Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is associated with inflammation and disease severity in pemphigus.

Background:Considering the critical role of early diagnosis and management of acute ischemic stroke, biomarkers that can reliable assist in the diagnosis are still needed. These biomarkers should rapidly analyze, have high specificity for brain damage, and be available in the emergency settings for early diagnosis and exclusion of other conditions that mimic acute ischemic stroke. Soluble tumor necrosis factor-like weak inducer of apoptosis, a protein involved in the regulation of several biological functions, could be a potential acute ischemic stroke biomarker.Aims:To investigate the diagnostic value of soluble tumor necrosis factor-like weak inducer of apoptosis in patients with acute ischemic stroke and examine the relationship between ischemic area volume determined at diffusion-weighted magnetic resonance imaging and soluble tumor necrosis factor-like weak inducer of apoptosis.Study Design:A prospective, case-control study.Methods:This case-control prospective study included 36 patients with acute ischemic stroke and 36 healthy volunteers. Information on age, sex, presence of chronic disease, neurological examination findings, times of presentation to the emergency department after acute ischemic stroke, soluble tumor necrosis factor-like weak inducer of apoptosis levels, ischemic area volumes at diffusion-weighted magnetic resonance imaging, and 6-month mortality rates after stroke were recorded. The results were analyzed on SPSS 22.0 software (SPSS Inc., Chicago, IL, USA), and p<0.05 was considered statistically significant.Results:A soluble tumor necrosis factor-like weak inducer of apoptosis cut-off value of 995.5 pg/mL exhibited a sensitivity of 80.5% and a positive predictive value of 82.5% with an area under the curve of 0.84 (95% confidence interval: 0.74-0.94; p<0.001). The mean soluble tumor necrosis factor-like weak inducer of apoptosis levels in the acute ischemic stroke group (1968.08±1441.99 μg/L) were significantly higher than those in the control group (704.81±291.72 μg/L) (p<0.001). No correlation was observed between soluble tumor necrosis factor-like weak inducer of apoptosis levels and ischemic area volume measured at diffusion-weighted magnetic resonance imaging (r=-0.008; p=0.07). The mean ischemic area volume was 505.68±381.10 and 60.96±80.89 mm3 in the nonsurviving and surviving patients, respectively (p=0.002).Conclusion:Soluble tumor necrosis factor-like weak inducer of apoptosis can be used in the diagnosis of acute ischemic stroke. However, it is inconclusive in estimating ischemic area volume and early mortality following acute ischemic stroke. Ischemic area volume measured at diffusion-weighted magnetic resonance imaging is a marker of poor prognosis and can be used in predicting early mortality.

In this study, we aimed to examine the relationship between the serum cytokine levels of patients with pemphigus vulgaris (PV) and the Pemphigus Disease Area Index (PDAI), along with the presence of anti-desmoglein (Dsg) 1 antibody, anti-Dsg3 antibody and co-infection among patients with pemphigus vulgaris. This retrospective study included 62 PV patients and 59 healthy individuals who attended the Second Affiliated Hospital of Kunming Medical University from November 2014 to November 2022. The serum concentrations of cytokines and chemokines were assessed using the Luminex 200 System (a high-throughput cytokine detection method). Additionally, anti-Dsg1 and anti-Dsg3 antibodies were determined through enzyme-linked immunosorbent assay, while disease severity was evaluated using the PDAI scoring system. The PV group exhibited elevated levels of Th1 cytokines (such as interleukin (IL)-1RA, IL-1β, IL-2, IL-12p70, GM-CSF, TNF-α, IL-18, IFN-γ), Th2 cytokines (IL-5, IL-10, IL-13) and Th17/Th22-related cytokines (IL-17A, IL-22) compared to the healthy control group (p < 0.05). Conversely, the levels of chemokines (macrophage inflammatory protein-1 alpha (MIP-1α), stromal cell-derived factor-1 alpha (SDF-1α), interferon-inducible protein-10 (IP-10), Regulated on Activation in Normal T-Cell Expressed And Secreted (RANTES), growth-regulated on-gene-alpha (GRO-α), MIP-1β) and Th2 (IL-31) were lower in the PV group compared to the healthy control group (p < 0.05). No significant differences were observed in other cytokines and chemokines (p > 0.05). Additionally, IL-7, IFN-γ, IL-18 and GRO-α showed positive correlations with PDAI, IL-6 correlated positively with anti-Dsg3 antibody levels, and IL-12p70, IL-18, and IFN-γ correlated positively with anti-Dsg1 antibody levels. Furthermore, IL-15 exhibited a positive association with skin infections. PV patients have elevated levels of various cytokines and chemokines, and there are different degrees of elevation in cytokines and chemokines associated with the activation of various T cell subsets. PDAI and the Dsg1 antibody levels are mainly related to the Th1-related cytokines.

