Cytokines Modulate the “Immune-Metabolism” Interactions during Behçet Disease: Effect on Arginine Metabolism

Aim and Methods. In this study, we evaluated NOS and arginase activities and their regulation during Behçet disease, a systemic chronic inflammatory disorder with uncertain etiology. The peripheral blood mononuclear cells of 36 patients and 15 control samples (PBMC) were cultured in either RPMI 1640, MEM, or DMEM complemented with 10% of FBS and antibiotics. Cultures were performed with or without the control or patients plasma. Subsequent treatment contained anticytokines (IL-6, TGF-β), a mitogenic effector (PHA), or NOS modulators (L-NMMA, BH4). Culture supernatants were harvested after 24 h of incubation. NO and urea measurements were, respectively, performed by modified Griess and Berthelot methods.Results. Higher urea levels were found in patients’ plasma compared to the control’s (P< 0.05). NOS modulators induced inverted production profiles for NO and urea (P< 0.05). Their results differed depending on the clinical findings (P< 0.05). It was also found that cytokine neutralization induced different response profiles in patients as opposed to control cultures (P< 0.05).Conclusion. Our results suggest that arginases can compete with NOS2 for L-arginine during Behçet disease. Both enzymes are regulated by environmental cytokines and substrate availability. Furthermore, it seems that NOS/arginase balance is dependent on clinical expression.

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THU0590 WHEN RARE IS EVEN RARER: A COMPLEX CASE OF BEHCET DISEASE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5663 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 537.3-537

Author(s):

M. DI Cicco ◽

O. M. Epis ◽

C. Casu ◽

A. Adinolfi ◽

L. Alvaro ◽

...

Keyword(s):

Pulmonary Artery ◽

Vascular Complications ◽

Artery Aneurysm ◽

Skin Lesions ◽

Complex Case ◽

Behçet Disease ◽

Inflammatory Disorder ◽

X Rays ◽

Behcet Disease ◽

Intracardiac Thrombosis

Background:Behcet disease is a rare inflammatory disorder with the unique ability to affect vessels of any size. The disease could be associated to thrombosis in both the venous and arterial compartment, and often aneurysms. In particular, the presence of aneurysms of the pulmonary artery is rarely, if ever, seen in conditions other than Behcet. Cardiac involvement, albeit uncommon, is also described and associated to a severe prognosis. The treatment is based on immunosuppressants, meanwhile the use of anticoagulants -especially when aneurysms are present- is debated.Objectives:To describe a complex case of Behcet disease.Methods:We report the case of a 45 years old man of Chinese origin who presented to A&E with fever and acute dyspnea. Blood test revealed raised ESR and CRP and raised neutrophil count. Chest X rays showed bilateral opacities suggesting pneumonia. The patient did not improve over the course of antibiotics. Later on, he presented with an episode of hemoptysis and worsening dyspnea, so he was admitted to the Intensive Care Unit. CT showed bilateral pulmonary thromboembolism and aneurysm of the pulmonary artery. Echocardiogram and cardio-MRI revealed a large, mobile thrombus within the right atrium. Extensive work-up for infections and cancer was unrevealing. ANA, ENA and ANCA antibodies were negative. On the basis of a past medical history of recurrent oral ulcers and papulopustular skin lesions that patient admitted on questioning, a diagnosis of Behcet disease was suspected. In keeping with that, HLA-B51 turned out positive. The patient was promptly started on IV steroid pulses followed by Cyclophosphamide 1 gr IV monthly for six months, then on IV anti-TNF alpha Infliximab. He was also commenced on low molecular weight heparin (LMWH) and subsequently direct factor Xa inhibitor Apixaban.Results:The patient improved significantly with progressive regression of the pulmonary CT changes. He was discharged and able to get back to his daily life activities. After 2 years and a half of treatment, the aneurysm was stable and the intracardiac thrombus completely cleared.Conclusion:This case is of particular interest because of the concomitant presence of two rare vascular complications of Behcet disease-intracardiac thrombosis (<1-2%, less than 100 cases described worldwide) and pulmonary artery aneurysm (1-2%). Prompt introduction of immunosuppressant therapy was associated with a favorable outcome with no recurrence. We could speculate that, to some extent, the concomitant use of anticoagulants may have contributed to the complete resolution of the intracardiac thrombosis.Disclosure of Interests :MARIA DI CICCO: None declared, oscar massimiliano epis Consultant of: yes, Speakers bureau: yes, Cinzia Casu: None declared, Antonella Adinolfi: None declared, Luisa Alvaro: None declared, Valeria Campanella: None declared, Michel Chevallard: None declared, Marina Muscarà: None declared, Mariaeva Romano: None declared, Emanuela Schito: None declared, Nicola Ughi: None declared, Elisa Verduci: None declared, Davide Antonio Filippini: None declared

