Fat‐resident Tregs: an emerging guard protecting from obesity‐associated metabolic disorders

Obesity, a chronic, low‐grade inflammatory disease, is associated with alterations of multiple immune‐cell components in the visceral adipose tissue (VAT), in which CD4⁺Foxp3⁺ regulatory T cells (Tregs) have been suggested to be a critical regulator. This review focuses on the current understanding of VAT‐resident Tregs (VAT Tregs) and their intriguing roles in modulating fat tissue inflammation and obesity‐associated metabolic disorders. The potential mechanisms for the regulation of VAT Tregs in lean vs. obese individuals are also discussed. Accumulating evidence reveals that the modulation of VAT Tregs may offer a potential novel strategy for treating obesity‐related metabolic disorders, such as insulin resistance and type 2 diabetes.     

Differences in the incidence of flares or new onset of inflammatory bowel diseases in patients with ankylosing spondylitis exposed to therapy with anti–tumor necrosis factor α agents

Objective

Ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) are clinically and pathologically linked. Anti–tumor necrosis factor (anti‐TNF) agents are efficacious in treating AS, but not all are equally effective in treating IBD (Crohn's disease [CD] and ulcerative colitis [UC]). The purpose our study was to analyze the incidence of flares and new onset of IBD in patients with AS treated with anti‐TNF agents.

Methods

Data from 9 trials, 7 placebo‐controlled trials and 2 open studies, were analyzed.

Results

Data were available on 419 AS patients exposed to etanercept (625 patient‐years), 366 exposed to infliximab (618 patient‐years), 295 exposed to adalimumab (132 patient‐years), and 434 placebo patients (150 patient‐years). A history of IBD was reported in 76 of 1,130 patients (6.7%). There were 2 reports of IBD while receiving placebo (1.3 per 100 patient‐years), 1 while receiving infliximab, and 3 while receiving adalimumab. Among the 14 IBD cases receiving etanercept (2.2 per 100 patient‐years) there were 8 CD and 6 UC cases, significantly different from infliximab (P = 0.01) but not from placebo. Patients with a history of IBD had an IBD flare odds ratio of 18.0 (95% confidence interval [95% CI] 2–154) while taking etanercept and 4.2 (95% CI 0.4–44) while taking adalimumab, in comparison with infliximab. The incidence rates of new onset of IBD showed no significant difference between etanercept (0.8 per 100 patient‐years) and placebo (0.5 per 100 patient‐years).

Conclusion

New onset and flare of IBD are infrequent events in AS patients receiving anti‐TNF therapy. Infliximab (but not etanercept) largely prevents IBD activity. More data are required for adalimumab. The incidence of new onset of IBD was statistically not different from placebo for all anti‐TNF agents.     

IL28B genetic variation and hepatitis C virus–specific CD4+ T‐cell responses in anti‐HCV‐positive blood donors

Summary. Epidemiological, viral and host factors are associated with the outcome of hepatitis C virus (HCV) infection, and strong host immune responses against HCV favour viral clearance. Recently, genome‐wide association studies have shown a strong correlation between single‐nucleotide polymorphisms (SNPs) near the interleukin‐28B (IL28B) gene and spontaneous or treatment‐induced HCV clearance. We have investigated whether protective IL28B genetic variants are associated with HCV‐specific T‐cell responses among Spanish blood donors. The rs12979860 IL28B haplotype was determined in 69 anti‐HCV‐positive blood donors (21 HCV RNA negative and 48 HCV RNA positive) and 30 seronegative donors. In all cases, HCV‐specific CD4⁺ T‐cell responses to HCV recombinant proteins (core, NS3 and NS3 helicase) were assessed by ex vivo interferon‐γ ELISpot assay. The rs12979860‐CC genotype was highly overrepresented in donors with spontaneous HCV clearance when compared to those with chronic infection (76.2%vs 29.2%, P < 0.001; odds ratio, 7.77; 95% confidence interval, 2.4–25.3, P < 0.001). HCV‐specific CD4⁺ T‐cell responses were detected in 16 (76.2%) spontaneous resolvers especially towards nonstructural proteins, but with no correlation with IL28B genotype. Chronic individuals had a significantly lower overall T‐cell response again irrespective of IL28B genotype. When spontaneous resolvers and chronic individuals were stratified according to their IL28B genotype, significantly stronger T‐cell responses were only observed among those with non‐CC haplotypes. Although the protective rs12979860 IL28B CC genotype is associated with spontaneous HCV clearance, stronger CD4⁺ T‐cell responses towards NS3 were only evident among those with non‐CC haplotypes.     

