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ID PMID Title PublicationDate abstract
23180035 Genetics of ANCA-associated vasculitis in Japan: a role for HLA-DRB1*09:01 haplotype. 2013 Oct The epidemiology of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is considerably different between European and Asian populations. Whereas granulomatosis with polyangiitis is the most common form of AAV in northern European populations, microscopic polyangiitis (MPA) accounts for the majority of AAV in Japan. This difference may at least in part derive from the difference in genetic background. In this review, I focus on our observation on HLA, an obvious candidate gene for immune disorders, and discuss its potential implication. In Japanese AAV, significant association was detected with HLA-DRB1*09:01, the carrier frequency of which was increased in MPA [P=0.0087, odds ratio (OR) 1.90, 95% confidence interval (CI) 1.17-3.08] and in myeloperoxidase (MPO)-ANCA-positive AAV (P=0.0016, OR 2.05, 95% CI 1.31-3.23) when compared with healthy Japanese controls. HLA-DRB1*09:01 is one of the most common HLA-DRB1 alleles in Asians but is rare in Caucasian populations. Interestingly, HLA-DRB1*09:01 has been shown to be associated with multiple autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus, suggesting that either HLA-DRB1*09:01 itself or other genes in tight linkage disequilibrium may play a role in a molecular pathway shared by various autoimmune diseases in Japanese and possibly in other Asian populations.
23164706 Identification of inhibitors against interaction between pro-inflammatory sPLA2-IIA protei 2013 Jan 1 Increased concentrations of secreted phospholipase A2 type IIA (sPLA2-IIA), have been found in the synovial fluid of patients with rheumatoid arthritis. It has been shown that sPLA2-IIA specifically binds to integrin αvβ3, and initiates a signaling pathway that leads to cell proliferation and inflammation. Therefore, the interaction between integrin and sPLA2-IIA could be a potential therapeutic target for the treatment of proliferation or inflammation-related diseases. Two one-bead-one-compound peptide libraries were constructed and screened, and seven target hits were identified. Herein we report the identification, synthesis, and biological testing of two pyrazolylthiazole-tethered peptide hits and their analogs. Biological assays showed that these compounds were able to suppress the sPLA2-IIA-integrin interaction and sPLA2-IIA-induced migration of monocytic cells and that the blockade of the sPLA2-IIA-integrin binding was specific to sPLA2-IIA and not to the integrin.
23138975 Socio-demographic and clinical profile of chronic pain with neuropathic characteristics in 2013 Jul Data on characteristics of neuropathic pain (NP) in sub-Saharan Africa are scarce, especially in the elderly. We conducted this study to appreciate the socio-demographic and clinical profile of chronic pain (CP) with neuropathic characteristics in sub-Saharan African elderly with musculoskeletal pain. From January to December 2011, we performed a cross-sectional study in all Rheumatology outpatients over 60 years at the Center for Gerontology and Geriatrics, Dakar, Senegal. In this study, we included patients who experienced musculoskeletal pain for 3 months or longer (CP) and with a DN4 score ≥ 4 (NP). A complete clinical examination was performed to make the diagnosis of NP 'definite' or 'probable', and to identify the aetiologies of NP. During the study period, 698 outpatients were examined. There were 394 out of the 549 patients over 60 years who reported CP. Among them, 28 patients (7.1%) scored ≥4 on the DN4 questionnaire. Female patients, low educational attainment, manual professions, non-workers and diabetes were associated with NP (p < 0.05). The symptoms described by patients with NP, often intricate, were lumboradiculalgia (n = 9), cervico-brachial neuralgia (n = 3), polyneuropathy (n = 12) and mononeuropathy (n = 6). The presumed aetiologies in patients with NP were: chronic spine diseases (n = 14), painful diabetic peripheral neuropathy (n = 8), Sjögren's syndrome (n = 1), tarsal tunnel syndrome in rheumatoid arthritis (n = 1) and bone metastasis (n = 1). No aetiology was identified among three patients. Chronic spine diseases associated with radiculopathies and diabetic neuropathy are the main causes of NP, well detected by DN4 questionnaire and clinical examination in Senegalese sub-Saharan African elderly.
