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Biomedical subjects

Bruce C Richardson

Publications and source records attributed to Bruce C Richardson.

13 recordsLinked to original sources
PubMed2006

The epigenetic face of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an archetypical systemic, autoimmune inflammatory disease characterized by the production of autoantibodies to multiple nuclear Ags. Apoptotic defects and impaired removal of apoptotic cells contribute to an overload of autoantigens that become available to initiate an autoimmune response. Besides the well-recognized genetic susceptibility to SLE, epigenetic factors are important in the onset of the disease, as even monozygotic twins are usually discordant for the disease. Changes in DNA methylation and histone modifications, the major epigenetic marks, are a hallmark in genes that undergo epigenetic deregulation in disease. In SLE, global and gene-specific DNA methylation changes have been demonstrated to occur. Moreover, histone deacetylase inhibitors reverse the skewed expression of multiple genes involved in SLE. In the present study, we discuss the implications of epigenetic alterations in the development and progression of SLE and how epigenetic drugs constitute a promising source of therapy to treat this disease.

Animals↗
PubMed2006

Accelerated macrophage apoptosis induces autoantibody formation and organ damage in systemic lupus erythematosus.

Increased monocyte/macrophage (Mphi) apoptosis occurs in patients with systemic lupus erythematosus (SLE) and is mediated, at least in part, by an autoreactive CD4(+) T cell subset. Furthermore, autoreactive murine CD4(+) T cells that kill syngeneic Mphi in vitro induce a lupus-like disease in vivo. However, it is unclear whether increased Mphi apoptosis in SLE per se is sufficient to accelerate/promote autoimmunity. We have investigated whether increased Mphi apoptosis in vivo, induced by the administration of clodronate liposomes, can exacerbate the autoimmune phenotype in NZB x SWR (SNF(1)) lupus-prone mice, and induce autoantibody production in haplotype-matched BALB/c x DBA1 (DBF(1)) non-lupus-prone mice. Lupus-prone mice SNF(1) mice that were treated with clodronate liposomes, but not mice treated with vehicle, developed significant increases in autoantibodies to dsDNA, nucleosomes, and the idiotypically related family of nephritic Abs Id(LN)F(1), when compared with untreated SNF(1) mice. Furthermore, clodronate treatment hastened the onset of proteinuria and worsened SNF(1) lupus nephritis. When compared with vehicle-treated controls, clodronate-treated non-lupus-prone DBF(1) mice developed significantly higher levels of anti-nucleosome and Id(LN)F(1) Abs but did not develop lupus nephritis. We propose that Mphi apoptosis contributes to the pathogenesis of autoantibody formation and organ damage through both an increase in the apoptotic load and impairment in the clearance of apoptotic material. This study suggests that mechanisms that induce scavenger cell apoptosis, such as death induced by autoreactive cytotoxic T cells observed in SLE, could play a pathogenic role and contribute to the severity of the disease.

Animals↗
PubMed2005

Estrogen regulates CCR gene expression and function in T lymphocytes.

Estrogen has been implicated in the observed female bias in autoimmune diseases. However, the mechanisms behind this gender dimorphism are poorly defined. We have previously reported that in vivo T cell trafficking is gender- and estrogen-dependent. Chemokine receptors are critical determinants of T cell homing and immune response. In this study, we show that the female gender is associated with increased CD4(+) T cell CCR1-CCR5 gene and protein expression in mice. The increased CCR expression correlates with enhanced in vitro chemotaxis response to MIP-1beta (CCL4). In vivo treatment of young oophorectomized and postmenopausal female mice with 17beta-estradiol also increased CD4(+) T cell CCR expression. Finally, 17beta-estradiol enhances tyrosine phosphorylation in T cells stimulated with MIP-1alpha in a time-dependent manner. Our results indicate an important role of estrogen in determining T cell chemokine response that may help explain the increased susceptibility and severity of autoimmune diseases in females.

Animals↗
PubMed2005

Demethylation of the same promoter sequence increases CD70 expression in lupus T cells and T cells treated with lupus-inducing drugs.

