Safety and efficacy of oral febuxostat for treatment of HLA-B*5801-negative gout: a randomized, open-label, multicentre, allopurinol-controlled study.

OBJECTIVES: This phase IIIB study compared the efficacy and safety of febuxostat and allopurinol in gout patients with or without tophi who were HLA-B*5801 negative. METHOD: Eligible patients were randomized to a febuxostat group (80 mg QD) or an allopurinol group (300 mg QD). Following an initial 2-week washout period, over the next 12 weeks we made five measurements of serum urate levels along with assessments of adverse events (AEs). RESULTS: Forty-three out of 152 screened subjects (28.3%) were ineligible either because of the presence of the HLA-B*5801 allele or for various other reasons. The febuxostat group (n = 54) and the allopurinol group (n = 55) had no significant differences in demographic or baseline characteristics. From week 2 to week 12, the febuxostat group had a significantly lower serum urate level than the allopurinol group (p ≤ 0.001 for all comparisons) and significantly more patients with serum urate levels less than 6.0 mg/dL. The serum urate levels of the febuxostat group declined by more than 40% from week 2 to week 12 and this decrease was greater than that in the allopurinol group (~30%). The two groups were similar in terms of AEs. CONCLUSIONS: Febuxostat was more effective than allopurinol in reducing the serum urate levels of Han Chinese patients with gout or tophaceous gout who were HLA-B*5801 negative, without causing any serious skin reactions. Febuxostat should be considered for treatment of Han Chinese patients with gout who are HLA-B*5801 negative.

Increased programmed death-ligand-1 expression in human gastric epithelial cells in Helicobacter pylori infection.

B7-H1 [programmed death-ligand-1 (PD-L1)] is a B7-family member that binds to programmed death-1 (PD-1). Recently, deficiency of PD-L1 has been demonstrated to result in accelerated gastric epithelial cell damage in gastritis, and PD-L1 is suggested to play a critical role in regulating T cell homeostasis. Here, we aimed to gain more insight into gastric PD-L1 expression, regulation and function during Helicobacter pylori infection. PD-L1 expression in human gastric epithelial cells was analysed using Western blotting, quantitative polymerase chain reaction and fluorescence activated cell sorter analysis. Furthermore, co-culture experiments of human gastric epithelial cells with primary human T cells or Jurkat T cells were conducted. PD-L1 expression in primary human gastric epithelial cells was strongly enhanced by H. pylori infection and activated T cells, and augmented markedly by further stimulation with interferon-γ or tumour necrosis factor-α. Moreover, PD-L1 expression in gastric epithelial cells significantly induced apoptosis of T cells. Our results indicate that a novel bidirectional interaction between human gastric epithelial cells and lymphocytes modulates PD-L1 expression in human gastric epithelial cells, contributing to the unique immunological properties of the stomach.

TRAIL suppresses gut inflammation and inhibits colitogeic T-cell activation in experimental colitis via an apoptosis-independent pathway.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell apoptosis by transducing apoptosis signals. Recently, accumulating evidence demonstrated that TRAIL regulates autoimmune inflammation and immune cell homeostasis in several autoimmune animal models, suggesting a novel immunoregulatory role of TRAIL in autoimmune diseases. However, the impact of TRAIL in inflammatory bowel disease is yet undefined. This study is to address the therapeutic effects and immunoregulatory role of TRAIL in autoimmune gut inflammation. We demonstrated herein that TRAIL significantly suppressed gut inflammation and reduced the severity of colitis in a dextran sodium sulfate (DSS)-induced colitis model. Suppression of gut inflammation was not due to induction of apoptosis in colonic T cells, dendritic cells, or epithelium cells by TRAIL. In contrast, TRAIL directly inhibited activation of colitogenic T cells and development of gut inflammation in an adoptive transfer-induced colitis model. The anti-inflammatory effects of TRAIL on colitis were abolished when T cells from TRAIL receptor (TRAIL-R) knockout mice were adoptively transferred, suggesting that TRAIL regulates autoreactive colitogenic T-cell activation in the development of gut inflammation. Our results demonstrate that TRAIL effectively inhibited colonic T-cell activation and suppressed autoimmune colitis, suggesting a potential therapeutic application of TRAIL in human inflammatory bowel disease.