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In Vitro Effects of Olive Vegetation Water on IFN-γ and IL-10 Secretion in Multiple Sclerosis Patients

Trends in Medical Sciences ◽

10.5812/tms.113795 ◽

2021 ◽

Vol 1 (1) ◽

Author(s):

Mahboubeh Baheri ◽

Mohammadreza Dayer ◽

Narges Baharifar ◽

Abdolkarim Sheikhi ◽

Abolfazl Sheikh

Keyword(s):

Multiple Sclerosis ◽

Mononuclear Cells ◽

Inhibitory Effect ◽

Inflammatory Disorder ◽

Peripheral Blood Mononuclear ◽

Inflammatory Reactions ◽

Ifn Γ ◽

Vegetation Water ◽

Multiple Sclerosis Patients

Background: Multiple Sclerosis (MS) is an autoimmune and inflammatory disorder of the central nervous system (CNS), which is associated with the imbalance of pro- and anti-inflammatory cytokines. Evidence indicates that nutritional interventions have some immunomodulatory impacts. Objectives: In this study, we investigated the effect of olive vegetation water (OVW) on IFN-γ and IL-10 secretion by peripheral blood mononuclear cells (PBMCs) of MS patients. Methods: In this study, PBMCs of MS patients were separated by Ficoll-Hypaque centrifugation. The cytotoxicity of OVW was assessed by the MTT assay. The treatments were performed for 48 and 72 hours, and IFN-γ and IL-10 were measured by ELISA. Results: No cytotoxicity was observed for OVW. Besides, OVW showed a significant inhibitory effect on IFN-γ secretion but augmenting effect on IL-10 secretion by PBMCs dose-dependently. Conclusions: This study indicated that OVW could have immunoregulatory effects on inflammatory reactions in MS patients.

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Vascular Remodeling in Moyamoya Angiopathy: From Peripheral Blood Mononuclear Cells to Endothelial Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21165763 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5763

Author(s):

Francesca Tinelli ◽

Sara Nava ◽

Francesco Arioli ◽

Gloria Bedini ◽

Emma Scelzo ◽

...

Keyword(s):

