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Quantification of polyreactive immunoglobulin G facilitates the diagnosis of autoimmune hepatitis.
Taubert, R, Engel, B, Diestelhorst, J, Hupa-Breier, KL, Behrendt, P, Baerlecken, NT, Sühs, KW, Janik, MK, Zachou, K, Sebode, M, et al
Hepatology (Baltimore, Md.). 2022;(1):13-27
Abstract
BACKGROUND AND AIMS Detection of autoantibodies is a mainstay of diagnosing autoimmune hepatitis (AIH). However, conventional autoantibodies for the workup of AIH lack either sensitivity or specificity, leading to substantial diagnostic uncertainty. We aimed to identify more accurate serological markers of AIH with a protein macroarray. APPROACH AND RESULTS During the search for more-precise autoantibodies to distinguish AIH from non-AIH liver diseases (non-AIH-LD), IgG antibodies with binding capacities to many human and foreign proteins were identified with a protein macroarray and confirmed with solid-phase ELISAs in AIH patients. Subsequently, polyreactive IgG (pIgG) was exemplarily quantified by reactivity against human huntingtin-interacting protein 1-related protein in bovine serum albumin blocked ELISA (HIP1R/BSA). The diagnostic fidelity of HIP1R/BSA binding pIgG to diagnose AIH was assessed in a retrospective training, a retrospective multicenter validation, and a prospective validation cohort in cryoconserved samples from 1,568 adults from 10 centers from eight countries. Reactivity against HIP1R/BSA had a 25% and 14% higher specificity to diagnose AIH than conventional antinuclear and antismooth muscle antibodies, a significantly higher sensitivity than liver kidney microsomal antibodies and antisoluble liver antigen/liver pancreas antigen, and a 12%-20% higher accuracy than conventional autoantibodies. Importantly, HIP1R/BSA reactivity was present in up to 88% of patients with seronegative AIH and in up to 71% of AIH patients with normal IgG levels. Under therapy, pIgG returns to background levels of non-AIH-LD. CONCLUSIONS pIgG could be used as a promising marker to improve the diagnostic workup of liver diseases with a higher specificity for AIH compared to conventional autoantibodies and a utility in autoantibody-negative AIH. Likewise, pIgG could be a major source of assay interference in untreated AIH.
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Anti-SARS-CoV-2 immunoglobulin profile in patients with celiac disease living in a high incidence area.
Elli, L, Facciotti, F, Lombardo, V, Scricciolo, A, Sanders, DS, Vaira, V, Barisani, D, Vecchi, M, Costantino, A, Scaramella, L, et al
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2022;(1):3-9
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BACKGROUND AND AIM How symptoms and antibodies related to SARS-CoV-2 infection develop in patients with celiac disease (CD) is unclear. We aimed to investigate the impact of SARS-CoV-2 infection in CD patients. METHODS CD patients were interviewed about the development of COVID-19 symptoms, compliance with anti-virus measures and adherence to a gluten-free diet (GFD). The presence of anti-SARS-CoV-2 IgG and IgA (anti-RBD and N proteins) was compared to that in non-CD subjects. Expression of the duodenal ACE2 receptor was investigated. When available, data on duodenal histology, anti-tissue transglutaminase IgA (tTGA), comorbidities and GFD adherence were analyzed. RESULTS Of 362 CD patients, 42 (12%) reported COVID-19 symptoms and 21% of these symptomatic patients presented anti-SARS-CoV-2 Ig. Overall, 18% of CD patients showed anti-SARS-CoV-2 Ig versus 25% of controls (p = 0.18). CD patients had significantly lower levels of anti-N IgA. tTGA, duodenal atrophy, GFD adherence or other comorbidities did not influence symptoms and/or antibodies. The ACE2 receptor was detected in the non-atrophic duodenal mucosa of patients; atrophy was associated with lower expression of the ACE2 receptor. CONCLUSION CD patients have an anti-SARS-CoV-2 Ig profile similar to non-celiac controls, except for anti-N IgA. No risk factors were identified among CD parameters and GFD adherence.
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Quantity of IgG response to SARS-CoV-2 spike glycoprotein predicts pulmonary recovery from COVID-19.