Elevated serum decoy receptor 3 with enhanced T cell activation in systemic lupus erythematosus.

Decoy receptor 3 (DcR3/TR6) is a decoy receptor for the Fas ligand (FasL) and can inhibit FasL-induced apoptosis. It has been reported recently that DcR3 can induce T cell activation via co-stimulation of T cells, suggesting that DcR3 may be involved in the pathophysiology of autoimmune diseases. This study aims to analyse the serum DcR3 in patients with systemic lupus erythematosus (SLE) and to investigate the role of DcR3 in the pathogenesis of SLE. Significantly elevated serum DcR3 was observed in SLE patients, and the mean serum DcR3 level was significantly higher for those with active disease [SLE disease activity index (SLEDAI) >/= 10] compared with that in patients with inactive disease (SLEDAI < 10). In addition to reducing activation-induced cell death in activated T cells via neutralization of the FasL, soluble DcR3-Fc enhanced T cell proliferation and increased interleukin-2 and interferon-gamma production via co-stimulation of T cells. Moreover, enhanced T cell reactivity to DcR3-induced co-stimulation was demonstrated in lymphocytes from patients with SLE, suggesting the elevated serum DcR3 may associate with enhanced T cell activation in vivo. These findings are the first to demonstrate that serum DcR3 concentrations are increased in SLE patients, and this may imply a possible role of DcR3 in the pathogenesis of SLE via enhanced T cell hyperreactivity and reduced apoptosis in activated T cells.

Superantigens. Gazing into the crystal ball.

The recently determined crystal structures of complexes between bacterial toxin 'superantigens' and MHC class II molecules shed light on the nature of the interactions between these two molecules.

Risks of interleukin-1 genetic polymorphisms and Helicobacter pylori infection in the development of gastric cancer.

BACKGROUND: The host genetic factors that determine the clinical outcomes of Helicobacter pylori-infected individuals remain unclear. AIM: To elucidate the risks of host interleukin-1 (IL-1) genetic polymorphisms and H. pylori infection in the development of gastric cancer. METHODS: In a case-control study of 164 controls and 142 patients with gastric cancer, the IL-1B-511 biallelic polymorphisms and the IL-1RN penta-allelic variable number of tandem repeats were genotyped. RESULTS: The carriage of IL-1RN*2, male gender, old age and H. pylori infection independently increased the risk of gastric cancer, with odds ratios of 3.3 [95% confidence interval (CI), 1.4-7.7], 2.1 (95% CI, 1.2-3.8), 5.3 (95% CI, 3.1-9.0) and 2.2 (95% CI, 1.3-3.8), respectively. H. pylori-infected individuals who were carriers of IL-1RN*2 showed increased risks of both intestinal and diffuse types of gastric cancer, with odds ratios of 11.0 and 8.7, respectively. In addition, these individuals also had a higher score of intestinal metaplasia in the corpus than did uninfected non-carriers. CONCLUSIONS: This study is the first to verify IL-1RN*2 as an independent factor governing the development of gastric cancer in Asian individuals. A combination of H. pylori testing and host genotyping may target the eradication of H. pylori to high-risk individuals.

Eradication of Helicobacter pylori prevents ulcer development in patients with ulcer-like functional dyspepsia.

