Recognition of oxidized albumin and thyroid antigens by psoriasis autoantibodies: A possible role of reactive-oxygen-species induced epitopes in chronic plaque psoriasis

Objectives:

To investigate the role of reactive-oxygen-species (ROS) induced epitopes on human-serum-albumin (HSA) and thyroid antigens in psoriasis autoimmunity.

Methods:

This study was performed in the College of Medicine, Qassim University, Buraidah, Saudi Arabia between May 2014 and February 2015. The study was designed to explore the role of ROS-induced epitopes in psoriasis autoimmunity. Singlet-oxygen (or ROS)-induced epitopes on protein (ROS-epitopes-albumin) was characterized by in-vitro and in-vivo. Thyroid antigens were prepared from rabbit thyroid, and thyroglobulin was isolated from thyroid extract. Immunocross-reactions of protein-A purified anti-ROS-epitopes-HSA-immunoglobulin G (IgGs) with thyroid antigen, thyroglobulin, and their oxidized forms were determined. Binding characteristics of autoantibodies in chronic plaque psoriasis patients (n=26) against ROS-epitopes-HSA and also with native and oxidized thyroid antigens were screened, and the results were compared with age-matched controls (n=22).

Results:

The anti-ROS-epitopes-HSA-IgGs showed cross-reactions with thyroid antigen, thyroglobulin and with their oxidized forms. High degree of specific binding by psoriasis IgGs to ROS-epitopes-HSA, ROS-thyroid antigen and ROS-thyroglobulin was observed. Immunoglobulin G from normal-human-controls showed negligible binding with all tested antigens. Moreover, sera from psoriasis patients had higher levels of carbonyl contents compared with control sera.

Conclusion:

Structural alterations in albumin, thyroid antigens by ROS, generate unique neo-epitopes that might be one of the factors for the induction of autoantibodies in psoriasis.Psoriasis, a chronic skin disorder is known to be the most prevalent autoimmune disorder in humans.1 It is characterized by hyperplasia of the epidermis, infiltration of leukocytes of dermis and epidermis as well as dilatation and proliferation of blood vessels, which are likely to be triggered by multiple factors such as drugs, physical and psychological stress, bacterial infections, or injury.2 Psoriasis appears in different clinical variants and the most frequently is the plaque psoriasis (also known as psoriasis vulgaris), presents with scaly red plaques on common areas, such as on scalp, the back, dorsal skin of the elbows, and ventral skin of knees.3 Although, the role of immunologic and environmental factors in the pathogenesis of plaques psoriasis has been proposed, but the precise etiology of disease remains poorly understood.1,3 It is well documented that oxidative stress is one of the major factors involved in the pathogenesis of psoriasis4-6 and now it has been well established that excess generation of reactive oxygen species (ROS) by the immune system play a vital role in the development of psoriasis.7 Cellular events such as cell proliferation, apoptosis, cell differentiation, and immune response are influenced by ROS, and these events are altered in psoriasis patients.4-7 Although the exact pathogenesis of psoriasis is unknown, but the occurrence of autoimmune reactions has been assumed,8-10 the presence of autoantibodies and various underlying immunologic abnormalities in the affected sites of these patients have also been reported.8,11-15 The autoimmune etiology has been also proposed on the basis of its association with various autoimmune diseases,8,10 but the precise mechanism of generation of autoantibodies in psoriasis remains unclear.Thyroid disorders have a high prevalence in medical practice; they are associated with a wide range of diseases with which they may or may not share etiological factors. One of the organs which best show this wide range of clinical signs of thyroid dysfunctions is the skin.16-18 Thyroid abnormalities are well documented in psoriasis patients, thyroid gland causes an increase of epidermal growth factor levels, which has an important role in keratinocytes proliferation in psoriasis.19-21 In addition, a high prevalence of thyroid associated autoimmunity has also been reported in patients with psoriasis.20 Moreover, elevated ROS levels are often seen to be associated with thyroid dysfunctions, and now it is proposed that the thyroid hormones influence the ROS steady-state environment in the cell.22-24 The most common idea is the hyperthyroidism, which enhances the ROS production that perturbs the ROS steady-state environment to facilitate the cellular damage or damage to the cellular components as also reported in psoriasis patients.22,25 Therefore, it is assumed that in psoriasis, cells or cellular components are continuously exposed to oxidative stress, so that alterations in conformation and function of these cellular components may occur, which may results in modification of their biological properties. In view of these, this study was aimed to investigate the role of ROS-induced epitopes on albumin and thyroid antigens in psoriasis autoimmunity. To test this, ROS-modified epitopes were generated on albumin and antibodies against ROS-modified-albumin (anti-ROS-modified-epitopes antibodies) were experimentally generated. Cross-reactions of affinity purified anti-ROS-modified-epitopes immunoglobulin Gs (IgGs) with native- and ROS- modified thyroid antigen, thyroglobulin or human DNA were determined. Our data showed that anti-ROS-modified-epitopes-IgGs showed immunospecificity with thyroid antigen, thyroglobulin and with their oxidized forms. Importantly, the antigen(s) binding characteristics of naturally occurring chronic plaque psoriasis antibodies to ROS-modified epitopes, thyroid antigen, ROS-modified thyroid antigen, thyroglobulin, ROS-modified thyroglobulin, human DNA, and ROS-modified human DNA were determined.     

