scholarly journals Anti-phospholipids antibodies and immune complexes in COVID-19 patients: a putative role in disease course for anti-annexin-V antibodies

Author(s):  
Antonio Cristiano ◽  
Valentina Fortunati ◽  
Fabio Cherubini ◽  
Sergio Bernardini ◽  
Marzia Nuccetelli

Abstract Introduction Besides distinctive respiratory and digestive hallmarks, COVID-19 has been recently associated with a high prevalence of pro-inflammatory and hypercoagulable states known as “COVID-19 Associated Coagulopathy” (CAC), corresponding to a worsening in patients’ conditions, whose causes are still to be elucidated. A link between anti-phospholipid antibodies (aPLs) and viral infections has long been suggested. APLs are assessed for anti-phospholipid syndrome (APS) diagnosis, characterized by thrombocytopenia, thrombosis, and coagulopathy. Furthermore, circulating immune complexes (CICs), arisen upon inflammatory responses and related immune dysregulation, can lead to endothelial cell damage and thrombotic complications. Method We performed an extended panel including IgG/IgM anti-cardiolipin, IgG/IgM anti-β2-glycoprotein-1, coupled with IgG/IgM anti-prothrombin, IgG/IgM anti-annexin-V on two COVID-19 patient groups (early and late infection time), and a negative control group. IgG CIC analysis followed to evaluate inflammatory status, through a possible complement system activation. Results Our results showed low positive case percentage in IgG/IgM anti-cardiolipin and IgG/IgM anti-β2-glycoprotein-1 assays (4.54%, 6.25%, and 4.55%; in early infection group, late infection group, and control group, respectively); few positive cases in IgG/IgM anti-prothrombin and IgG/IgM anti-annexin-V immunoassays; and no IgG CIC positivity in any patient. Conclusions In conclusion, our data show a low aPL prevalence, likely excluding an involvement in the pathogenesis of CAC. Interestingly, IgG/IgM anti-prothrombin and anti-annexin-V positive cases, detected in late infection group, suggest that aPLs could temporarily increase or could trigger a “COVID-19-induced-APS-like-syndrome” in predisposed patients. Key Points•To our knowledge, anti-prothrombin (aPT) antibodies, anti-annexin-V antibodies and CICs in COVID-19 patients have not been reported in the scientific literature.•Lack of uniformity and the low percentage of aCL/aβ2GP1 positivity preclude a putative role in CAC pathogenesis.•IgG/IgM anti-prothrombin and IgG/IgM anti-annexin-V data show that distribution of positive case number increases in late infection patients, significantly in anti-annexin-V results, suggesting a possible role for these anti-phospholipid antibodies in disease course.•aPLs can arise transiently in some patients with critical illness and SARS-CoV-2 infection (disappearing in a few weeks), as well as in other genetically predisposed patients; they could trigger a “COVID-19-induced-APS-like-syndrome”.

2020 ◽  
Author(s):  
Antonio Cristiano ◽  
Valentina Fortunati ◽  
Fabio Cherubini ◽  
Sergio Bernardini ◽  
Marzia Nuccetelli

Abstract Introduction: Besides distinctive respiratory and digestive hallmarks, COVID-19 has been recently associated with a high prevalence of pro-inflammatory and hypercoagulable states known as “COVID-19 Associated Coagulopathy” (CAC), corresponding to a worsening in patients’ conditions, whose causes are still to be elucidated. A link between anti-phospholipids antibodies (aPLs) and viral infections has long been suggested. APLs are assessed for Anti-phospholipid Syndrome (APS) diagnosis, characterized by thrombocytopenia, thrombosis and coagulopathy. Furthermore, circulating immune complexes (CICs), arisen upon inflammatory responses and related immune dysregulation, can lead to endothelial cells damage and thrombotic complications.Method: We performed an extended panel including IgG/IgM anti-cardiolipin, IgG/IgM anti-β2-glycoprotein-1, coupled with IgG/IgM anti-prothrombin, IgG/IgM anti-annexin-V on two COVID-19 patient groups (early and late infection time) and a negative control group. IgG CICs analysis followed to evaluate inflammatory status, through a possible complement system activation.Results: Our results showed low positive cases percentage in IgG/IgM anti-cardiolipin and IgG/IgM anti-β2-glycoprotein-1 assays (4.54%, 6.25%, 4.55%; in early infection group, late infection group and control group, respectively); few positive cases in IgG/IgM anti-prothrombin and IgG/IgM anti-annexin-V immunoassays; no IgG CICs positivity in any patient.Conclusions: In conclusion, our data show a low aPLs prevalence, likely excluding an involvement in the pathogenesis of CAC.Interestingly, IgG/IgM anti-prothrombin and anti-annexin-V positive cases, detected in late infection group, suggest that aPLs could temporarily increase or could trigger a “COVID-19-induced-APS-like-syndrome” in predisposed patients.Finally, even though aPLs are transient, they may still have a thrombotic potential in genetically predisposed COVID-19 patients.