Severe cardiomyopathy following treatment with the tumour necrosis factor‐α inhibitor adalimumab for Crohn's disease

Adalimumab belongs to the group of tumour necrosis factor‐α inhibitors and has been approved for the treatment Crohn's Disease since 2007. Herein we report a severe adverse reaction to adalimumab in a 25‐year‐old female patient. One week after the initial‐dose of adalimumab (160 mg), which was initiated due to an acute exacerbation of Crohn's disease, the patient developed a fulminant cardiomyopathy. In severe cardiogenic shock, the patient required an extracorporeal membrane‐oxygenation system for 8 days until cardiac recovery.     

The infectious profiles of anti‐tumor necrosis factor agents in a Thai population: a retrospective study a the university‐based hospital

Aims: Anti‐tumour necrosis factor‐α (anti‐TNF) agents represented treatment advances in a number of rheumatologic diseases. However, adverse effects of anti‐TNF agents have been identified through both clinical trials and post‐marketing surveillance, especially an increased risk of serious infections. This study firstly described the infectious profiles of anti‐TNF agents in a Thai population. Methods: We retrospectively reviewed all infectious incidences from 100 consecutive medical records of patients who were treated with either etanercept or infliximab for any rheumatologic and non‐rheumatologic conditions. Results: Indications for anti TNF‐α agents were mainly rheumatoid arthritis (46%) and spondyloarthropathy (SpA) (41%). Seventy‐seven patients were treated with etanercept and 23 with infliximab. For those whose initial treatment was etanercept, there were two events of suspected active pulmonary tuberculosis (TB) and suspected hepatitis‐B virus (HBV) reactivation. Two out of 23 patients (8.7%) who were firstly treated with infliximab had herpes zoster skin infection. Incidence of overall infection before anti‐TNF treatment were significantly higher in patient who started with etanercept (0.065 vs. 0.019 cases per person‐years in etanercept and infliximab respectively, P < 0.0001). Incidence of overall infection post‐anti‐TNF treatment were 0.122 and 0.201 cases per person‐years in patients who started with etanercept and infliximab with no significant difference (P > 0.05). The overall infection rates were significantly increased after infliximab treatment (P < 0.0001). Conclusion: Even thought there were two new events of TB and HBV reactivation after etanercept treatment, incidence of overall infection seemed to be increased after infliximab treatment. The infectious screening and monitoring with high index of suspicion as well as the pre‐emptive treatment are still important whenever either etanercept or infliximab is started.     

Extended indications for anti‐tumor necrosis factor‐α therapy

Tumour necrosis factor‐α is a pleiotropic cytokine which has a broad range of actions in inflammation, infection and immunity. TNF‐α is supposed to play a crucial role in the pathogenesis of various autoimmune diseases. TNF‐α blocking agents have been demonstrated to be highly effective in the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and juvenile rheumatoid arthritis. TNF‐α inhibitors also have been tried with other rheumatic diseases and have emerged as promising treatments. We here review the current evidences of effectiveness of the anti‐TNF‐α therapy in various autoimmune diseases.     