Vascular Remodeling ◽

Mononuclear Cells ◽

Functional Characterization ◽

Endothelial Progenitor ◽

Peripheral Blood Mononuclear ◽

Moyamoya Angiopathy ◽

Circulating Endothelial Progenitor Cells ◽

Potential Marker ◽

Healthy Donors ◽

Disease Effect

The pathophysiological mechanisms of Moyamoya angiopathy (MA), which is a rare cerebrovascular condition characterized by recurrent ischemic/hemorrhagic strokes, are still largely unknown. An imbalance of vasculogenic/angiogenic mechanisms has been proposed as one possible disease aspect. Circulating endothelial progenitor cells (cEPCs) have been hypothesized to contribute to vascular remodeling of MA, but it remains unclear whether they might be considered a disease effect or have a role in disease pathogenesis. The aim of the present study was to provide a morphological, phenotypical, and functional characterization of the cEPCs from MA patients to uncover their role in the disease pathophysiology. cEPCs were identified from whole blood as CD45dimCD34+CD133+ mononuclear cells. Morphological, biochemical, and functional assays were performed to characterize cEPCs. A significant reduced level of cEPCs was found in blood samples collected from a homogeneous group of adult (mean age 46.86 ± 11.7; 86.36% females), Caucasian, non-operated MA patients with respect to healthy donors (HD; p = 0.032). Since no difference in cEPC characteristics and functionality was observed between MA patients and HD, a defective recruitment mechanism could be involved in the disease pathophysiology. Collectively, our results suggest that cEPC level more than endothelial progenitor cell (EPC) functionality seems to be a potential marker of MA. The validation of our results on a larger population and the correlation with clinical data as well as the use of more complex cellular model could help our understanding of EPC role in MA pathophysiology.

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Differential effects of colchicine in blood mononuclear cells of patients with Behçet disease in relation to colchicine responsiveness

British Journal of Dermatology ◽

10.1111/j.1365-2133.2012.11067.x ◽

2012 ◽

Vol 167 (4) ◽

pp. 914-921 ◽

Cited By ~ 1

Author(s):

M.Y. Woo ◽

O. Cho ◽

M.J. Lee ◽

K. Kim ◽

E.S. Lee ◽

...

Keyword(s):

Mononuclear Cells ◽

Behçet Disease ◽

Behcet Disease ◽

Differential Effects ◽

Blood Mononuclear Cells

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mRNA Expression Profile of SFKs and Involvement of SFKs in the Regulation of LPS-Induced Erk1/2 Signaling in PBMCs of Active BD Patients

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530319666190119101756 ◽

2019 ◽

Vol 19 (6) ◽

pp. 809-817

Author(s):

Sevgi Irtegun-Kandemir ◽

Irmak Icen-Taskin ◽

Mehtap Bozkurt ◽

Sevgi Kalkanli-Tas

Keyword(s):

Mrna Expression ◽

Mononuclear Cells ◽

Gradient Centrifugation ◽

Mrna Level ◽

Inflammatory Disorder ◽

Protein Activity ◽

Total Blood ◽

Peripheral Blood Mononuclear ◽

Expression Levels ◽

Mrna Expression Levels

Background: Behcet’s Disease (BD) is a multisystemic inflammatory disorder affecting large vessels, lungs joints, gastrointestinal and neurological systems. The pathogenesis of BD remains poorly understood. Identifying the key signaling pathway is crucial for a complete understanding of the pathogenesis of BD. Objective: The aim of this study was to determine mRNA expression level of Src family kinases (SFKs) members and their involvement in lipopolysaccharide (LPS)-induced mitogen-activated protein kinases (MAPKs) regulation in peripheral blood mononuclear cells (PBMCs) of active BD patients. Methods: Twenty- five active BD patients and twenty-five healthy controls were included in the study. PBMCs were isolated from total blood by density gradient centrifugation. The mRNA expression levels of SFKs members were measured by real-time quantitative PCR (RT-qPCR). The effect of SFKs activity on LPS-induced activation MAPKs (Erk1/2, p38 and JNK) was examined by Western blot. Results: The mRNA expression levels of Hck, Src, Lyn, Yes and Fyn were found to be slightly decreased in active BD patients compared to the control subjects, but a slight change in mRNA level of SFKs members did not impact on protein levels and protein activity. LPS-induced Erk1/2 phosphorylation was significantly increased in the absence of SFKs activity in active BD patients. However, inhibition of SFKs activity had no effect on LPS-induced phosphorylation of p38 and JNK in both controls and active BD patients. Conclusion: SFKs downregulate LPS-induced Erk1/2 phosphorylation in PBMCs of active BD patients.