BACKGROUND: Although the eradication of Helicobacter pylori infection benefits patients with gastric or duodenal ulcers, the value of eradicating the infection in the patients with functional dyspepsia (FD) remains controversial. AIMS: To determine whether eradicating H. pylori can prevent the subsequent development of ulcers or relieve the symptoms of functional dyspepsia patients. METHODS: In a double-blind, placebo-controlled trial, 161 patients infected with H. pylori who had functional dyspepsia were randomly assigned to 7 days of treatment with a lansoprazole-based triple therapy or placebo and then followed for 1 year. The main outcome measures were the development of peptic ulcers and the resolution of symptoms. RESULTS: H. pylori was eradicated in 63 out of 81 patients (78%) in the treatment group and none of the 80 patients (0%) in the placebo group. During the follow-up period, two patients in the treatment group and six patients in the placebo group developed peptic ulcers at repeat endoscopy (2.5% vs. 7.5%; 95% CI: -12 to 2). The reduction in ulcer rates was statistically significant in the 'ulcer-like' sub-group (0% vs. 16.7%; 95% CI: -32 to -2), but not in the 'dysmotility-like' and 'unclassifiable' sub-groups. Regarding symptom response, the resolution rates of symptoms were similar between the treatment and placebo groups (58.0% vs. 55.0%, 95% CI: -12 to 18). Additionally, no significant differences existed in the symptom responses between the treatment and control arms in each of the dyspepsia sub-groups. CONCLUSIONS: Eradicating H. pylori can prevent the subsequent development of peptic ulcers in the patients with 'ulcer-like' functional dyspepsia. However, this approach does not significantly reduce the symptoms of functional dyspepsia patients.

Double-blind, randomised, comparative trial of etodolac SR versus diclofenac in the treatment of osteoarthritis of the knee.

A multi-centre, double-blind, randomised parallel-group study was conducted to compare the efficacy and safety between etodolac SR and diclofenac in treating patients with osteoarthritis of the knee. Thirty-two patients receiving etodolac SR (400 mg/day) and 32 patients receiving diclofenac (100 mg/day) were included for analyses. After receiving the study treatment, etodolac SR and diclofenac were shown to produce comparable improvement in pain relief as measured by a 10-cm visual analogue scale. There was no statistically significant difference observed between groups for the degree of functional impairment or the amount of paracetamol taken. The etodolac SR treatment group showed fewer incidents of adverse event. In addition, fewer gastrointestinal symptoms were observed in the etodolac SR treatment group. A statistically higher percentage of etodolac SR-treated patients were better tolerated to the study treatment compared with the diclofenac-treated patients. Etodolac SR-treated patients also took fewer antacids than the diclofenac-treated patients during the treatment period. In conclusion, etodolac SR is an effective treatment with fewer side-effects than diclofenac for patients with osteoarthritis of the knee.

Impact of bacterial eradication on the cell proliferation and p53 protein accumulation in Helicobacter pylori-associated gastritis.

BACKGROUND: This study investigates the cell proliferation and the expression of p53 protein in Helicobacter pylori (H. pylori)-associated gastritis and assesses the effect of bacterial eradication on these epithelial factors. MATERIAL AND METHODS: Seventy-nine patients with H. pylori-associated gastritis were randomized into the control group (n = 38) and anti-H. pylori group (n = 41). Each patient received endoscopic examinations with gastric biopsy before and 8 weeks after the treatment. The specimens from gastric antrum were immunostained for monoclonal antibodies against the proliferating cell nuclear antigen (PCNA) and p53 protein. RESULTS: In the control group, the total labeling index (L.I.) of PCNA and the positive index (P.I.) of p53 in the whole foveolar epithelium were unchanged after treatment. In the anti-H. pylori group, 35 of 41 cases (85.3%) achieved eradication of H. pylori. Amongst the H. pylori-eradicated cases, the total L.I. of PCNA in the whole foveolar epithelium did not meaningfully alter after H. pylori elimination (p > 0.05). However, a significant reduction of L.I. was observed in the middle compartments of the gastric pits (before vs. after treatment: 14.0 vs. 7.3, p < 0.05). With regard to the p53 expression, the P.I.s were significantly decreased in the whole foveolar epithelium (before vs. after treatment: 0.57 vs. 0.17, p < 0.05) and in each compartment of the gastric pits (before vs. after treatment: [upper compartment]: 0.34 vs. 0.15, p < 0.05; [middle compartment]: 0.67 vs. 0.23, p < 0.05; [lower compartment]: 0.71 vs. 0.20, p < 0.05) after eradication of H. pylori. CONCLUSIONS: Bacterial eradication reverses the hyperproliferating status of the foveolar epithelium in patients with H. pylori gastritis and leads to a decrease in p53 accumulation in the epithelial cells.