2021 ◽  
Vol 8 (2) ◽  
pp. 18
Author(s):  
Xiao-li Geng ◽  
Ya-xuan Zhang ◽  
Qi-zhi Ren

Objective: To investigate the effects of intrauterine infection in different periods on the placenta and endometrial blood vessel formation of pregnant rats and the growth and development of fetal rats.Methods: According to the random number table method, 32 pregnant rats were divided into the early infection group, the mid-term infection group, the late infection group and the control group, with 8 rats in each group. On the 3rd, 9th and 15th day of pregnancy, lipopolysaccharide was injected intraperitoneally to construct intrauterine infection models. The pregnant rats in the control group were intraperitoneally injected with the same dose of 0.9% sodium chloride solution. On the 18th day of pregnancy, the inflammatory factors [interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)], the blood vessel density of placenta and endometrium in the placental tissues of pregnant rats, dead fetus + absorbed fetus, the inflammatory factors IL-6, TNF-α and oxidation reaction indicators [malondialdehyde (MDA) and myeloperoxidase (MPO)] in the fetal rat lung and brain tissues were detected.Results: The changing trend of IL-6 and TNF-α levels in the placental tissues of pregnant rats with intrauterine infection in different periods was: the control group < the late infection group < the mid-term infection group < the early infection group, the differences were statistically significant (p <.05). The changing trend of fetal rat weight, placental weight and placental coefficient in the intrauterine infection groups in different periods was: the control group > the late infection group > the mid-term infection group > the early infection group, the differences were statistically significant (p < .05). The blood vessel density of placenta and endometrium, the mean number of fetuses, brain coefficient and lung coefficient in the late infection group were significantly increased in comparison with the early infection group and the mid-term infection group. The total number and the ratio of dead fetus + absorbed fetus, the levels of IL-6, TNF-α, MDA and MPO in brain and lung tissues were significantly reduced, and the differences were statistically significant (p < .05). The blood vessel density of placenta and endometrium, brain coefficient and lung coefficient of pregnant rats in the mid-term infection group were significantly increased in comparison with the early infection group, and the differences were statistically significant (p < .05). There was no statistically significant difference in the other indicators between the two groups (p > .05).Conclusions: Intrauterine infection in different periods can inhibit placental and endometrial angiogenesis, and affect the survival rate of fetal rats and the growth and development of brain and lung. The reason may be related to the aggravation of fetal inflammatory responses and oxidative stress. The earlier the intrauterine infection occurs, the severer the adverse effects on the fetal rats will be.


2021 ◽  
Vol 15 (5) ◽  
pp. 548-561
Author(s):  
K. G. Sultangadzhieva ◽  
N. N. Babaeva ◽  
E. S. Egorova ◽  
J. Kh. Khizroeva ◽  
M. G. Sultangadzhiev