Inhibition of Mitochondrial Permeability Transition Pores by Cyclosporine A Improves Cytochrome c Oxidase Function and Increases Rate of ATP Synthesis in Failing Cardiomyocytes

Background: We previously showed that mitochondrial respiratory function is abnormal in dogs with chronic heart failure (HF). Mitochondrial permeability transition pores (MPTP) can affect mitochondrial inner membrane potential (Δ < eqid1 > _m) and mitochondrial function in normal cardiomyocytes. The potential impact of MPTP on Δ < eqid2 > _m and mitochondrial respiratory function in HF has not yet been determined. We tested the hypothesis that cyclosporine A, a potent blocker of the MPTP, can improve mitochondrial function in HF. Methods: Cardiomyocytes were isolated from the left ventricular myocardium of 7 dogs with HF produced by intracoronary microembolizations and from 7 normal dogs. Cardiomyocytes were treated for 24 hours with cyclosporine A. Δ < eqid3 > _m, cytochrome c oxidase protein expression, mitochondrial cytochrome c oxidase-dependent respiration (CDOR) and ATP synthesis were measured. Results: Δ < eqid4 > _m, protein expression of cytochrome c oxidase, CDOR and the rate of ATP synthesis were decreased in HF compared to normal controls. Inhibition of MPTP in failing cardiomyocytes with low dose of cyclosporine A (0.2 μM) increased Δ < eqid5 > _m, preserved expression of cytochrome c oxidase, improved CDOR and the rate of ATP synthesis. Conclusion: MPTP opening contributes to the loss of mitochondrial function observed in the failing heart. Inhibition of MPTP opening represents a potential therapeutic target for the treatment of HF. This study was supported by a grant from the National Heart, Lung, and Blood Institute PO1 HL074237-01.     

Clinical outcomes of percutaneous interventions in saphenous vein grafts using drug-eluting stents compared to bare-metal stents: a comprehensive meta-analysisof all randomized clinical trials

Background:

Clinical outcomes of percutaneous coronary intervention (PCI) in patients with saphenous vein grafts (SVGs) remain poor despite the use of drug‐eluting stents (DES). There is a disparity in clinical outcomes in SVG PCI based on various registries, and randomized clinical data remain scant. We conducted a meta‐analysis of all existing randomized controlled trials (RCTS) comparing bare‐metal stents (BMS) and DES in SVGPCIs.

Hypothesis:

PCI in patients with SVG disease using DES may reduce need for repeat revascularization without an excess mortality when compared to BMS.

Methods:

An aggregate data meta‐analysis of clinical outcomes in RCTs comparing PCI with DES vs BMS for SVGs reporting at least 12 months of follow‐up was performed. A literature search between Janurary 1, 2003 and September 30, 2011 identified 4 RCTs (812 patients; DES = 416, BMS = 396). Summary odds ratio (OR) and 95% confidence interval (CI) were calculated using the random‐effects model. The primary endpoint was all‐cause mortality. Secondary outcomes included nonfatal myocardial infarction (MI), repeat revascularization, and major adverse cardiac events (MACE). These outcomes were assessed in a cumulative fashion at 30 days, 18 months, and 36 months.

Results:

There were no intergroup differences in baseline clinical and sociodemographic characteristics. At a median follow‐up of 25 months, patients in the DES and BMS group had similar rates of death (OR: 1.63, 95% CI: 0.45–5.92), MI (OR; 0.83, 95% CI: 0.27‐2.60), and MACE (OR: 0.58, 95% CI: 0.25–1.32). Patients treated with DES had lower rates of repeat revascularization (OR: 0.40, 95% CI: 0.22–0.75).

Conclusions:

In this comprehensive meta‐analysis of all RCTs comparing clinical outcomes of PCI using DES vs BMS in patients with SVG disease, use of DES was associated with a reduction in rate of repeat revascularization and no difference in rates of all‐cause death and MI. Clin. Cardiol. 2012 DOI: 10.1002/clc.21984 Dr. Virani is supported by a Department of Veterans Affairs Health Services Research and Development Service (HSR&D) Career Development Award (CDA‐09‐028), and has research support from Merck and National Football League Charities (all grants to the institution and not individual). The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. The authors have no other funding, financial relationships, or conflicts of interest to disclose.     