A subset of acute lymphoblastic leukemia with co-expression of myeloid antigens: prevalence and clinical significance.

In order to evaluate the biological features and clinical significance of myeloid antigen expression in acute lymphoblastic leukemia (ALL), immunophenotype analysis was performed on leukemic cells from 160 patients diagnosed as ALL by the French, American and British (FAB) criteria using a comprehensive panel of monoclonal antibodies to lymphoid and myeloid associated antigens. Expression of myeloid antigens was found in 32 cases (20%), including 11 out of 49 adults (22.4%) and 21 out of 111 children (18.9%). CD33 was positive in 18 patients (11.3% of the total cases), CD13 in 15 patients (9.4%), CD 11b in 12 patients (7.5%) and CD14 in 1 patient (0.6%). Nine patients expressed two or more myeloid antigens. There were no significant differences in clinical manifestations and hematological pictures between the ALL patients with myeloid antigen expression (My+ ALL) and those without (My- ALL). No consistent chromosomal abnormality was found in My+ ALL. Eighty percent of the childhood and 44.4% of the adult My+ ALL patients achieved complete remission, compared with 87% and 80%, respectively, for childhood and adult My- ALL, but the differences were not statistically significant. After a median follow-up of 2.1 years, there were also no statistically significant associations between myeloid antigen expression and shorter duration of remission or poorer survival rate for patients with both adult and childhood ALL.

Helicobacter pylori sensitizes TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human gastric epithelial cells through regulation of FLIP.

Helicobacter pylori (H. pylori) infection is associated with chronic gastritis, peptic ulcer and gastric cancer. Apoptosis induced by microbial infections is implicated in the pathogenesis of H. pylori infection. Here we show that human gastric epithelial cells sensitized to H. pylori confer susceptibility to TRAIL-mediated apoptosis via modulation of death receptor signaling. Human gastric epithelial cells are intrinsically resistant to TRAIL-mediated apoptosis. The induction of TRAIL sensitivity by H. pylori is dependent on the activation of caspase-8 and its downstream pathway. H. pylori induces caspase-8 activation via enhanced assembly of the TRAIL death-inducing signaling complex (DISC) through downregulation of cellular FLICE-inhibitory protein (FLIP). Overexpression of FLIP abolished the H. pylori-induced TRAIL sensitivity in human gastric epithelial cells. Our study thus demonstrates that H. pylori induces sensitivity to TRAIL apoptosis by regulation of FLIP and assembly of DISC, which initiates caspase activation, resulting in the breakdown of resistance to apoptosis, and provides insight into the pathogenesis of gastric damage in Helicobacter infection. Modulation of host apoptosis signaling by bacterial interaction adds a new dimension to the pathogenesis of Helicobacter.

Helicobacter pylori-related diffuse large B-cell lymphoma of the stomach: a distinct entity with lower aggressiveness and higher chemosensitivity.