24507879 Vitamin D levels in Indian systemic lupus erythematosus patients: association with disease 2014 Feb 10 INTRODUCTION: Low levels of vitamin D have been associated with several autoimmune disorders including multiple sclerosis, rheumatoid arthritis, type 1 diabetes and systemic lupus erythematosus (SLE). The major source of vitamin D is sunlight but exposure of SLE patients to UV rays has been shown to exacerbate disease pathology. Studies in various populations have shown an association between low vitamin D levels and higher SLE disease activity. METHODS: We enrolled 129 patients who fulfilled American College of Rheumatology criteria in the study. There were 79 treatment-naïve cases and 50 patients who were under treatment for underlying SLE. There were 100 healthy subjects from similar geographical areas included as controls. Plasma 25-OH vitamin D₃ and interferon (IFN)-α levels were quantified by enzyme-linked immunosorbent assay (ELISA). The gene expression level of IFN-α was determined by quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Plasma 25-OH vitamin D₃ significantly correlated in an inverse manner with systemic lupus erythematosus disease activity index (SLEDAI) scores (P <0.0001, r = -0.42), anti-dsDNA (P <0.0001, r = -0.39), plasma IFN-α (P <0.0001, r = -0.43) and levels of IFN-α gene expression (P = 0.0009, r = -0.45). Further, plasma levels of IFN-α positively correlated with gene expression of IFN-α (P <0.0001, r = 0.84). Treatment-naïve SLE patients displayed significantly higher plasma levels of IFN-α compared to patients under treatment (P <0.001) and controls (P <0.001). CONCLUSIONS: These results suggest an important role of vitamin D in regulating disease activity in SLE patients and the need to supplement vitamin D in their treatment.
23874021 Closing the loop on inflammation and atherothrombosis: why perform the CIRT and CANTOS tri 2013 Inflammation contributes to all phases of the atherothrombotic process, patients with elevated inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP) have increased cardiovascular risk, and recent work directly implicates the interleukin-1 (IL-1) and interleukin-6 (IL-6) pathways in atherogenesis. Yet, it remains unknown whether targeted inhibition of inflammation will reduce cardiovascular event rates. To address directly this fundamental hypothesis, our research group has initiated two large-scale, randomized, placebo-controlled trials using targeted anti-inflammatory agents for the secondary prevention of myocardial infarction. The first trial, the Cardiovascular Inflammation Reduction Trial (CIRT), has been funded by the NHLBI and will evaluate whether low-dose methotrexate (target dose, 20 mg/wk) as compared to placebo will reduce major vascular events among a group of post-myocardial infarction patients with either diabetes or metabolic syndrome, groups known to have high risk on the basis of a persistent pro-inflammatory response. CIRT is based, in part, on observational evidence of reduced vascular event rates among those treated with methotrexate in the setting of rheumatoid arthritis or psoriatic arthritis and on the ability of methotrexate to reduce TNF, IL-6, and CRP levels. The second trial, the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS), will evaluate whether interleukin-1β (IL-1β) inhibition as compared to placebo can reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among stable coronary artery disease patients who remain at high vascular risk due to persistent elevations of hsCRP (_2 mg/L) despite contemporary secondary prevention strategies. Canakinumab is a human monoclonal antibody that selectively neutralizes IL-1β, a pro-inflammatory cytokine that plays multiple roles in the atherothrombotic process and that undergoes activation by the NLRP3 inflammasome, a process promoted by cholesterol crystals that in turn leads directly to increased production of IL-1 and IL-6. Together, CIRT and CANTOS will enroll more than 25,000 patients worldwide and provide a fundamental test of the inflammatory hypothesis of atherothrombosis.