Outcomes of preoperative Angiotensin-converting enzyme inhibitor therapy in patients undergoing isolated coronary artery bypass grafting

The association between preoperative use of angiotensin-converting enzyme (ACE) inhibitors and outcomes after coronary artery bypass grafting (CABG) remain controversial. Our aim was to study in-hospital outcomes after isolated CABG in patients on preoperative ACE inhibitors. A retrospective analysis of 8,889 patients who underwent isolated CABG from 2000 through 2011 was conducted. The primary outcome of interest was the incidence of major adverse events (MAEs) defined as a composite of mortality, postoperative renal dysfunction, myocardial infarction, stroke, and atrial fibrillation during index hospitalization. The secondary outcome was the incidence of individual outcomes included in MAEs. Logistic regression analyses were performed. Of 8,889 patients, 3,983 (45%) were on preoperative ACE inhibitors and 4,906 (55%) were not. Overall incidence of MAEs was 38.1% (n = 1,518) in the ACE inhibitor group compared to 33.6% (n = 1,649) in the no-ACE inhibitor group. Preoperative use of ACE inhibitors was independently associated with MAEs (odds ratio 1.13, 95% confidence interval 1.03 to 1.24), most of which was driven by a statistically significant increase in postoperative renal dysfunction (odds ratio 1.18, 95% confidence interval 1.03 to 1.36) and atrial fibrillation (odds ratio 1.15, 95% confidence interval 1.05 to 1.27). In-hospital mortality, postoperative myocardial infarction, and stroke were not significantly associated with preoperative ACE inhibitor use. Analyses performed after excluding patients with low ejection fractions yielded similar results. In conclusion, preoperative ACE inhibitor use was associated with an increased risk of MAEs after CABG, in particular postoperative renal dysfunction and atrial fibrillation.     

Ghrelin inhibits insulin release by regulating the expression of inwardly rectifying potassium channel 6.2 in islets

IntroductionThe objective is to investigate the influence of ghrelin administration on both the insulin secretion and the expression of ATP-sensitive K⁺ channels in islet.MethodsGhrelin and [D-Lys³] growth hormone releasing peptide-6 were administered via intraperitoneal injection in Wistar rats at the doses 10 and 10 μmol/kg/d for 2 weeks, respectively. Then glucose tolerance tests were performed and plasma insulin concentrations were measured. Islets were isolated for insulin release experiments. Single β cells were isolated for electrophysiological experiments. Determination of the Kir6.2 and SUR1 mRNA and protein expression levels in islets was performed by polymerase chain reaction and western blotting.ResultsIntraperitoneal administration of exogenous ghrelin significantly (P < 0.05) increased blood glucose concentrations, attenuated insulin responses during glucose tolerance tests, reduced insulin release from the isolated islets induced by 11.1 and 16.7 mmol/L glucose, hyperpolarized the resting membrane potential and increased the Kir6.2 mRNA and protein expression levels. In contrast, counteraction of ghrelin by intraperitoneal injection of [D-Lys³] growth hormone releasing peptide-6 significantly (P < 0.05) attenuated the aforementioned changes. SUR1 expression levels were not altered in this study.ConclusionsGhrelin via pancreatic growth hormone secretagogue receptor up-regulates the Kir6.2 expression in islet by hyperpolarizing the resting membrane potential which results in the inhibition of insulin release.     

Detection of Chikungunya virus in Aedes aegypti during 2011 outbreak in Al Hodayda, Yemen

In October 2010, the Ministry of Public Health and Population reported an outbreak of dengue-like acute febrile illness in Al Hodayda governorate. By January 2011, a total of 1542 cases had been recorded from 19 of the 26 districts in the governorate with 104 purportedly associated deaths. In response this event, in January 2011 entomological investigations aimed at identifying the primary vector and the epidemic associated etiological agent were carried out. Based on the reported cases and the progress of the outbreak in the governorate, mosquito collection was undertaken in two of the most recent outbreak areas; Al Khokha district (130 km south of Al Hodayda) and Al Muneera district (100 km north). Mosquito adults were collected from houses using BG-sentinel? traps, aspiration of resting mosquitoes and knock-down spraying. Indoor and outdoor containers adjacent to the houses were inspected for larvae. Subsequently mosquito pools were analyzed by RT-PCR for detection of the four dengue virus serotypes (DENV-1, DENV-2, DENV-3, DENV-4), and for Chikungunya virus (CHIKV). Aedes aegypti was the dominant mosquito species collected. Four pools represent 40% of the tested pools, all containing adult female Ae. aegypti, were positive for CHIKV. Three CHIKV isolates were obtained from the RNA positive mosquito pools and identified by rRT-PCR. This finding marks the first record of CHIKV isolated from Ae. aegypti in Yemen. The larval container and Breteau indices in the visited localities surveyed were estimated at 53.8 and 100, respectively. The emergence of this unprecedented CHIKV epidemic in Al Hodayda is adding up another arboviral burden to the already existing vector-borne diseases. Considering the governorate as one focal port in the Red Sea region, the spread of the disease to other areas in Yemen and in neighboring countries is anticipated. Public health education and simple measures to detect and prevent mosquito breeding in water storage containers could prevent and reduce the spread of mosquito-borne viruses like CHIKV and DENV in Yemen.