We recently showed that Helicobacter pylori (HP)-positive gastric 'pure' diffuse large B-cell lymphoma (DLBCL) may respond to HP eradication therapy. However, whether these HP-related 'pure' DLBCL of the stomach may differ fundamentally from those unrelated to HP remains unclear. In this study, we compared the clinicopathologic features of these two groups of patients who had been uniformly treated by conventional chemotherapy. Forty-six patients were designated HP-positive and 49 were HP-negative by conventional criteria. HP-positive patients had a lower International Prognostic Index score (0-1, 65% vs 43%, P=0.029), a lower clinical stage (I-IIE1, 70% vs 39%, P=0.003), a better tumor response to chemotherapy (complete pathologic response, 76% vs 47%, P=0.004) and significantly superior 5-year event-free survival (EFS) (71.7% vs 31.8%, P<0.001) and overall survival (OS) (76.1% vs 39.8%, P<0.001). To draw a closer biologic link with HP, HP-positive tumors were further examined for CagA expression in lymphoma cells. Compared with CagA-negative cases (n=16), CagA-positive cases (n=27) were associated with high phosphorylated SHP-2 expression (P=0.016), and even better 5-year EFS (85.2% vs 46.3%, P=0.002) and OS (88.9% vs 52.9%, P=0.003). HP-related gastric 'pure' DLBCL may be a distinct tumor entity, which is less aggressive, and responds better to conventional chemotherapy.

Genetic polymorphisms and tissue expression of interleukin-22 associated with risk and therapeutic response of gastric mucosa-associated lymphoid tissue lymphoma.

Chronic Helicobacter pylori-stimulated immune reactions determine the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. We aimed to explore the genetic predisposition to this lymphoma and its clinical implication. A total of 68 patients and 140 unrelated controls were genotyped for 84 single-nucleotide polymorphisms in genes encoding cytokines, chemokines and related receptors that play important roles in T cell-mediated gastrointestinal immunity. Five genotypes in IL-22, namely CC at rs1179246, CC at rs2227485, AA at rs4913428, AA at rs1026788 and TT at rs7314777, were associated with disease susceptibility. The former four genotypes resided in the same linkage disequilibrium block (r(2)=0.99) that conferred an approximately threefold higher risk. In vitro experiments demonstrated that co-culturing peripheral mononuclear cells or CD4(+) T cells with H. pylori stimulated the secretion of interleukin-22 (IL-22), and that IL-22 induced the expression of antimicrobial proteins, RegIIIα and lipocalin-2, in gastric epithelial cells. Furthermore, patients with gastric tissue expressing IL-22 were more likely to respond to H. pylori eradication (14/22 vs 4/19, P<0.006). We conclude that susceptibility of gastric MALT lymphoma is influenced by genetic polymorphisms in IL-22, the product of which is involved in mucosal immunity against H. pylori and associated with tumor response to H. pylori eradication.

Detection of the Helicobacter pylori CagA protein in gastric mucosa-associated lymphoid tissue lymphoma cells: clinical and biological significance.

We previously reported that CagA can be translocated into B cells in Helicobacter pylori (HP) coculture media, and the translocation appears biologically significant as activation of the relevant cellular pathways was noticed. In this study, we further explore if CagA can be detected in malignant B cells of HP-positive gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Expression of CagA was evaluated by immunohistochemistry. CagA expression was further confirmed by western blot analysis. The association between CagA expression in malignant B cells and tumor response to HP eradication therapy (HPE) was evaluated in 64 stage IE gastric MALT lymphoma patients. We detected CagA expression in 31 (48.4%) of 64 patients: 26 (68.4%) of the 38 HP-dependent cases and 5 (19.2%) of the 26 HP-independent cases (P<0.001). Patients with CagA expression responded to HPE quicker than those without (median time to complete remission, 3.0 vs 6.5 months, P=0.025). Our results indicated that CagA can be translocated into malignant B cells of MALT lymphoma, and the translocation is clinically and biologically significant.

Genetic polymorphism in milk fat globule-EGF factor 8 (MFG-E8) is associated with systemic lupus erythematosus in human.