Exposing genetically predisposed individuals to certain environmental agents is believed to cause human lupus. How environmental agents interact with the host to cause lupus is poorly understood. Procainamide and hydralazine are drugs that cause lupus in genetically predisposed individuals. Understanding how these environmental agents cause lupus may indicate mechanisms relevant to the idiopathic disease. Abnormal T cell DNA methylation, a repressive epigenetic DNA modification, is implicated in procainamide and hydralazine induced lupus, as well as idiopathic lupus. Procainamide is a competitive DNA methyltransferase (Dnmt) inhibitor, hydralazine inhibits ERK pathway signaling thereby decreasing Dnmt expression, and in lupus T cells decreased ERK pathway signaling causing a similar Dnmt decrease. T cells treated with procainamide, hydralazine, and other Dnmt and ERK pathway inhibitors cause lupus in mice. Whether the same genetic regulatory elements demethylate in T cells treated with Dnmt inhibitors, ERK pathway inhibitors, and in human lupus is unknown. CD70 (TNFSF7) is a B cell costimulatory molecule overexpressed on CD4(+) lupus T cells as well as procainamide and hydralazine treated T cells, and contributes to excessive B cell stimulation in vitro and in lupus. In this report we identify a genetic element that suppresses CD70 expression when methylated, and which demethylates in lupus and in T cells treated with Dnmt and ERK pathway inhibitors including procainamide and hydralazine. The results support a model in which demethylation of specific genetic elements in T cells, caused by decreasing Dnmt expression or inhibiting its function, contributes to drug-induced and idiopathic lupus through altered gene expression.

5' Flanking Region↗
PubMed2005

The MAPK signalling pathways and colorectal cancer.

There are three major subfamilies of mitogen-activated protein kinases (MAPK): the extracellular-signal-regulated kinases (ERK MAPK); the c-jun N-terminal kinase or stress-activated protein kinases (JNK or SAPK); and MAPK14. The ERK MAPK pathway is one of the most important for cell proliferation. The MAPK pathways are located downstream of many growth-factor receptors, including that for epidermal growth factor. Overexpression and activation of this receptor are commonly detected in colorectal cancer, and several lines of evidence indicate that overexpression and activation of ERK MAPK play an important part in progression of this cancer. ERK MAPK could be a molecular target for treatment of the disorder. This review focuses on the ERK MAPK signal-transduction pathway, the consequences of its dysregulation in colorectal cancer, and its potential as an approach to cancer treatment. Future challenges for the assessment of these targeted agents in the clinic are also presented.

Cell Cycle↗
PubMed2004

Endothelial cell apoptosis in systemic lupus erythematosus: a common pathway for abnormal vascular function and thrombosis propensity.

Women with systemic lupus erythematosus (SLE) are at risk for premature atherothrombosis independent of Framingham risk factors. We investigated whether endothelial cell (EC) apoptosis predicts abnormal vasomotor tone and contributes to circulating tissue factor (TF) levels in this disease. Brachial artery flow-mediated dilation (FMD) and nitroglycerin-mediated dilation were determined in women with SLE, healthy control subjects, and subjects with coronary artery disease (CAD) (n = 43/group). Quantification of circulating apoptotic ECs was performed by flow cytometry (CD146(+) cells that stained for Annexin V [CD146(AnnV+)]) and immunofluorescent microscopy. Plasma TF was measured by enzyme-linked immunosorbent assay (ELISA). Compared with healthy control and CAD subjects, patients with SLE had higher numbers of circulating CD146(AnnV+) cells (10 +/- 3, 18 +/- 5, and 89 +/- 32 cells/mL, respectively, mean +/- SEM; P <.01). Increased CD146(AnnV+) cells correlated strongly with abnormal vascular function (P =.037). After adjusting for known predictors of endothelial function, CD146(AnnV+) was the only variable that predicted FMD (beta = -4.5, P <.001). Increased CD146(AnnV+) was strongly associated with elevated levels of circulating TF (r =.46, P =.002). Circulating apoptotic ECs are elevated in young women with SLE and strongly correlate with markedly abnormal vascular function and elevated TF levels. Heightened endothelial apoptosis may represent an important mechanism for development of atherothrombosis in SLE.

Adult↗
PubMed2004

Tissue-specific effect of estradiol on endothelial cell-dependent lymphocyte recruitment.