The aim of this study is to assess the utility of anti-desmoglein (Dsg) antibodies levels, hematological biomarkers levels, the albumin to globulin (A/G) ratio, blood lipids levels, and lymphocyte subpopulation percentages as objective laboratory indicators of disease severity of pemphigus vulgaris (PV). A retrospective study of 187 PV patients with 256 medical records between January 2013 and December 2020. PV patients were divided into three groups by disease severity according to the pemphigus disease area index (PDAI) score: mild (0-8), moderate (9-24), and severe (≥ 25). The levels of anti-Dsg antibodies, hematological biomarkers, A/G ratio, blood lipids, and the percentage of lymphocyte subpopulations were measured. We assessed the correlations of quantitative variables by Pearson correlation (r). Multivariable linear regression was used to identify the variables associated with the disease severity of PV (PDAI score). The results show that the levels of Dsg1 (r = 0.294, P < 0.001) and Dsg3 (r = 0.206, P = 0.011), monocyte count (r = 0.210, P = 0.001), neutrophil-to-lymphocyte ratio (NLR) (r = 0.123, P = 0.049), and platelet-to-lymphocyte ratio (PLR) (r = 0.170, P = 0.006) were positively correlated with the PDAI score. However, the A/G ratio (r = -0.399, P < 0.001), and the levels of total serum cholesterol (r = -0.140, P = 0.026) and HDL (r = -0.143, P = 0.023) were negatively correlated with the PDAI score. Multiple linear regression showed that the factors associated with the PDAI score were higher level of anti-Dsg1 antibody (P = 0.001), a higher NLR (P = 0.005), and a lower A/G ratio (P < 0.001). The linear regression equation was Y(PDAI) = 32.798 + 0.058X(Dsg1) + 0.846 X(NLR)-16.472 X(A/G) (R2 = 0.586). Therefore, high levels of anti-Dsg1 antibody and NLR combined with a low A/G ratio could explain the PDAI score. These findings might provide a more comprehensive and objective evaluation system for reflecting the disease severity of PV based on laboratory indicators.

BackgroundCerebral cortical neurons have a high vulnerability to the harmful effects of hypoxia. However, the brain has the ability to detect and accommodate to hypoxic conditions. This phenomenon, known as preconditioning, is a natural adaptive process highly preserved among species whereby exposure to sub-lethal hypoxia promotes the acquisition of tolerance to a subsequent lethal hypoxic injury. The cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are found in neurons and their expression is induced by exposure to sub-lethal hypoxia. Accordingly, in this work we tested the hypothesis that the interaction between TWEAK and Fn14 induces tolerance to lethal hypoxic and ischemic conditions.MethodsHere we used in vitro and in vivo models of hypoxic and ischemic preconditioning, an animal model of transient middle cerebral artery occlusion and mice and neurons genetically deficient in TWEAK, Fn14, or tumor necrosis factor alpha (TNF-α) to investigate whether treatment with recombinant TWEAK or an increase in the expression of endogenous TWEAK renders neurons tolerant to lethal hypoxia. We used enzyme-linked immunosorbent assay to study the effect of TWEAK on the expression of neuronal TNF-α, Western blot analysis to investigate whether the effect of TWEAK was mediated by activation of mitogen-activated protein kinases and immunohistochemical techniques and quantitative real-time polymerase chain reaction analysis to study the effect of TWEAK on apoptotic cell death.ResultsWe found that either treatment with recombinant TWEAK or an increase in the expression of TWEAK and Fn14 induce hypoxic and ischemic tolerance in vivo and in vitro. This protective effect is mediated by neuronal TNF-α and activation of the extracellular signal-regulated kinases 1 and 2 pathway via phosphorylation and inactivation of the B-cell lymphoma 2-associated death promoter protein.ConclusionsOur work indicate that the interaction between TWEAK and Fn14 triggers the activation of a cell signaling pathway that results in the induction of tolerance to lethal hypoxia and ischemia. These data indicate that TWEAK may be a potential therapeutic strategy to protect the brain from the devastating effects of an ischemic injury.