Introduction. Retrochorial hematoma (RH) often detected during routine ultrasound examination represents one of the multiple causes resulting in early pregnancy loss. RH results from the detachment of the chorionic plate from the vertebrae of the uterine decidual membrane and may lead to complicated course of pregnancy.Aim: to develop a differential approach to diagnose and manage pregnancy with RH.Materials and Methods. A prospective open-ended interventional non-randomized study was conducted by enrolling 170 women. The main group consisted of 85 pregnant women with RH, which were divided into 2 groups: group I (n = 45) – patients with RH and burdened obstetric history; and group II (n = 40) – pregnant women with RH without a history of obstetric complications. The control group included 85 women with uncomplicated pregnancy. The incidence of hereditary thrombophilia was assessed by measuring rate of high thrombogenic risk mutations in the genes of factor (F) V Leiden and prothrombin (FII) G20210A; blood levels of lupus anticoagulant (LA) and anti-cardiolipin antibodies (aCL), β2-glycoprotein 1 (β2-GP1), annexin V and prothrombin; ADAMTS-13; rate of low thrombogenic risk polymorphisms, prevalence and spectrum of bacterial-viral infections.Results. It was revealed that women with RH had occasional genetic and acquired hemostasis defects as well as impaired florocenosis of the urogenital tract. Defects in the fibrinolysis system prevailed among the hereditary hemostasis defects: 75.5 % in group I, 32.2 % in group II, and 4.7 % in the control group. No decrease in the activity of natural anticoagulants – antithrombin and protein C was found. Among the acquired thrombophilic conditions, a large proportion of circulating antiphospholipid antibodies (APA) was found: 46.6 % in group I, 27.5 % in group II, and 2.3 % in the control group. Cervicitis of nonspecific etiology prevailed among dysbiosis signs: 53.3 % in group I, 47.5 % in group II and 11.7 % in the control group.Conclusion. RG formation is a multifactorial process, which pathogenesis involves both genetic and acquired factors such as APA, especially in combination with genetic thrombophilia (FV Leiden and FII G20210A), as well as inflammatory or pro-inflammatory status. We consider that all patients with RG as well as those with former RG are indicated to undergo the above-mentioned studies. It is advisable to include tranexamic acid, progesterone, low molecular weight heparins and antibiotics in the therapy regimen if indicated. 


2019 ◽  
Vol 16 (1) ◽  
pp. 91-95 ◽  
Author(s):  
Hamid Farhang ◽  
Laleh Sharifi ◽  
Mohammad Mehdi Soltan Dallal ◽  
Mona Moshiri ◽  
Zahra Norouzbabaie ◽  
...  

Background: The non-steroidal anti-inflammatory drugs (NSAIDs) play crucial role in the controlling of inflammatory diseases. Due to the vast side effects of NSAIDs, its use is limited. G2013 or &amp;#945;-L-Guluronic Acid is a new NSAID with immunomodulatory features. Objectives: Considering the leading role of TLRs in inflammatory responses, in this study, we aimed to evaluate G2013 cytotoxicity and its effect on the expression of TLR2 and TLR4 molecules. Methods: HEK293-TLR2 and HEK293-TLR4 cells were cultured and seeded on 96-well cell plate, and MTT assay was performed for detecting the viability of the cells after treatment with different concentrations of G2013. HT29 cells were grown and treated with low and high doses of G2013. After total RNA extraction and cDNA synthesis, quantitative real-time PCR were performed to assess the TLR2 and TLR4 mRNA synthesis. Results: We found that concentrations of ≤125 &amp;#181;g/ml of G2013 had no apparent cytotoxicity effect on the HEK293-TLR2 and -TLR4 cells. Our results indicated that after G2013 treatment (5 &amp;#181;g/ml) in HT29 cells, TLR2 and TLR4 mRNA expression decreased significantly compared with the untreated control group (p=0.02 and p=0.001 respectively). Conclusion: The results of this study revealed that G2013 can down regulate the TLR2 and TLR4 gene expression and exerts its inhibitory effect. Our findings are parallel to our previous finding which showed G2013 ability to down regulate the signaling pathway of TLRs. However, further studies are needed to identify the molecular mechanism of G2013.<p&gt;


2020 ◽  
Vol 20 (18) ◽  
pp. 2316-2323 ◽  
Author(s):  
Alican Kusoglu ◽  
Bakiye G. Bagca ◽  
Neslihan P.O. Ay ◽  
Guray Saydam ◽  
Cigir B. Avci

