mice with an increased GC sensitivity in T cell lineage were generated by overexpressing GR cDNA in sense orientation under the control of the p56 proximal lck promoter (lckPr-sGR). Analysis of transgene expression showed it was restricted to lymphoid tissues like the thymus, spleen, and lymph nodes. No expression was seen in nonlymphoid tissues: liver, heart, and kidney. Quantification of the GR concentration in thymocytes from lckPr-sGR mice showed it had increased by ∼twofold in mice homogeneous for the transgene. This...

Effects of altered glucocorticoid sensitivity in the T-cell lineage on thymocyte and T-cell homeostasis

Thymocytes differentiate by positive and negative selection of immature CD4+ CD8+ T cells. Negative selection occurs by default or by high-affinity recognition of peptides bound to proteins encoded by the major histocompatibility complex (MHC). MHC class I molecules are expressed on many different cell types, although at different levels, whereas MHC class II molecules are selectively expressed on thymic epithelial cells (TEC) and dendritic cells (DC). We investigated the role of the glucocorticoid receptor (GR) in thymic negative selection using the receptor antagonist RU486. Glucocorticoids (GC) are known to be potent inducers of apoptosis in CD4+ CD8+ thymocytes, and we have earlier shown that anti-CD3-induced thymic apoptosis can be blocked by RU486 in vivo. We now show that anti-CD3 induces thymic apoptosis in mice that have been adrenalectomized (ADX), and that RU486 inhibits anti-CD3 antibody-mediated thymocyte killing in newborn thymic organ cultures. Thymocyte apoptosis induced by ovalbumin peptide OVA323-339 treatment of mice transgenic for the DO11.10T cell receptor (TCR), which recognizes this peptide in the context of I-Ad, was found to be inhibited by RU486. These mice responded to peptide treatment by an extensive activation of the peripheral immune system, which became lethal in 60% of the mice when accompanied by simultaneous RU486 treatment. In contrast, RU486 had no effect on thymic apoptosis induced by the influenza A nucleoprotein NP366-374 peptide, recognized in context of Db, in F5 TCR transgenic mice. We interpret the results to demonstrate that different deletion systems operate in the thymus. We propose that endogenous GC may be important for negative selection by default and by high-affinity recognition of endogenous MHC-presented peptides on TEC.

Inhibition of I-Ad-, but not Db-restricted peptide-induced thymic apoptosis by glucocorticoid receptor antagonist RU486 in T cell receptor transgenic mice.

Oxygenated derivatives of sterols (oxysterols), including 25-hydroxycholesterol and 27-hydroxycholesterol, have immunosuppressive effects. Oxysterols can directly induce apoptosis in immature thymocytes, cells which are inherently sensitive to induction of programmed cell death. For that reason, the metabolism of 25-hydroxycholesterol and 27-hydroxycholesterol in mouse thymus has been studied. When incubated with thymic tissue, both oxysterols were found to be 7alpha-hydroxylated with subsequent oxidation to 7alpha-hydroxy-3-oxo-delta4 steroids. A minor fraction of 27-hydroxycholesterol was also metabolised to 3beta-hydroxy-5-cholestenoic, 3beta,7alpha-dihydroxy-5-cholestenoic and 7alpha-hydroxy-3-oxo-4-cholestenoic acids. The 7alpha-hydroxylase was found to be localised to the thymic epithelial cells and the reaction was stimulated by interleukin-1beta and inhibited by metyrapone and RU486. In contrast to 25-hydroxycholesterol and 27-hydroxycholesterol, the 7alpha-hydroxylated metabolites, 7alpha,25-dihydroxycholesterol, 7alpha,25-dihydroxy-4-cholesten-3-one and 7alpha,27-dihydroxy-4-cholesten-3-one did not induce thymocyte apoptosis. The results suggest that 7alpha-hydroxylation may be of regulatory importance, possibly by protecting the developing thymocytes against toxic effects by oxysterols.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1997.00129.x

7alpha-Hydroxylation and 3-dehydrogenation abolish the ability of 25-hydroxycholesterol and 27-hydroxycholesterol to induce apoptosis in thymocytes.

The T cell receptor (TCR) repertoire is known to arise from a series of random genetic recombinational events, similar to the generation of immunoglobulin diversity, which give rise to antigen binding heterodimers capable of responding to a wide spectrum of MHC-presented peptides. However, in this differentiation process only a small number of cells reach the mature state, as most are deleted by a process called negative selection (von Boehmer et al. 1989; Janeway et al. 1992). In the mouse around 50 × 106 cells/day are formed in the thymus; of these, only approximately 1–2 × 106 mature to CD4+ helper and CD8+ cytotoxic T cells. Negative selection can be a consequence of either lack of self-MHC recognition or high avidity recognition of dominant self-peptides (Ashton-Rickardt et al. 1994; Janeway et al. 1992; Sebzda et al. 1994).

Yintong Xue

Papers

Paracrine glucocorticoid activity produced by mouse thymic epithelial cells

Effects of altered glucocorticoid sensitivity in the T-cell lineage on thymocyte and T-cell homeostasis

Inhibition of I-Ad-, but not Db-restricted peptide-induced thymic apoptosis by glucocorticoid receptor antagonist RU486 in T cell receptor transgenic mice.

7alpha-Hydroxylation and 3-dehydrogenation abolish the ability of 25-hydroxycholesterol and 27-hydroxycholesterol to induce apoptosis in thymocytes.

Thymocyte Apoptosis by Glucocorticoids and cAMP