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A252 FUNCTIONAL ANALYSIS OF GENETIC AETIOLOGIES IN A DOWNSTREAM OF TYROSINE KINASE (DOK) PROTEIN IN THE PATHOGENESIS OF PEDIATRIC INFLAMMATORY BOWEL DISEASE (IBD)

Journal of the Canadian Association of Gastroenterology ◽

10.1093/jcag/gwz047.251 ◽

2020 ◽

Vol 3 (Supplement_1) ◽

pp. 129-130

Author(s):

V Batura ◽

C Guo ◽

N Warner ◽

G Leung ◽

A Ricciuto ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Mononuclear Cells ◽

Cell Function ◽

Immune Cell ◽

Imaging Techniques ◽

Inflammatory Disorder ◽

Zebrafish Model ◽

Peripheral Blood Mononuclear

Abstract Background IBD is a form of chronic inflammatory disorder of the gastrointestinal tract that arises due to genetic, environmental, immunological and microbial factors. The precise pathological mechanisms remain elusive. It is thought that the onset of pediatric IBD can largely be attributed to genetics. Muise lab, at SickKids, regularly screens children at the SickKids IBD clinic and through an international consortium to find possible genetic links to the disease. We report a patient at SickKids with biallelic mutations in DOK4 who has severe Crohn’s Disease along with other inflammatory conditions. Downstream of kinase (DOK) proteins are a family of adaptor molecules that serve as scaffolding proteins important in regulating cell signaling, especially in T cells. DOK4 has been shown to have negative regulatory effects on T cell activation but is also expressed across various other tissues where its function is yet to be determined. We predict that these mutations are causing immune cell dysregulation, which may be contributing to the patients IBD. Aims Through this study, we aim to enhance our understanding of the pathobiological mechanism of novel mutations in DOK4. Methods We have established T cell lines, expressing wild type and mutated DOK4, which will be used to perform functional tests, such as localization analysis through immunofluorescence and cytokine profiling, to check for T cell function. We have patient derived organoids, which will be used to assess changes in gut morphology using imaging techniques. We will also generate mutant zebrafish model that will be used to determine the susceptibility to colitis related to this mutation, disease progression and gut peristalsis using live imaging technology. Results Preliminary data shows variation in expression of the protein within patient derived peripheral blood mononuclear cells (PBMCs) compared to a healthy donor. Conclusions With this study, we hope to identify new therapeutic targets for patients with DOK4 mutations. Funding Agencies CIHRThe Leona M. and Harry B. Helmsley Charitable Trust

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A Severe Necrotizing Inflammatory Reaction of Leg Wounds Following Autologous Peripheral Blood Total Nucleated Cells Treatment in an Old Patient With Rheumatoid Arthritis and No-Option Chronic Limb-Threatening Ischemia: Is Cell Therapy Suitable for All Patients?

The International Journal of Lower Extremity Wounds ◽

10.1177/1534734621997570 ◽

2021 ◽

pp. 153473462199757

Author(s):

Valerio Vallini ◽

Luigi Venturini ◽

Paolo Carnesecchi ◽

Roberto Andreini ◽

Simone Meini

Keyword(s):

Rheumatoid Arthritis ◽

Cell Therapy ◽

Inflammatory Reaction ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Inflammatory Diseases ◽