Significance of anti‐α‐fodrin autoantibody in diagnosis of Sjogren's syndrome

Objective: Anti‐α‐fodrin autoantibody has been reported to be a highly specific and sensitive test for the diagnosis of Sjogren's syndrome (SS). The objective of our report is to investigate the sensitivity and specificity of anti‐α‐fodrin antibody in patients with SS and its correlation with clinical manifestations. Methods: Recombinant human α‐fodrin was used as envelope antigen in enzyme‐linked immunosorbent assay (ELISA) to detect the relatively specific autoantibody in sera of 42 primary SS, 24 secondary SS with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), and 40 other connective tissue diseases (CTDs) (SLE 17, RA 8, ankylosing spondylitis 5, dermatomyositis 5, systemic schlerosis 3, mixed connective tissue disease 1, Takayasu's disease 1) patients. Results: Antibodies against α‐fodrin were present in 59.5% of primary SS patients, 31.5% of secondary SS patients, 35.0% and 11.3% of other CTD patients and controls, respectively; the specificity of anti‐α‐fodrin antibody was 79.4% in patients with SS. It showed no significant difference between primary and secondary SS (P > 0.05), as well as SS compared with other CTD patients (P > 0.05). The positive rates of antibodies against α‐fodrin in CTD patients were significantly higher than those in non‐CTD patients and normal controls (P < 0.01). The presence of anti‐α‐fodrin antibodies has no significant correlation with clinical manifestations or other autoantibodies, while the levels of sera IgG and erythrocyte sedimentation rate (ESR) are higher in α‐fodrin antibody‐positive patients (IgG: 23.2 vs. 18.6, P < 0.05; ESR: 52.9 vs. 37.1, P < 0.05) than α‐fodrin antibody‐negative patients. Anti‐α‐fodrin antibodies are all negative in anti‐SS antigen A and antinuclear antibody‐negative SS patients. Conclusion: The result showed a lower sensitivity and specificity for anti‐α‐fodrin antibody as a diagnostic marker of SS, compared with previous reports. Anti‐α‐fodrin antibodies had no significant association with clinical manifestations, but might be related to the sera IgG level. Antibodies against α‐fodrin played no important roles in diagnosis of antibody‐negative SS patients.     

Transforming growth factor‐β induces epithelial to mesenchymal transition by down‐regulation of claudin‐1 expression and the fence function in adult rat hepatocytes

Background/Aims: Transforming growth factor‐β (TGF‐β) initiates and maintains epithelial–mesenchymal transition (EMT), which causes disassembly of tight junctions and loss of epithelial cell polarity. In mature hepatocytes during EMT induced by TGF‐β, changes in the expression of tight junction proteins and the fence function indicated that epithelial cell polarity remains unclear. Methods: In the present study, using primary cultures of adult rat hepatocytes at day 10 after plating, in which epithelial cell polarity is well maintained by tight junctions, we examined the effects of 0.01–20 ng/ml TGF‐β on the expression of the integral tight junction proteins, claudin‐1, ‐2 and occludin, as well as the fence function. Results: In adult rat hepatocytes, TGF‐β induced EMT, which was indicated as upregulation of Smad‐interacting protein‐1 (SIP1) and Snail and down‐regulation of E‐cadherin. Down‐regulation of claudin‐1 and upregulation of occludin were observed beginning from a low dose of TGF‐β, whereas upregulation of claudin‐2 was observed at a high dose of TGF‐β. Furthermore, treatment with TGF‐β caused disruption of the fence function, which was closely associated with the expression of claudin‐1 via p38 mitogen‐activated protein kinase (MAPK), phosphoinositide‐3 kinase and protein kinase C but not MAPK signalling pathways. Conclusion: These results suggest that in mature hepatocytes in vitro, TGF‐β induces EMT by down‐regulation of claudin‐1 and the fence function via distinct signalling pathways.     