Estrogen profoundly affects onset and severity of many immune-mediated diseases. In our murine model of drug-induced autoimmunity, female-specific, estrogen-dependent increase in splenic lymphocyte homing was directly implicated in increased disease severity. The present study evaluated the effect of estradiol on microvascular endothelial cells from the spleen compared to endothelial cells from the dermis, which has no disease manifestation in this model. Estradiol increased spleen endothelial cell estrogen receptor (ER) alpha 2.9-fold and decreased estrogen receptor beta 2.1-fold while decreasing both receptors on dermal cells. Estradiol enhanced adhesion of D10 cells to spleen but not dermal endothelial cells 1.53-fold (P < 0.001), an increase that was inhibited by antibodies to VCAM-1 and ICAM-1, and by the estrogen receptor antagonists tamoxifen and ICI 182,780. Estradiol induced greater VCAM-1 expression on spleen than dermal endothelial cells (P < 0.05). Estradiol increased spleen endothelial cell estrogen receptor alpha 2.9-fold and decreased estrogen receptor beta 2.1-fold while decreasing both receptors on the dermal cells. Estrogen specifically and preferentially promoted spleen chemokine protein expression for MCP-1 and MCP-3, while having no effect on dermal protein expression for these chemokines. Estradiol-mediated effects on splenic chemokines were abrogated by tamoxifen and ICI 182,780. The gender-specific increase in lymphocyte homing to spleen may be attributable, at least in part, to tissue-specific estrogen-mediated effects on microvascular endothelial cells.

Animals↗
PubMed2003

Attenuation of autoimmune disease in Fas-deficient mice by treatment with a cytotoxic benzodiazepine.

OBJECTIVE: Elimination of autoreactive cells relies on Fas-dependent activation-induced cell death mechanisms, an important component of peripheral tolerance. Defects in Fas or its cognate ligand lead to inefficient activation-induced cell death and are specific causes of lymphoproliferative and autoimmune diseases. The present study was undertaken to investigate a novel 1,4-benzodiazepine (Bz-423) that induces apoptosis and limits autoimmune disease in NZB/NZW mice, to determine its activity against lupus-like disease associated with defective Fas expression. We investigated the Fas-dependence of its cytotoxic actions, its therapeutic potential in mice deficient in Fas, and its therapeutic mechanism of action. METHODS: Primary lymphocytes isolated from Fas-deficient MRL/MpJ-Fas(lpr) (MRL-lpr) mice were tested for sensitivity to Bz-423. Bz-423 was administered to MRL-lpr mice for short (1-week) or long (14-week) periods, and its effects on cell survival were determined along with measures of nephritis, arthritis, antibody titers, and Th subpopulations. BALB/c mice were similarly treated to determine if Bz-423 alters normal immune functions in vivo. RESULTS: Administration of Bz-423 to MRL-lpr mice significantly reduced autoimmune disease including glomerulonephritis and arthritis. Treatment was associated with decreases in CD4+ T cells and an alteration in the Th1/Th2 balance. At the therapeutic dosage, Bz-423 did not interfere with normal T and B cell responses in BALB/c mice, suggesting that this agent is not globally immunosuppressive. CONCLUSION: Bz-423 is a novel immunomodulatory agent that is active against disease even in the context of defective Fas signaling. It is a leading compound for further investigation into the development of selective therapies for lupus.

Adjuvants, Immunologic↗
PubMed2002

The apoptotic ligands TRAIL, TWEAK, and Fas ligand mediate monocyte death induced by autologous lupus T cells.

Individuals with systemic lupus erythematosus show evidence of a significant increase in monocyte apoptosis. This process is mediated, at least in part, by an autoreactive T cell subset that kills autologous monocytes in the absence of nominal Ag. We have investigated the apoptotic pathways involved in this T cell-mediated process. Expression of the apoptotic ligands TRAIL, TNF-like weak inducer of apoptosis (TWEAK), and Fas ligand on lupus T cells was determined, and the role of these molecules in the monocyte apoptotic response was examined. We report that these apoptotic ligands mediate the autologous monocyte death induced by lupus T cells and that this cytotoxicity is associated with increased expression of these molecules on activated T cells, rather than with an increased susceptibility of lupus monocytes to apoptosis induced by these ligands. These results define novel mechanisms that contribute to increased monocyte apoptosis characterizing patients with lupus. We propose that this mechanism could provide a source of potentially antigenic material for the autoimmune response and interfere with normal clearing mechanisms.