Inflammatory Disorder ◽

Skin Atrophy ◽

Chronic Inflammatory Disorder ◽

Increased Risk

Chronic limb-threatening ischemia (CLTI) represents an unfavorable evolution of peripheral artery disease, characterized by pain at rest, ulceration, and gangrene and also by an increased risk of cardiovascular events, amputations, and death. According to scientific literature, in almost one third of cases affected by CLTI, defined as no-option CLTI patients, revascularization strategies are not feasible. In the past decade, several studies investigated the role of therapeutic angiogenesis through cell autologous therapy, administered through intramuscular injections or multiple local intralesional and perilesional injections. In this article, we report the case of a necrotizing inflammatory reaction in a patient affected by CLTI and chronic leg wounds that occurred on the multiple injection sites after autologous peripheral blood-derived mononuclear cells (PB-TNCs) transplantation. Since the patient was affected by corticosteroid-induced skin atrophy and rheumatoid arthritis, we hypothesize that an increased skin fragility and a mechanism of immune-mediated pathergy could have been main factors leading to worsening of wounds. This case report strongly suggests the urgent need to better define the indications and contraindications of cell therapy, and further studies of adequate methodology are required to definitively assess the efficacy and safety of autologous cell therapy by local injections of PB-TNCs in patients with chronic inflammatory disorder, such as rheumatoid arthritis, especially in case of concomitant marked skin atrophy. Pending definitive evidence from literature, a strong caution is needed in patients affected by chronic systemic inflammatory diseases, since multiple injections, acting as mechanical stimulus and pathergy trigger, might exacerbate a severe and uncontrolled inflammatory response.

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Association of Behçet disease with psoriasis and psoriatic arthritis

Scientific Reports ◽

10.1038/s41598-021-81972-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hyung Jin Hahn ◽

Sang Gyu Kwak ◽

Dong-Kyu Kim ◽

Jong-Yeup Kim

Keyword(s):

Psoriatic Arthritis ◽

Systemic Vasculitis ◽

Behçet Disease ◽

Inflammatory Disorder ◽

Behcet Disease ◽

Cutaneous Manifestations ◽

Increased Risk ◽

Lethal Complications ◽

Male Cohort ◽

Clinical Pictures

AbstractBehçet disease (BD) is a debilitating multi-systemic vasculitis with a litany of muco-cutaneous manifestations and potentially lethal complications. Meanwhile, psoriasis (PSO) is a cutaneous and systemic inflammatory disorder marked by hyperplastic epidermis and silvery scales, which may be accompanied by a distinct form of arthropathy called psoriatic arthritis (PsA). While the clinical pictures of these two are quite different, they feature some important similarities, most of which may stem from the autoinflammatory components of BD and PSO. Therefore, the aim of this study was to investigate the prospective link between BD and cutaneous and articular manifestations of psoriasis. BD, PSO, and PsA cohorts were extracted using the National Health Insurance Service of Korea database. Using χ2 tests, prevalence of PSO and PsA with respect to BD status was analysed. Relative to non-BD individuals, those with personal history of BD were nearly three times more likely to be diagnosed with PSO. The adjusted odds ratio (aOR) was 2.36 [95% confidence interval (CI), 1.91–2.93, p < 0.001]. Elevated PSO risk was more pronounced in the male BD cohort (aOR = 1.19, 95% CI 1.16–1.23, p < 0.001). In age-group sub-analysis, individuals over 65 years with PSO were one and a half times more likely to be affected with BD, relative to those under 65. The adjusted OR for the older group was 1.51 (95% CI 1.43–1.59, p < 0.001). BD individuals with “healthy” body weight were significantly less likely to be affected by PSO (aOR = 0.59, 95% CI 0.57–0.62, p < 0.001). On the other hand, there was a correlation between BMI and the risk of BD, with the “moderately obese (30–35 kg/m2)” group having an aOR of 1.24 (95% CI 1.12–1.38, p < 0.001). BD patients were also twice more likely to be associated with PsA (aOR = 2.19, 95% CI 1.42–3.38, p < 0.001). However, in contrast to the case of psoriatic disease itself, females were exposed to a greater risk of developing BD compared to the male PsA cohort (aOR = 2.02, 95% CI 1.88–2.16, p < 0.001). As with PSO, older BD patients were exposed to a significantly higher risk of developing PsA (aOR = 3.13, 95% CI 2.90–3.40, p < 0.001). Behçet disease may place an individual at a significantly increased risk of psoriasis, and still greater hazard of being affected with psoriatic arthritis. This added risk was pronounced in the male cohort, and tended to impact senile population, and this phenomenon may be related with the relatively poor prognosis of BD in males and PSO in older patients.

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