Background: Ruxolitinib is a selective JAK1/2 inhibitor approved by the FDA for myelofibrosis in 2014 and nowadays, comprehensive investigations on the potential of the agent as a targeted therapy for haematological malignancies are on the rise. In multiple myeloma which is a cancer of plasma cells, the Interleukin- 6/JAK/STAT pathway is emerging as a therapeutic target since the overactivation of the pathway is associated with poor prognosis. Objective: In this study, our purpose was to discover the potential anticancer effects of ruxolitinib in ARH-77 multiple myeloma cell line compared to NCI-BL 2171 human healthy B lymphocyte cell line. Methods: Cytotoxic effects of ruxolitinib in ARH-77 and NCI-BL 2171 cells were determined via WST-1 assay. The autophagy mechanism induced by ruxolitinib measured by detecting autophagosome formation was investigated. Apoptotic effects of ruxolitinib were analyzed with Annexin V-FITC Detection Kit and flow cytometry. We performed RT-qPCR to demonstrate the expression changes of the genes in the IL-6/JAK/STAT pathway in ARH-77 and NCI-BL 2171 cells treated with ruxolitinib. Results: We identified the IC50 values of ruxolitinib for ARH-77 and NCI-BL 2171 as 20.03 and 33.9μM at the 72nd hour, respectively. We showed that ruxolitinib induced autophagosome accumulation by 3.45 and 1.70 folds in ARH-77 and NCI-BL 2171 cells compared to the control group, respectively. Treatment with ruxolitinib decreased the expressions of IL-6, IL-18, JAK2, TYK2, and AKT genes, which play significant roles in MM pathogenesis. Conclusion: All in all, ruxolitinib is a promising agent for the regulation of the IL-6/JAK/STAT pathway and interferes with the autophagy mechanism in MM.


BMJ Open ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. e043699
Author(s):  
Morten Riemenschneider ◽  
Lars G Hvid ◽  
Steffen Ringgaard ◽  
Mikkel K E Nygaard ◽  
Simon F Eskildsen ◽  
...  

IntroductionIn the relapsing remitting type of multiple sclerosis (MS) reducing relapses and neurodegeneration is crucial in halting the long-term impact of the disease. Medical disease-modifying treatments have proven effective, especially when introduced early in the disease course. However, patients still experience disease activity and disability progression, and therefore, supplemental early treatment strategies are warranted. Exercise appear to be one of the most promising supplemental treatment strategies, but a somewhat overlooked ‘window of opportunity’ exist early in the disease course. The objective of this study is to investigate exercise as a supplementary treatment strategy early in the disease course of MS.Methods and analysisThe presented Early Multiple Sclerosis Exercise Study is a 48-week (plus 1-year follow-up) national multicentre single-blinded parallel group randomised controlled trial comparing two groups receiving usual care plus supervised high-intense exercise or plus health education (active control). Additionally, data will be compared with a population-based control group receiving usual care only obtained from the Danish MS Registry. The primary outcomes are annual relapse rate and MRI derived global brain atrophy. The secondary outcomes are disability progression, physical and cognitive function, MS-related symptoms, and exploratory MRI outcomes. All analyses will be performed as intention to treat.Ethics and disseminationThe study is approved by The Central Denmark Region Committees on Health Research Ethics (1-10-72-388-17) and registered at the Danish Data Protection Agency (2016-051-000001 (706)). All study findings will be published in scientific peer-reviewed journals and presented at relevant scientific conferences.Trial registration numberNCT03322761.


2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 819.1-819
Author(s):  
L. Long ◽  
G. Tang ◽  
Y. Han ◽  
Q. Peng ◽  
J. Liu ◽  
...  