Adult↗
PubMed2002

Age-related changes in mature CD4+ T cells: cell cycle analysis.

T cell proliferative responses decrease with age, but the mechanisms responsible are unknown. We examined the impact of age on memory and naive CD4(+) T cell entry and progression through the cell cycle using acridine orange to identify cell cycle stage. For both subsets, fewer stimulated cells from old donors were able to enter and progress through the first cell cycle, with an increased number of cells arrested in G(0) and fewer cells in post G(0) phases. The number of dead cells as assessed by sub-G(0) DNA was also significantly greater in the old group. CD4(+) T cells from old mice also exhibited a significant reduction in clonal history as assessed by CFSE staining. This was associated with a significant decline in cyclin D2 mRNA and protein. We propose that decreases in cyclin D2 are at least partially responsible for the proliferative decline found in aged CD4(+) T cells.

Acridine Orange↗
PubMed2002

Role of DNA methylation in the regulation of cell function: autoimmunity, aging and cancer.

DNA methylation plays an essential role in maintaining cellular function, and changes in methylation patterns may contribute to the development of autoimmunity, aging and cancer. Evidence for a role in autoimmunity comes from studies demonstrating that inhibiting T lymphocyte DNA methylation causes autoreactivity in vitro and a lupus-like disease in vivo. The autoimmunity is due in part to the heterodimeric beta(2) integrin lymphocyte function-associated antigen-1 (LFA-1) (CD11a/CD18) overexpression, and T lymphocytes from lupus patients hypomethylate the same CD11a promoter sequences, overexpress LFA-1 and demonstrate the same autoreactivity. Procainamide and hydralazine, two drugs that cause a lupus-like disease, also inhibit T cell DNA methylation, increase LFA-1 expression and induce autoreactivity in vitro and autoimmunity in vivo, supporting the association of DNA hypomethylation and autoimmunity. Methylation patterns also change with age in T lymphocytes as well as other tissues, typically with an overall decrease in methylcytosine content, but with increases in some cytosine guanine dinucleotide (CpG) islands. Age-dependent hypomethylation contributes to LFA-1 overexpression with aging, which may play a role in the development of autoimmunity in the elderly and age-dependent methylation of CpG islands in the promoters of tumor suppressor genes is an early event in the development of some cancers. DNA hypomethylation also may contribute to carcinogenesis by promoting overexpression of proto-oncogenes, chromosomal translocations and loss of imprinting. The mechanisms causing altered DNA methylation in autoimmunity, aging and carcinogenesis are incompletely characterized but include exposure to environmental agents and drugs, diet, altered signaling in pathways regulating DNA methyltransferase expression and changes in endogenous regulatory mechanisms. Other mechanisms are likely to be identified as well.

Aging↗
PubMed2002

Benzodiazepine-induced superoxide signals B cell apoptosis: mechanistic insight and potential therapeutic utility.

The properties of a proapoptotic 1,4-benzodiazepine, Bz-423, identified through combinatorial chemistry and phenotype screening are described. Bz-423 rapidly generated superoxide (O(2)(-)) in transformed Ramos B cells. This O(2)(-) response originated from mitochondria prior to mitochondrial transmembrane gradient collapse and opening of the permeability transition pore. Bz-423-induced O(2)(-) functioned as an upstream signal that initiated an apoptotic program characterized by cytochrome c release, mitochondrial depolarization, and caspase activation. Pretreatment of cells with agents that either block the formation of Bz-423-induced O(2)(-) or scavenge free radicals attenuated the death cascade, which demonstrated that cell killing by Bz-423 depends on O(2)(-). Parallels between Ramos cells and germinal center B cells prompted experiments to determine whether Bz-423 had therapeutic activity in vivo. This possibility was tested using the (NZB x NZW)F(1) murine model of lupus, in which the pathologically enhanced survival and expansion of germinal center B cells mediate disease. Administration of Bz-423 for 12 weeks specifically controlled germinal center hyperplasia and reduced the histological evidence of glomerulonephritis. Collectively, these studies define a new structure-function relationship for benzodiazepines and point to a new target and mechanism that could be of value for developing improved drugs to manage systemic lupus erythematosus and related disorders.

Animals↗