24164839 Hepatitis B virus reactivation in HBsAg-positive patients with rheumatic diseases undergoi 2013 Oct OBJECTIVE: The aim of this study was to assess the effects of anti-tumor necrosis factor (TNF) agents or disease-modifying antirheumatic drugs (DMARDs) on hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)-positive patients with rheumatic diseases. METHODS: Evidence of HBV reactivation after anti-TNF therapy or DMARDs in HBsAg-positive patients with rheumatic disease was summarized by performing a systematic review. RESULTS: A total of 122 HBsAg-positive rheumatic disease-positive patients undergoing treatment with an anti-TNF agent or with DMARDs were identified in nine studies. In eight of the studies, the anti-TNF agents used were etanercept in 56 cases, adalimumab in 25 cases and infliximab in 14 cases. Follow-up periods ranged from 6 to 52 months. Antiviral prophylaxis was administrated in 48 of the 122 patients (39.3%). HBV reactivation in HBsAg-positive patients taking an anti-TNF agent or DMARD was reported in 15 cases (15/122 = 12.3%). Ten of the 15 patients provided individual data on HBV reactivation: four patients had rheumatoid arthritis, four had ankylosing spondylitis and two had psoriatic arthritis; four received etanercept, and two received infliximab. In one of the four etanercept-treated cases in which the patient had elevated HBV-DNA levels, antiviral prophylaxis was also administered. Antiviral treatment was also administered in seven patients receiving other treatments: lamivudine in one, adefovir in one and entecavir in five. Clinical outcomes were satisfactory in all 10 cases of HBV reactivation. CONCLUSIONS: Hepatitis B virus reactivation was found in 15 (12.3%) patients among the 122 HBsAg-positive patients with rheumatic diseases treated with anti-TNF agents or DMARDs.
23357924 Physical and mental quality of life in chronic pancreatitis: a case-control study from the 2013 Mar OBJECTIVES: The objective of this study was to define the quality of life (QOL) in patients with chronic pancreatitis (CP). METHODS: We studied 443 well-phenotyped CP subjects and 611 control subjects prospectively enrolled from 20 US centers between 2000 and 2006 in the North American Pancreatitis Study 2. Responses to the SF-12 questionnaire were used to calculate the mental (MCS) and physical component summary scores (PCS) with norm-based scoring (normal ≥50). Quality of life in CP subjects was compared with control subjects after controlling for demographic factors, drinking history, smoking, and medical conditions. Quality of life in CP was also compared with known scores for several chronic conditions. RESULTS: Both PCS (38 [SD, 11.5] vs 52 [SD, 9.4]) and MCS (44 [SD, 11.5] vs 51 [SD, 9.2]) were significantly lower in CP compared with control subjects (P < 0.001). On multivariable analyses, compared with control subjects, a profound decrease in physical QOL (PCS 12.02 points lower) and a clinically significant decrease in mental QOL (MCS 4.24 points lower) was seen due to CP. Quality of life in CP was similar to (heart, kidney, liver, lung disease) or worse than (nonskin cancers, diabetes mellitus, hypertension, rheumatoid arthritis) other chronic conditions. CONCLUSIONS: The impact of CP on QOL appears substantial. The QOL in CP subjects appears to be worse or similar to the QOL of many other chronic conditions.
23111095 Hepatitis B virus (HBV) reactivation in rheumatic patients with hepatitis core antigen (HB 2013 Jan OBJECTIVES: The aim of this study was to assess the effects of anti-tumour necrosis factor (TNF) agents on hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)-negative and anti-hepatitis B core (HBc)-positive patients (HBV occult carriers) with rheumatic diseases. METHODS: Evidence of HBV reactivation after anti-TNF therapy in HBV occult carriers with a rheumatic disease was studied by summarising results and by performing meta-analysis analysis. RESULTS: A total of 468 HBsAg-negative and anti-HBc-positive patients with a rheumatic disease undergoing treatment with an anti-TNF agent were identified in nine studies. The anti-TNF agents used were etanercept in 269 cases, adalimumab in 95, and infliximab in 100 cases, and these were administered for rheumatoid arthritis (RA) in 327 patients, ankylosing spondylitis in 49, and psoriatic arthritis (PsA) in 73 patients. Follow-up periods ranged from 6 to 60 months. HBV reactivation in patients on an anti-TNF agent was reported in 8 cases (8/468 = 1.7%). Seven of these patients had RA and 1 had PsA. Seven patients received etanercept and one adalimumab. HBV-DNA was detectable in 7 of these 8 cases. Antiviral treatment was administered in 6 of the 8 (lamivudine in 2, entecavir in 4) and clinical outcomes were satisfactory in all 8 patients. CONCLUSIONS: HBV reactivation was found in 8 (1.7%) patients among 468 HBsAg-negative and anti-HBc-positive patients with rheumatic diseases treated with anti-TNF agents. Our data suggest that HBsAg-negative and anti-HBc-positive patients undergoing anti-TNF therapy need to be carefully monitored during anti-TNF therapy.