Atherosclerosis is a very complex pathology. Over the past two decades we have come to appreciate that a major component of this pathological process is chronic inflammation. This inflammatory state is not only characterized by infiltration of lipid laden macrophages, the hallmark cell of this disease, into the vascular wall, but also is characterized by the infiltration of a host of other inflammatory cells. The complex interaction of inflammatory cells with the normal residents of the vascular wall (ie, endothelial and smooth muscle cells) directs the progression of the disease. Inflammatory cells secrete a variety of chemokines and cytokines which have a profound effect on the development and progression of the plaque. Moreover, many of these cytokines can mediate both pro- and antiatherogenic processes depending on the cellular milieu. The tumor necrosis factor (TNF) and TNF receptor (TNFR) superfamilies encompass numerous cytokines and receptors suggested to play a pivotal role in atherogenesis. Although many members of these families such as TNF-α and CD40 ligand and their putative receptors are considered to be proatherogenic,1–4 studies have also demonstrated an antiatherogenic role for others, including the p55 TNFR.5 TNF-like weak inducer of apoptosis (TWEAK) and its putative receptor, fibroblast growth factor-inducible 14 (Fn14), are also members of the TNF and TNFR superfamilies, respectively. Both TWEAK and Fn14 have been detected in human atherosclerotic plaques, suggesting that these molecules may also play a role in the atherogenic process. Clinical …

Host-derived enzymes, cytokines and other proinflammatory mediators play an integral role in periodontal destruction. The levels of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor, fibroblast growth factor-inducible 14 protein (Fn14), are elevated in tissues from a number of chronic inflammatory diseases. The aim of the present study was to investigate the expression of TWEAK and Fn14 at the protein and mRNA levels in gingival biopsies from periodontitis patients and from clinically healthy patients. Gingival biopsies were obtained from healthy sites (n = 7) and from sites affected by periodontitis (n = 27). The expression of TWEAK and Fn14 was investigated by immunohistochemistry in formalin-fixed, paraffin-embedded tissues. The levels of mRNA for TWEAK and Fn14 were also investigated by RT-PCR. The expression of TWEAK and Fn14 proteins was significantly higher in periodontitis tissue than in healthy tissue. In periodontitis tissues, TWEAK and Fn14 proteins were mainly expressed by mononuclear leukocytes (morphologically resembling lymphocytes and plasma cells), by cells lining blood vessels, by spindle-shaped cells resembling fibroblasts and by multinucleated cells. The Fn14 mRNA level in periodontitis tissue was significantly higher than that in healthy tissue. A moderate correlation between TWEAK/Fn14 expression and inflammation and bone loss, but not pocket depth, was noted. This study demonstrates higher expression of TWEAK protein and of Fn14 mRNA and protein in periodontitis tissues than in clinically healthy controls. Our data support the concept that TWEAK/Fn14 signaling is an additional player in the pathogenesis of periodontitis and adds to the increasing number of cytokine networks involved in periodontal inflammation.

No previous study has examined the association of an acid-base imbalanced diet to autoimmune bullous disease. The present study aimed to investigate the association between dietary acid load (DAL) as either potential renal acid load (PRAL) and net endogenous acid production (NEAP) intake on the odds of high-severity Pemphigus Vulgaris (PV) disease in adult Iranian patients to fill this gap. A cross-sectional study was conducted on 138 patients, aged 18–65 years with confirmed diagnoses of PV in a referral university center for autoimmune bullous diseases. The dietary intakes of all patients during the last year before enrollment in the study were assessed using a 168-item semi-quantitative food frequency questionnaire. Dietary acid load was calculated based on the PRAL and NEAP scores. To assess PV severity, the pemphigus disease area index (PDAI) score was used. Logistic regression was used to evaluate the association between DAL and PDAI. A positive association was observed between PRAL and PDAI score in the crude (adjusted R2 = 0.088, B = 6.88, P < 0.0001) and all other adjusted models, as well as the crude model for NEAP (adjusted R2 = 0.037, B = 4.72, P = 0.013). In terms of adherence to NEAP and PRAL, those in the top tertile of PRAL and NEAP had a higher vulnerability for severe PV in unadjusted (OR = 5.18, 95% (CI) 2.19–12.25) and (OR = 2.48, 95% (CI) 1.08–5.68) respectively. In the present study, we found a significant direct association between DAL and severity of disease in PV patients. Further studies are required to confirm these findings.

Fn14-TRAIL, a Chimeric Intercellular Signal Exchanger, Attenuates Experimental Autoimmune Encephalomyelitis

Chronic inflammation develops in the retinal microvasculature under sustained hyperglycemia and is implicated in the pathogenesis of diabetic retinopathy. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 have been reported to promote pro-inflammatory cytokines, which are involved in the pathogenesis of proliferative diabetic retinopathy (PDR). It is therefore possible that the TWEAK/Fn14 pathway can play a regulatory role in PDR. In the present study, we examined the expression of TWEAK and Fn14 in vitreous fluid from PDR patients. To confirm the correlation between the TWEAK expression and clinical pathological characteristics of PDR, we investigated the regulatory role of the TWEAK/Fn14 pathway in cell proliferation and collagen synthesis in retinal ARPE-19 cells. The results demonstrated that vitreous fluid from patients with PDR had higher levels of TWEAK and Fn14 than that from T2DM patients without PDR, thus suggesting an important regulatory role of TWEAK/Fn14 signaling in the pathogenesis of PDR. Furthermore, overexpression of TWEAK in ARPE-19 cells also promoted proliferation of and collagen synthesis in these retinal cells. It is possible that TWEAK/Fn14 upregulation in PDR may contribute to PDR progression by promoting the proliferation or fibrosis of retinal cells.