Background:Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and syndrome(SS) are common rheumatic diseases with high incidence. Patients with those rheumatic diseases are at high risk of tuberculosis (TB) infection. However, manifestations can be atypical and easily confused with those of rheumatic disease itself. For those patients, diagnosis is usually much more difficult and further make treatment delayed. Sometimes it may lead to mistreatment. Therefore, it is important to recognize the clinical characteristics of those patients.Objectives:To explore the clinical characteristics and high risk factors of common systemic rheumatism complicated with tuberculosis infection.Methods:A total of 3,906 cases of RA, SLE, and SS common systemic rheumatism diagnosed in the People’s Hospital of Sichuan Province from January 2007 to January 2017 were collected with carefully exclusion with other infectious diseases and neoplastic disease. One hundred and five patients with TB were included as infection group, including 42 cases of RA, 41 cases of SLE, and 22 cases of SS. In the control group, 84 patients with RA, 82 patients with SLE, and 44 patients with SS were randomly selected from the corresponding rheumatoid non-infected patients hospitalized during the same period.Results:Fever was the most common symptom among 42 cases of RA, 41 cases of SLE, and 22 cases of SS with TB, accounting for 83.3%, 92.7%, and 68.2%, respectively. Cough, weight loss or fatigue was less common. For 41 cases of SLE and 22 cases of SS with TB, the proportion of pulmonary was 46.3%, 59.01%, respectively.In TB infection group, 27 cases of RA, 21 cases of SLE, and 13 cases of SS with TB had two or more chest CT findings, accounting for 59%, 57%, 62%, respectively. Lesions located in the posterior or posterior segment which TB usually affected were 9 cases(33.3%),9cases(42.9%),6cases(27.2%),respectively.The daily average dose of hormones within 1 year in TB infection group was higher than that in the control group (P<0.05). For SLE patients, lower counts of CD4+TL were found in TB infection group (P<0.05), while no such differences were found in RA and SS group.Conclusion:Patients with RA who have TB infection are mainly pulmonary TB. For SLE and SS patients, the chance of pulmonary tuberculosis and extra-pulmonary tuberculosis is similar.Symptoms of RA, SLE, SS with TB, such as fever, cough, weight loss, fatigue, are similar with the primary disease or other infection. Chest imaging is diversity. It is difficult to diagnose.Daily average dose of hormone within one year may be a common risk factor for RA, SLE and SS patients with TB. Decreased CD4+TL may also be a risk factor for SLE patients with TB.References:[1]Cantini F, Nannini C, Niccoli L, et al. Risk of Tuberculosis Reactivation in Patients with Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Receiving Non-Anti-TNF-Targeted Biologics[J]. Mediators of Inflammation, 2017, 2017(6):1-15.[2]Ruangnapa K, Dissaneewate P, Vachvanichsanong P. Tuberculosis in SLE patients: rare diagnosis, risky treatment.[J]. Clinical & Experimental Medicine, 2015, 15(3):429-432.[3]Manuela D F, Bruno L, Martina S, et al. Lung Infections in Systemic Rheumatic Disease: Focus on Opportunistic Infections[J]. International Journal of Molecular Sciences, 2017, 18(2):293-315.[4]Disseminated tuberculosis masquerading as a presentation of systemic lupus erythematosus.Li JC, Fong W, Wijaya L, Leung YY.Int J Rheum Dis. 2017 Oct 2. doi: 10.1111/1756-185X.13195.[5]Handa R, Upadhyaya S, Kapoor S, et al. Tuberculosis and biologics in rheumatology: India – A special situation[J]. International Journal of Rheumatic Diseases, 2017, 51(2):115.Disclosure of Interests:None declared


Author(s):  
M.L. Bellotto ◽  
A. Castro ◽  
I.L.P. Bonfante ◽  
D.T. Brunelli ◽  
M.P.T. Chacon-Mikahil ◽  
...  

BACKGROUND: High visceral fat storage unbalance secretion inflammatory peptides, however diet plays an important role-protecting metabolism against chronic diseases inherent to this condition. OBJECTIVE: To assess obese diet quality and find association with inflammatory biomarkers. METHODS: aMED, a Food Quality Index, classified the inflammatory power of 26 obese men’s diet (aged: 48.1±5.1; BMI: 31.1±2.45). Pearson correlation coefficient associated diet quality in tertiles (1st as low, 2nd as average and 3 rd as high quality diet) with inflammatory variables (cytokines and waist circumference). RESULTS: The intake of anti-inflammatory food groups was significantly higher among tertiles (3rd >  2nd >  1st; P <  0.001). Adiponectin was lower in the 2nd tertile than in the 1st (P <  0.05). Whole cereal presented a positive correlation with TNF-alpha (p = 0.049), and a negative correlation with IL–15 (p = 0.002). Fish presented a positive correlation with IL–10 (p = 0.024), Resistin (p = 0.039) and PGE–2 (p = 0.001). These findings pointed to pro and anti-inflammatory responses. CONCLUSIONS: The method may need adjustments when used to assess obese food intake, since they don't usually meet the daily-recommended intake. Other lifestyles variables should be considered, which may affect the inflammatory status.