25545915 Bornyl acetate has an anti-inflammatory effect in human chondrocytes via induction of IL-1 2014 Dec Both pro-inflammatory cytokines and anti-inflammatory cytokines generated by chondrocytes play essential roles in the process of Rheumatoid arthritis and osteoarthritis (OA). Bornyl acetate is the main volatile constituent in numerous conifer oils and some Chinese traditional herbs, which has displayed an anti-inflammatory effect before. In this study, we found that bornyl acetate elevates the expression of IL-11 at both the mRNA and protein levels. Interestingly, our results indicated that IL-1β-mediated up-regulation of IL-6, IL-8, MMP-1, and MMP-13 was significantly compromised by IL-11 co-treatment on mRNA levels and protein levels. The antagonistic effects of bornyl acetate on IL-1β induced targets MMP-1 and MMP-13 were diminished by IL-11 knockdown. Mechanistically, our results indicated that bornyl acetate significantly elevates the expression of AP-1 component c-fos, which may influence gross AP-1 activity and initial the transcription of IL-11. Indeed, expression of IL-11 was reversed upon c-fos knockdown. Our results suggest the therapeutic potentials of bornyl acetate in patients with OA.
25439045 The role of serotonin and its receptors in activation of immune responses and inflammation 2015 Mar Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter and hormone that contributes to the regulation of various physiological functions by its actions in the central nervous system (CNS) and in the respective organ systems. Peripheral 5-HT is predominantly produced by enterochromaffin (EC) cells of the gastrointestinal (GI) tract. These gut-resident cells produce much more 5-HT than all neuronal and other sources combined, establishing EC cells as the main source of this biogenic amine in the human body. Peripheral 5-HT is also a potent immune modulator and affects various immune cells through its receptors and via the recently identified process of serotonylation. Alterations in 5-HT signalling have been described in inflammatory conditions of the gut, such as inflammatory bowel disease. The association between 5-HT and inflammation, however, is not limited to the gut, as changes in 5-HT levels have also been reported in patients with allergic airway inflammation and rheumatoid arthritis. Based on searches for terms such as '5-HT', 'EC cell', 'immune cells' and 'inflammation' in pubmed.gov as well as by utilizing pertinent reviews, the current review aims to provide an update on the role of 5-HT in biological functions with a particular focus on immune activation and inflammation.
25305238 An overview on biologic medications and their possible role in apical periodontitis. 2014 Dec INTRODUCTION: Apical periodontitis (AP) is the expression of a deficient balance between infection and the host immune response. METHODS: If reducing the bacterial load from the root canal and preventing its reinfection may lead to clinical success, then the integrity of the nonspecific immune system has a relevant influence on the outcome of endodontic treatment. RESULTS: Compromised immune systems and/or genetic alterations of the host's response may as well play an important role on the development, progression, and healing of AP. Thus, immunomodulatory drugs might have the potential to influence both the severity of AP and the outcome of endodontic treatment. Biologic medications are a new class of drugs of monoclonal antibodies or fusion proteins that include fragments of a peculiar cytokine receptor. Specific inflammatory molecules or cells, such as tumor necrosis factor, interleukins, and T or B cells, are the selective targets of these drugs. They modulate the altered immune response and perform an important role in the short-term treatment of chronic inflammatory diseases such as rheumatoid arthritis, refractory Crohn disease, or ulcerative colitis. Despite the clinical positive outcomes and their widespread use, the consequences of administering biologic medications on the development of the dental diseases have not been adequately investigated. CONCLUSIONS: The aim of this review was to give an overview of biologic medications, their composition, their mechanisms of action, and their possible implications on endodontic and other dental diseases.