Milk fat globule-EGF factor 8 (MFG-E8) is a molecule implicated in phagocytic clearance of apoptotic cells by bridging between macrophages and apoptotic cells. Defects in MFG-E8 cause lupus-like disease in murine models. The aim of our study is to determine whether genetic variation in MFG-E8 predisposes human to systemic lupus erythematosus (SLE). A case-control study of MFG-E8 genetic polymorphism was performed on 147 SLE patients and 146 non-lupus control subjects. Single nucleotide polymorphisms (SNPs) in the coding sequence of human MFG-E8 gene were investigated. SNPs on MFG-E8 residues 3 (3(Arg or Ser)) and 76 (76(Leu or Met)) did not show genetic linkage. Genetic polymorphism on MFG-E8 residue 76 correlated significantly to SLE. The MFG-E8-76(Met) allele predisposed subjects to SLE in a recessive mode (odds ratio: 2.1, P = 0.020), while carriage of MFG-E8-76(Leu) were negatively associated with SLE. The MFG-E8 genotypic combinations with 3(Ser) and 76(Leu) showed the most pronounced protective effect on SLE when compared to the most predisposing genotype 3(Arg/Arg)-76(Met/Met) (OR: 0.29, P = 0.007). According to our result, MFG-E8 is associated with SLE predisposition in Taiwanese. Our study implicates that the impairment of phagocytic clearance of apoptotic cells through phosphotidylserine-dependent MFG-E8 system may lead to the development of human SLE.

Virus-encoded superantigens.

Superantigens are microbial agents that have a strong effect on the immune response of the host. Their initial target is the T lymphocyte, but a whole cascade of immunological reactions ensues. It is thought that the microbe engages the immune system of the host to its own advantage, to facilitate persistent infection and/or transmission. In this review, we discuss in detail the structure and function of the superantigen encoded by the murine mammary tumor virus, a B-type retrovirus which is the causative agent of mammary carcinoma. We will also outline what has more recently become known about superantigen activity associated with two human herpesviruses, cytomegalovirus and Epstein-Barr virus. It is likely that we have only uncovered the tip of the iceberg in our discovery of microbial superantigens, and we predict a flood of new information on this topic shortly.

HLA DPB1*0201 allele is negatively associated with immunoglobulin E responsiveness specific for house dust mite allergens in Taiwan.

BACKGROUND: House dust mite (HDM) Dermatophagoides pteronyssinus is the most important source of indoor allergens that cause allergic diseases in Taiwan. We prepared purified HDM allergens (Der p 1, Der p 2 and Der p 5) to detect allergen-specific immunoglobulin (Ig) E responsiveness among a large number of test subjects. The robust genetic typing system for HLA class II genes also facilitated the study on association of HLA and allergic response toward HDM. OBJECTIVE: This study intended to investigate the association between HLA class II alleles and the IgE responsiveness to the major allergens from HDM, D. pteronyssinus. METHODS: Two hundred and forty-eight subjects were selected for HLA association study. Plasma HDM allergen (Der p 1, Der p 2, Der p 5) -specific IgE and Der p 2-specific IgG antibodies were detected by ELISA, while HLA class II -DRB1, -DQA1, -DQB1, -DPB1 genetic polymorphism was determined by polymerase chain reaction/sequence-specific oligonucleotide probe hybridization (PCR/SSOPH). Statistical comparison of the allelic distribution of each HLA class II genes among the individuals with/without HDM allergen-specific IgE and IgG antibodies were performed. RESULTS: There was no significant association between HLA DRB1, DQB1, DQA1 alleles and HDM-specific IgE responsiveness noted. Only DRB1*0803 and the linked DQA1*0103 alleles showed positive association with Der p 5-specific IgE responsiveness. However, we found that HLA-DPB1*1301 predisposed subjects to IgE responsiveness to HDM Der p 5. HLA DPB1*0501 was weakly associated with the IgE responsiveness to HDM Der p 1 and Der p 5. There was a strong negative association between the HLA-DPB1*0201 allele with IgE responsiveness to Der p 1 (OR: 0.30, P