Animals ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 2072
Author(s):  
Zizy I. Elbialy ◽  
Abdallah S. Salah ◽  
Ahmed Elsheshtawy ◽  
Merna Rizk ◽  
Muyassar H. Abualreesh ◽  
...  

Ammonia is a critical hazardous nitrogen metabolic product in aquaculture. Despite trials for its control, ammonia intoxication remains one of the most critical issues to overcome. In this study, we explored the modulatory effect and potential mechanism by which Yucca schidigera extract (YSE) can ameliorate ammonia intoxication-induced adverse effects on tilapia health and metabolism. A total number of 120 Nile tilapia were evenly assigned into four groups with three replicates each. The first group served as normal control group; the second group was exposed to ammonia alone from the beginning of the experiment and for four weeks. The third group was supplied with YSE in water at a dose of 8 mg/L and exposed to ammonia. The fourth group was supplied with YSE only in water at a dose of 8 mg/L. YSE supplementation succeeded in improving water quality by reducing pH and ammonia levels. Moreover, YSE supplementation markedly alleviated chronic ammonia-induced adverse impacts on fish growth by increasing the final body weight (FBW), specific growth rate (SGR), feed intake and protein efficiency ratio (PER) while reducing the feed conversion ratio (FCR) via improvements in food intake, elevation of hepatic insulin-like growth factor (ILGF-1) and suppression of myostatin (MSTN) expression levels with the restoration of lipid reserves and the activation of lipogenic potential in adipose tissue as demonstrated by changes in the circulating metabolite levels. In addition, the levels of hepato-renal injury biomarkers were restored, hepatic lipid peroxidation was inhibited and the levels of hepatic antioxidant biomarkers were enhanced. Therefore, the current study suggests that YSE supplementation exerted an ameliorative role against chronic ammonia-induced oxidative stress and toxic effects due to its free radical-scavenging potential, potent antioxidant activities and anti-inflammatory effects.


2001 ◽  
Vol 10 (3) ◽  
pp. 263-275 ◽  
Author(s):  
Berit L. Strand ◽  
Liv Ryan ◽  
Peter In't Veld ◽  
Bård Kulseng ◽  
Anne Mari Rokstad ◽  
...  

Alginate – poly-l-lysine (PLL) microcapsules can be used for transplantation of insulin-producing cells for treatment of type I diabetes. In this work we wanted to study the inflammatory reactions against implanted microcapsules due to PLL. We have seen that by reducing the PLL layer, less overgrowth of the capsule is obtained. By incubating different cell types with PLL and afterwards measuring cell viability with MTT, we found massive cell death at concentrations of PLL higher than 10 μg/ml. Staining with annexin V and propidium iodide showed that PLL induced necrosis but not apoptosis. The proinflammatory cytokine, tumor necrosis factor (TNF), was detected in supernatants from monocytes stimulated with PLL. The TNF response was partly inhibited with antibodies against CD14, which is a well-known receptor for lipopolysaccharide (LPS). Bactericidal permeability increasing protein (BPI) and a lipid A analogue (B-975), which both inhibit LPS, did not inhibit PLL from stimulating monocytes to TNF production. This indicates that PLL and LPS bind to different sites on monocytes, but because they both are inhibited by a p38 MAP kinase inhibitor, they seem to have a common element in the signal transducing pathway. These results suggest that PLL may provoke inflammatory responses either directly or indirectly through its necrosis-inducing abilities. By combining soluble PLL and alginate both the toxic and TNF-inducing effects of PLL were reduced. The implications of these data are to use alginate microcapsules with low amounts of PLL for transplantation purposes.


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