Nairz, M, Sahanic, S, Pizzini, A, Böhm, A, Tymoszuk, P, Mitterstiller, AM, von Raffay, L, Grubwieser, P, Bellmann-Weiler, R, Koppelstätter, S, et al
Scientific reports. 2022;(1):3677
Abstract
The CovILD study is a prospective, multicenter, observational cohort study to systematically follow up patients after coronavirus disease-2019 (COVID-19). We extensively evaluated 145 COVID-19 patients at 3 follow-up visits scheduled for 60, 100, and 180 days after initial confirmed diagnosis based on typical symptoms and a positive reverse transcription-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We employed comprehensive pulmonary function and laboratory tests, including serum concentrations of IgG against the viral spike (S) glycoprotein, and compared the results to clinical data and chest computed tomography (CT). We found that at the 60 day follow-up, 131 of 145 (90.3%) participants displayed S-specific serum IgG levels above the cut-off threshold. Notably, the highly elevated IgG levels against S glycoprotein positively correlated with biomarkers of immune activation and negatively correlated with pulmonary function and the extent of pulmonary CT abnormalities. Based on the association between serum S glycoprotein-specific IgG and clinical outcome, we generated an S-specific IgG-based recovery score that, when applied in the early convalescent phase, accurately predicted delayed pulmonary recovery after COVID-19. Therefore, we propose that S-specific IgG levels serve as a useful immunological surrogate marker for identifying at-risk individuals with persistent pulmonary injury who may require intensive follow-up care after COVID-19.
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Impact of IgG response to malaria-specific antigens and immunity against malaria in pre-school children in Ghana. A cluster randomized, placebo-controlled trial.
Tchum, SK, Sakyi, SA, Adu, B, Arthur, F, Oppong, FB, Dzabeng, F, Amoani, B, Gyan, T, Poku-Asante, K
PloS one. 2021;(7):e0253544
Abstract
BACKGROUND Iron fortification and micronutrient initiatives, specifically, vitamin A, and zinc supplementation are the most cost-effective developmental strategies against malnutrition and health emergencies in pre-school children. Iron-deficiency among pre-school children have been documented, however, studies evaluating the impact of immunoglobulin G (IgG) isotype responses among iron-fortified pre-school children in malaria endemic communities has not been assessed. We evaluated the impact of iron fortification on the IgG responses to GLURP R0, GLURP R2 and MSP3 FVO malaria-specific antigens among pre-school children in malaria endemic areas. METHODS This community-based, placebo-controlled, double-blinded, cluster-randomized trial study was conducted in Wenchi Municipal and Tain District of Bono Region. The trial was registered at ClinicalTrials.gov-registered trial (Identifier: NCT01001871). Ethical approval was obtained and informed consent were sought from each participant parents/guardian. For the current objective, 871 children aged 6-35 months were screened, from which 435 children received semi-liquid home-made meals mixed with 12.5 mg of iron daily (intervention group), and 436 received micronutrient powder without iron (placebo group) for 5 months. Standardized clinical and epidemiological questionnaires were administered and blood samples taken to measure IgG responses to GLURP R0, GLURP R2 and MSP3 FVO recombinant antigens using the Afro Immunoassay (AIA) protocol. RESULTS Baseline anthropometry, malaria diagnosis, anaemia and iron status, demographic features and dietary intake were identical among the groups (p > 0.05). After the intervention, there was no significant difference in the IgG response against GLUP R0, GLUP R2 and MSP3 FVO between the iron-containing micronutrient and placebo groups (p > 0.05). The iron-containing micronutrient powder group who were iron-sufficient or iron replete had significantly higher IgG response to GLURP R0 and GLURP R2 compared to iron-deficient and iron-deficiency anaemia in the same group (p < 0.05). The IgG responses to all the three malaria specific antigens were low among children without malaria episode but high among those with two and four episodes due to exposure differences. CONCLUSION Iron fortification did not influence antibody response against endogenous malaria specific antigens among pre-school children in malaria endemic areas, however, IgG response to malaria specific antigens were high among children with sufficient iron status.
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Seroepidemiology of Toxoplasma gondii infection in people with alcohol consumption in Durango, Mexico.