Amyloid‐β neurotoxicity in organotypic culture is attenuated by melatonin: involvement of GSK‐3β, tau and neuroinflammation

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by accumulation of extracellular deposits of amyloid‐β (Aβ) peptide in brain regions that are important for memory and cognition. The buildup of Aβ aggregates in the AD is followed by the formation of intracellular neurofibrillary tangles and activation of neuroinflammatory reactions. The present study investigated whether melatonin possesses a neuroprotective effect against Aβ‐induced toxicity. For this purpose, organotypic hippocampal slices were cultured and exposed to 25 μm of Aβ_25–35 in the absence or in the presence of melatonin (25, 50, or 100 μm ). In addition, the authors have investigated the involvement of GSK‐3β, tau protein, astroglial, and microglial activation, and cytokine levels in the melatonin protection against Aβ‐induced neurotoxicity. Melatonin prevented the cell damage in hippocampus induced by the exposure to Aβ_25–35. In addition, melatonin significantly reduced the activation of GSK‐3β, the phosphorylation of tau protein, the glial activation and the Aβ‐induced increase of TNF‐α and IL‐6 levels. On the basis of these findings, we speculate that melatonin may provide an effective therapeutic strategy for AD, by attenuating Aβ‐induced phosphorylation of tau protein, and preventing GSK‐3β activation and neuroinflammation.     

Immunological interaction between Giardia cyst extract and experimental toxoplasmosis

Toxoplasmosis is mostly associated with other intestinal parasitic infections especially Giardia due to shared mode of peroral infection. Toxoplasma and Giardia induce a strong T‐helper 1‐ immune response. Our aim was to induce a protective immune response that results in significant impact on intestinal and extra‐intestinal phases of Toxoplasma infection. This study was conducted in experimental animals and assessment of Giardia cyst extract effect on Toxoplasma infection was investigated by histopathological examination of small intestine and brain, Toxoplasma cyst count and iNOS staining of the brain, measurement of IFN‐γ and TGF‐β in intestinal tissues. Results showed that the brain Toxoplasma cyst number was decreased in mice infected with Toxoplasma then received Giardia cyst extract as compared to mice infected with Toxoplasma only. This effect was produced because Giardia cyst extract augmented the immune response to Toxoplasma infection as evidenced by severe inflammatory reaction in the intestinal and brain tissues, increased levels of IFN‐γ and TGF‐β in intestinal tissues and strong iNOS staining of the brain. In conclusion, Giardia cyst extract generated a protective response against T. gondii infection. Therefore, Giardia antigen will be a suitable candidate for further researches as an immunomodulatory agent against Toxoplasma infection.     

Transforming Growth Factor‐β:A Promising Target for Anti‐Stenosis Therapy

Transforming growth factor‐β (TGF‐β) is the general name for a family of cytokines which have widespread effects on many aspects of growth and development. The TGF‐β isoforms are produced by most cell types and exert a wide range of effects in a context‐dependent autocrine, paracrine or endocrine fashion via interactions with distinct receptors on the cell surface. TGF‐β is involved in the wound healing process and, thus plays a significant role in the formation of a restenotic lesion after percutaneous transluminal coronary angioplasty (PTCA) or stenting. Perhaps because of its wide‐ranging effects, TGF‐β is usually released from cells in a latent form, and its activation and signaling are complex. Manipulation of the TGF‐β1, TGF‐β2, and TGF‐β3 isoforms by inhibiting their expression, activation, or signaling reduces scarring and fibrosis in animal models. However, to date, few have reached clinical trial. This review summarizes current knowledge on the activation and signaling of TGF‐β, and focuses on the anti‐TGF‐β strategies which may lead to clinical applications in the prevention of restenosis following PTCA or stenting.     

Peripheral T cell receptors αβ and γδ in patients with Hodgkin's lymphoma

Antigen recognition by T cells is determined by an antigen specific T cell receptor (TCR). Two heterodimeric TCR structures associated with CD3 have been defined: TCR αβ and TCR γδ. TCR αβ and its function are well described but the role of TCR γδ in normal and lymphoproliferative disorders is not well established. In newly diagnosed or relapsed/refractory Hodgkin's disease (HD), a disease associated with defective T cell functions and increased sIL-2R, We determined levels of seven TCR αβ variable regions [βV5(a), βV5(b), βV6(a), βV12(a), αβV(a), αV2(a)] and TCR γδ by using monoclonal antibodies (MCA). TCR γδ levels did not show any difference, but several variable regions of the TCR αβ differed when groups are compared with each other and the control group.