The Importance of Patient-Focused Drug Development in Pemphigus and Pemphigoid

Pemphigus is a group of immune-mediated blistering diseases of skin and mucus membrane caused by destruction of the intercellular junction (desmosomes) by autoantibodies. Pemphigus vulgaris (PV) is considered the most common type of all pemphigus family. Various cytokines play a major role in pemphigus pathogenesis. Interleukin-33 (IL-33) role has been studied in various autoimmune diseases as; psoriasis and rheumatoid arthritis, yet it has not been studied in Egyptian patients with PV. The study aimed to evaluate the possible role of IL-33 in PV by assessing its level in the serum using ELISA and to detect its correlation with activity score using Pemphigus Disease Area Index (PDAI). Forty-four patients with PV and 36 age and sex-matched healthy controls were enrolled in the study. After full history taking and complete dermatological examination, the severity score was calculated using PDAI, then serum samples were taken from each patient and control subjects and subjected to quantitative measurement of serum IL-33 using ELISA. Serum level of IL-33 is significantly raised in PV patients compared to control subjects (P-value = .007). The level of IL-33 was found to be strongly correlated with the activity of the disease measured by PDAI. IL-33 might have a role in PV pathogenesis as shown by its rising level in PV patients. In addition, serum level of IL-33 is strongly correlated with the activity of PV. Thus, we suspect that IL-33 can be used as marker for monitoring PV severity and measuring treatment efficacy.

A higher correlation of the antibody activities against the calcium-dependent epitopes of desmoglein 3 quantified by ethylenediaminetetraacetic acid-treated enzyme-linked immunosorbent assay with clinical disease activities of pemphigus vulgaris

Kidney disease is a significant public health problem that is increasing worldwide. Tumour necrosis factor superfamily molecules have recently been shown to be actively involved in renal pathophysiology. According to current reports, one of these molecules has significant clinical implications: TWEAK, a tumour necrosis factor-like weak inducer of apoptosis. TWEAK is a cytokine with important functions. By binding to induced fibroblast growth factor 14 (Fn14), its only receptor, TWEAK activates various biological processes, including cell growth, migration or death, angiogenesis and production of proinflammatory cytokines. TWEAK and Fn14 expression is relatively low in healthy tissues. Experimental studies have confirmed the important role of TWEAK/Fn14 pathway activation in physiological tissue repair and regeneration, while its excessive activation leads to acute and/or chronic damage. TWEAK production takes place in various inflammatory diseases of the kidneys with the participation of immune cells. In the case of inflammatory diseases characterised by increased chemokine production, TWEAK presents with apoptotic effects. In non-immune diseases, TWEAK stimulates renal tubular proliferation. The dualism of the TWEAK effect is multifactorial. TWEAK was proliferative in healthy kidneys and in a compensatory overgrowth model after nephrectomy in which inflammatory cytokine expression was low. Data obtained from experimental and clinical studies are useful for developing future diagnostic and therapeutic strategies focused on the role of TWEAK in kidney damage.

Effect of opioid receptor antagonist on mitigating tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-induced apoptolysis in pemphigus pathogenesis

Forty-two patients with systemic lupus erythematosus (SLE), including 26 patients with renal damage and 16 without, and 20 healthy controls were included in the study. The isolated peripheral blood mononuclear cells (PBMCs) were treated with a p38 inhibitor (SB203580) or anti-tumor necrosis factor-like weak inducer of apoptosis (TWEAK) mAb, with or without phytohemagglutinin/phorbol myristate acetate (PHA/PMA) stimulation. Western blot experiments were used to evaluate the protein expression of TWEAK and p38 MAPK in PBMCs .Next, the contents of interleukin-10 (IL-10) and monocyte chemoattractant protein-1 (MCP-1) in the supernatant were measured by ELISA. The results showed that expression of TWEAK protein in PBMCs from lupus nephritis patients was significantly higher than that from SLE patients without renal damage and healthy controls. PHA/PMA simulation could upregulate the productions of TWEAK and p-p38MAPK in PBMCs from patients with SLE. Anti-TWEAK mAb treatment downregulated both TWEAK and p-p38 MAPK expression in PBMCs, as well as IL-10 and MCP-1 in the supernatant; SB203580 had the same effect on cytokine production in PBMC, but had no effect on the expression of TWEAK. Our results suggested that TWEAK-p38 MAPK-IL-10, MCP-1 signaling pathway in PBMC played an important pathogenic role in lupus nephritis.