Estrada-Martinez, S, Pérez-Álamos, AR, Ibarra-Segovia, M, Beristaín-Garcia, I, Ramos-Nevárez, A, Saenz-Soto, L, Rábago-Sánchez, E, Guido-Arreola, CA, Alvarado-Esquivel, C
PloS one. 2021;(1):e0245701
Abstract
The seroepidemiology of infection with Toxoplasma gondii (T. gondii) in alcohol consumers is largely undeveloped. In light of this, we sought to determine the seroprevalence of T. gondii infection in alcohol consumers in Durango, Mexico, and the association of T. gondii seroprevalence with characteristics of the population studied. Anti-T. gondii IgG and IgM antibodies were searched in sera of participants using commercially available enzyme immunoassays. Bivariate and logistic regression analyses were then used to determine the association between T. gondii infection and the characteristics of the population studied. Of the 1544 people studied (mean age: 39.4±14.0 years), 173 (11.2%) tested positive for anti-T. gondii IgG antibodies. We were able to test 167 of the 173 anti-T. gondii IgG positive sera for anti-T. gondii IgM antibodies. Fifty-five (32.9%) of these 167 serum samples were positive for anti-T. gondii IgM antibodies. Bivariate analysis showed that visual impairment, history of surgery, and hepatitis were negatively associated with T. gondii IgG seropositivity (P<0.05). In women, seropositivity to T. gondii was positively associated with a history of pregnancy (P<0.05). Logistic regression analysis showed that T. gondii seropositivity was associated with the variables consumption of armadillo meat (OR = 2.33; 95% CI: 1.04-5.22; P = 0.03), and the use of latrines for elimination of excretes (OR = 2.27; 95% CI: 1.07-4.80; P = 0.03); and high (>150 IU/ml) anti-T. gondii IgG antibodies were associated with consumption of both armadillo meat (OR = 2.25; 95% CI: 1.01-5.02; P = 0.04) and crowding at home (OR = 1.63; 95% CI: 1.02-2.61; P = 0.03). We found a distinct T. gondii seroprevalence in people with alcohol consumption from those previously found in population groups in the region. This is the first study that illustrates the association between high anti-T. gondii antibodies and crowding in Mexico, and the second study on the association between T. gondii infection and consumption of armadillo meat and the use of latrines in this country. We conclude that epidemiology of T. gondii infection in people with alcohol consumption deserves further investigation.
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An advanced molecularly imprinted electrochemical sensor for the highly sensitive and selective detection and determination of Human IgG.
Axin Liang, A, Huipeng Hou, B, Shanshan Tang, C, Liquan Sun, D, Aiqin Luo, E
Bioelectrochemistry (Amsterdam, Netherlands). 2021;:107671
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An advanced molecularly imprinted electrochemical sensor with high sensitivity and selectivity for the detection of Human immunoglobulin G (IgG) was successfully constructed. With acrylamide imprinting systems, surface imprinting on the nanoparticles CuFe2O4 targeted at IgG was employed to prepare molecularly imprinted polymer, which served as recognition element for the electrochemical sensor. Furthermore, the sensor harnessed a molybdenum disulfide (MoS2)@nitrogen doped graphene quantum dots (N-GQDs) with ionic liquid (IL) nanocomposite for signal amplification. Under optimized experimental conditions, the sensor shortened the response time to less than 8 min, and the response was linear at the IgG concentration of 0.1-50 ng·mL-1 with a low detection limit of 0.02 ng·mL-1 (S/N = 3). Our findings suggested that, the sensor exhibited high detectability and long-time stability. The satisfactory results of human serum sample analysis showed that the developed IgG sensor had promising potential clinical applications in detecting IgG content.
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Begelomab for severe refractory dermatomyositis: A case report.
De Lorenzo, R, Sciorati, C, Monno, A, Cavalli, S, Bonomi, F, Tronci, S, Previtali, S, Rovere-Querini, P
Medicine. 2021;(9):e24372
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RATIONALE Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody. PATIENT CONCERNS A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia. DIAGNOSIS Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed. INTERVENTIONS The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26. OUTCOMES Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life. CONCLUSION Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
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Impact of macromolecular crowding on the mesomorphic behavior of lipid self-assemblies.