25026201 Effects of low doses of quercetin and genistein on oxidation and carbonylation in hemoglob 2014 Sep Protein-bound carbonyls have been shown to increase with age as well as in numerous diseases including rheumatoid arthritis, adult respiratory syndrome pulmonary fibrosis, diabetes, Parkinson's disease, and Alzheimer's just to mention a few. The effects of the flavonoids quercetin and genistein were investigated according to their ability to inhibit the oxidation of hemoglobin and myoglobin via the Fenton's pathway. Antioxidative activity of the flavonoids were determined by oxidizing hemoglobin and myoglobin in separate experiments with 50 μM Fe(2+) and 0.01 mM hydrogen peroxide (H2O2) with and without quercetin and/or genistein. The samples were treated singly with either quercetin, genistein, or in combination at concentrations of 1.0, 1.5, 2.0, 2.5, 3.0, and 3.5 μM, respectively, dissolved in dimethyl sulfoxide (DMSO). Samples were then incubated in a water bath at 37°C for 8, 12, and 24 hr, respectively. Levels of carbonylation were assayed by the protein carbonyl assay and the carbonyl levels quantified and expressed per mg of protein. The results indicate that protein carbonyls for samples treated with quercetin or genistein decreased in a dose-dependent manner compared to the controls. That of quercetin compared to genistein was more efficient in reducing the levels of protein carbonylation in hemoglobin and myoglobin, respectively. The combination of both flavonoids did show a gradual decrease in carbonyl compounds for only hemoglobin for all the doses and times tested. The results indicate that both flavonoids at low doses inhibited carbonylation in both hemoglobin and myoglobin and the inhibition may be attributed to the prevention of protein oxidation.
24946050 Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenol 2014 Oct 1 Human tumor necrosis factor (TNF), first isolated by our group as an anticancer agent, has been now shown to be a primary mediator of inflammation. Till today 19 different members of the TNF superfamily which interact with 29 different receptors, have been identified. Most members of this family exhibit pro-inflammatory activities, in part through the activation of the transcription factor, nuclear factor-kappaB (NF-κB). Thus TNF and the related pro-inflammatory cytokines have been shown to play a key role in most chronic diseases such as cancer, rheumatoid arthritis, cardiovascular diseases, psoriasis, neurologic diseases, Crohn's disease, and metabolic diseases. Therefore, agents that can modulate the TNF-mediated inflammatory pathways may have potential against these pro-inflammatory diseases. Although blockers of TNF-α, such as infliximab (antibody against TNF-α), adalimumab (humanized antibody against TNF-α), and etanercept (soluble form of TNFR2) have been approved for human use, these blockers exhibit numerous side effects. In this review, we describe various plant-derived polyphenols that can suppress TNF-α activated inflammatory pathways both in vitro and in vivo. These polyphenols include curcumin, resveratrol, genistein, epigallocatechin gallate, flavopiridol, silymarin, emodin, morin isoliquiritigenin, naringenin, ellagic acid, apigenin, kaempferol, catechins, myricetin, xanthohumol, fisetin, vitexin, escin, mangostin and others. Thus these polyphenols are likely to have potential against various pro-inflammatory diseases.
24842191 Miconazole inhibits receptor activator of nuclear factor-κB ligand-mediated osteoclast fo 2014 Aug 15 Osteoclasts are responsible for bone erosion in diseases as diverse as osteoporosis, periodontitis, and rheumatoid arthritis. Antifungal products have received recent attention as potential therapeutic and preventative drugs in human disease. Since little is known about the action of miconazole, an antifungal imidazole, on bone metabolism, we investigated the effects of miconazole on osteoclast formation using mouse bone marrow macrophages (BMMs). Miconazole inhibited RANKL-induced osteoclast formation in a dose-dependent manner without cytotoxicity. Furthermore, miconazole inhibited the bone resorptive activity of osteoclasts. Miconazole suppressed RANKL-induced expression of c-Fos and NFATc1, two essential transcription factors for osteoclast differentiation. Miconazole seemed to inhibit osteoclast formation MAPK pathways as well as Blimp1 through MafB expression. Miconazole also inhibited RANKL-induced expression of the pro-inflammatory cytokines, COX-2 and iNOS. In accordance with the in vitro study, miconazole reduced lipopolysaccharide-induced osteoclast formation in vivo. Therefore, miconazole exerted an inhibitory effect on osteoclast formation in vitro and in vivo. It could be useful for the treatment of bone diseases associated with excessive bone resorption.
24719044 Fatigue in adults with Marfan syndrome, occurrence and associations to pain and other fact 2014 Aug This study aims to investigate how fatigue affects adults with verified Marfan syndrome (MFS) in their daily lives, by examining fatigue levels and prevalence of severe fatigue compared to the general Norwegian population and individuals with other comparable chronic conditions. We investigated associations between socio-demographic characteristics, Marfan-related health problems, pain and fatigue. A cross-sectional study was conducted, using a postal questionnaire including the Fatigue Severity Scale (FSS) and questions on socio-demographic characteristics, Marfan-related health problems and pain. One hundred seventeen persons with MFS were invited to participate, 73 answered (62%). Participants reported significantly higher FSS scores and prevalence of severe fatigue compared to the general Norwegian population and patients with rheumatoid arthritis (RA), but lower than for other chronic conditions. Participants with chronic pain reported higher fatigue scores than those without chronic pain. Participants on disability benefits reported higher fatigue scores than participants who were working or enrolled in higher education. Marfan-related health problems like aortic dissection and use of blood pressure medication were not significantly associated with fatigue. In multivariable regression analyses chronic pain and employment status were significantly associated with fatigue. The final multivariable model explained 24% of the variance in fatigue scores. Our results show that fatigue is common in MFS patients and that it interferes with their daily lives. Chronic pain and employment status show significant associations to fatigue. This implies that fatigue is important to address when meeting MFS patients in clinical practice. There is need for more research on fatigue in Marfan syndrome.
24698574 The strength and function of hip abductors following anterolateral minimally invasive tota 2014 Apr 1 OBJECTIVE: To analyze the extent of postoperative hip abductor insufficiency in primary total hip arthroplasty (THA) patients undergoing anterolateral minimally invasive (ALMI) approach, and to investigate whether the clinical outcomes are more favorable in femoral neck fracture (FNF) patients than in non-femoral neck fracture (nFNF) patients. METHODS: A total of 48 patients were enrolled in this study. Each patient underwent a clinical examination preoperatively and 6, 12, 24 and 48 weeks postoperatively. The abductor torque, Trendelenburg's sign, gait velocity, Harris hip score, Oxford hip score, Westren Ontario and McMaster Universities (WOMAC) score and visual analog scale pain score were recorded. Statistical evaluation was performed with SPSS software version 18.0. The significance level was set at P<0.05. RESULTS: The abductor torque of the operated hip and the recovery ratio showed a gradual improving tendency from 6 weeks postoperatively until the last follow-up. Gait velocity, Harris hip score, Oxford hip score and WOMAC score improved significantly after the operation until 24 weeks postoperatively. In the FNF group, the abductor torque of the operated side and the recovery ratio were significantly higher than in nFNF group at 6 weeks postoperatively, however, as time passed, this trend tended to disappear. CONCLUSION: This study demonstrates that patients can obtain good abductor strength and function in the early postoperative period and the hip abductor function of patients who suffer from hip osteoarthritis, rheumatoid arthritis, avascular necrosis of the femoral head could be significantly improved following ALMI THA.
24679833 The pathogenesis and treatment of large granular lymphocyte leukemia. 2014 May Large granular lymphocyte (LGL) leukemia is a spectrum of rare lymphoproliferative diseases of T lymphocytes and natural killer cells. These diseases frequently present with splenomegaly, neutropenia, and autoimmune diseases like rheumatoid arthritis. LGL leukemia is more commonly of a chronic, indolent nature; however, rarely, they have an aggressive course. LGL leukemia is thought to arise from chronic antigen stimulation, which drives long-term cell survival through the activation of survival signaling pathways and suppression of pro-apoptotic signals. These include Jak-Stat, Mapk, Pi3k-Akt, sphingolipid, and IL-15/Pdgf signaling. Treatment traditionally includes immunosuppression with low dose methotrexate, cyclophosphamide, and other immunosuppressive agents; however, prospective and retrospective studies reveal very limited success. New studies surrounding Jak-Stat signaling suggest this may reveal new avenues for LGL leukemia therapeutics.
24645804 Absence of the adaptor protein Shb potentiates the T helper type 2 response in a mouse mod 2014 Sep Aberrant regulation of T helper (Th) cell maturation is associated with a number of autoimmune conditions, including allergic disorders and rheumatoid arthritis. The Src homology domain protein B (Shb) adaptor protein was recently implicated as a regulator of Th cell differentiation. Shb is an integral component of the T-cell receptor (TCR) signalling complex and in the absence of Shb the TCR is less responsive to stimulation, resulting in the preferential development of Th2 responses under conditions of in vitro stimulation. In the present study, we extend those observations to an in vivo situation using a murine model of atopic dermatitis. Shb knockout mice develop more pronounced symptoms of atopic dermatitis with increased localized oedema, epidermal hyperplasia and IgE production. Dermal infiltration of mast cells, eosinophils, CD4(+) Th cells and F4/80(+) macrophages was also significantly increased in Shb-deficient mice. This correlated with elevated transcription of the hallmark Th2 cytokines interleukin-4 and interleukin-5. The loss of Shb therefore alters TCR signalling ability, thereby favouring the development of Th2-driven inflammation and exacerbating symptoms of allergy.
24555773 Significance of epigenetic landscape in cartilage regeneration from the cartilage developm 2014 Jun 1 Regenerative therapies for cartilage defects have been greatly advanced by progress in both the stem cell biology and tissue engineering fields. Despite notable successes, significant barriers remain including shortage of autologous cell sources and generation of a stable chondrocyte phenotype using progenitor cells. Increasing demands for the treatment of degenerative diseases, such as osteoarthritis and rheumatoid arthritis, highlight the importance of epigenetic remodeling in cartilage regeneration. Epigenetic regulatory mechanisms, such as microRNAs, DNA methylation, and histone modifications, have been intensively studied due to their direct regulatory role on gene expression. However, a thorough understanding of the environmental factors that initiate these epigenetic events may provide greater insight into the prevention of degenerative diseases and improve the efficacy of treatments. In other words, if we could identify a specific factor from the environment and its downstream signaling events, then we could stop or retard degradation and enhance cartilage regeneration. A more operational definition of epigenetic remodeling has recently been proposed by categorizing the signals during the epigenetic process into epigenators, initiators, and maintainers. This review seeks to compile and reorganize the existing literature pertaining to epigenetic remodeling events placing emphasis on perceiving the landscape of epigenetic mechanisms during cartilage regeneration with the new operational definition, especially from the environmental factors' point of view. Progress in understanding epigenetic regulatory mechanisms could benefit cartilage regeneration and engineering on a larger scale and provide more promising therapeutic applications.
24498648 Differential expression of alternative splice variants of CTLA4 in Kuwaiti autoimmune dise 2014 Jan 25 Cytotoxic T lymphocyte associated antigen4 (CTLA4) is a candidate susceptibility gene for the study of autoimmune diseases. The present study sought to explore the expression profile of the CTLA4 gene in autoimmune patients, such as rheumatoid arthritis (RA), systemic lupus erythematous (SLE) and Hashimoto's thyroiditis (HT), compared to healthy controls (HCs). A total of 88 (22 RA, 22 SLE 22 HT, 22 HCs) age-, gender- and ethnicity-matched individuals were recruited. The hypersensitive capillary electrophoresis method was employed to detect the CTLA4 splice variants. PCRs of the patient's cDNA using CTLA4-specific primers followed by cloning and sequencing were used to distinguish the various splice variants. The biochemical properties of all known CTLA4 variants were analysed using the ExPASy and ESEfinder programmes. Six alternatively spliced variants of the CTLA4 gene were detected in this study. These included mCTLA4-672, sCTLA4-562, N-CTLA4-292, L-CTLA4-277, ssCTLA4-214 and K-CTLA4-142 bp. K-CTLA4-142 bp and N-CTLA4-292 bp represented two novel splice variants of the CTLA4 gene. A reduction in the frequency of mCTLA4-672 bp and sCTLA4-562 bp was observed in SLE and RA patients compared to healthy controls. The shortest splice variant, K-CTLA4-142 bp, was predominantly detected in all of the tested cohorts,while the decreased expression of the N-CTLA4-292 bp variant was observed in the autoimmune subjects. The exonic splice enhancer motifs of the SRp40 protein were found exactly at the splice junction of wCTLA4 (-ACAGAGC-, 2.7) and K-CTLA4 (-TGAAAAG-, 3.37), and that of the SRp55 protein was found at the splice junction of L-CTLA4 (-TGTGTG-, 2.82). Our study highlights the discrepancies in the expression spectrum of the CTLA4 gene in autoimmune patients and healthy subjects. The abnormal expression pattern of the CTLA4 gene in autoimmune patients suggests that in addition to allelic variation, the expression pattern of CTLA4 could contribute to autoimmunity.