Mangiarotti, A, Bagatolli, LA
Biochimica et biophysica acta. Biomembranes. 2021;(12):183728
Abstract
Using LAURDAN fluorescence we observed that water dynamics measured at the interface of DOPC bilayers can be differentially regulated by the presence of crowded suspensions of different proteins (HSA, IgG, Gelatin) and PEG, under conditions where the polymers are not in direct molecular contact with the lipid interface. Specifically, we found that the decrease in water dipolar relaxation at the membrane interface correlates with an increased fraction of randomly oriented (or random coil) configurations in the polymers, as Gelatin > PEG > IgG > HSA. By using the same experimental strategy, we also demonstrated that structural transitions from globular to extended conformations in proteins can induce transitions between lamellar and non-lamellar phases in mixtures of DOPC and monoolein. Independent experiments using Raman spectroscopy showed that aqueous suspensions of polymers exhibiting high proportions of randomly oriented conformations display increased fractions of tetracoordinated water, a configuration that is dominant in ice. This indicates a greater capacity of this type of structure for polarizing water and consequently reducing its chemical activity. This effect is in line with one of the tenets of the Association Induction Hypothesis, which predicts a long-range dynamic structuring of water molecules via their interactions with proteins (or other polymers) showing extended conformations. Overall, our results suggest a crucial role of water in promoting couplings between structural changes in macromolecules and supramolecular arrangements of lipids. This mechanism may be of relevance to cell structure/function when the crowded nature of the intracellular milieu is considered.
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Antibody-induced procoagulant platelets in severe COVID-19 infection.
Althaus, K, Marini, I, Zlamal, J, Pelzl, L, Singh, A, Häberle, H, Mehrländer, M, Hammer, S, Schulze, H, Bitzer, M, et al
Blood. 2021;(8):1061-1071
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The pathophysiology of COVID-19-associated thrombosis seems to be multifactorial. We hypothesized that COVID-19 is accompanied by procoagulant platelets with subsequent alteration of the coagulation system. We investigated depolarization of mitochondrial inner transmembrane potential (ΔΨm), cytosolic calcium (Ca2+) concentration, and phosphatidylserine (PS) externalization. Platelets from COVID-19 patients in the intensive care unit (ICU; n = 21) showed higher ΔΨm depolarization, cytosolic Ca2+, and PS externalization compared with healthy controls (n = 18) and non-ICU COVID-19 patients (n = 4). Moreover, significant higher cytosolic Ca2+ and PS were observed compared with a septic ICU control group (ICU control; n = 5). In the ICU control group, cytosolic Ca2+ and PS externalization were comparable with healthy controls, with an increase in ΔΨm depolarization. Sera from COVID-19 patients in the ICU induced a significant increase in apoptosis markers (ΔΨm depolarization, cytosolic Ca2+, and PS externalization) compared with healthy volunteers and septic ICU controls. Interestingly, immunoglobulin G fractions from COVID-19 patients induced an Fcγ receptor IIA-dependent platelet apoptosis (ΔΨm depolarization, cytosolic Ca2+, and PS externalization). Enhanced PS externalization in platelets from COVID-19 patients in the ICU was associated with increased sequential organ failure assessment score (r = 0.5635) and D-dimer (r = 0.4473). Most importantly, patients with thrombosis had significantly higher PS externalization compared with those without. The strong correlations between markers for apoptosic and procoagulant platelets and D-dimer levels, as well as the incidence of thrombosis, may indicate that antibody-mediated procoagulant platelets potentially contributes to sustained increased thromboembolic risk in ICU COVID-19 patients.
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Antibodies against phosphorylcholine in hospitalized versus non-hospitalized obese subjects.
Jujić, A, Korduner, J, Holm, H, Engström, G, Bachus, E, Bhattacharya, P, Nilsson, PM, Frostegård, J, Magnusson, M
Scientific reports. 2021;(1):20246
Abstract
Obesity associates with reduced life expectancy, type 2 diabetes, hypertension and cardiovascular disease, and is characterized by chronic inflammation. Phosphorylcholine (PC) is an epitope on oxidized low-density lipoprotein, dead cells and some microorganisms. Antibodies against PC (anti-PC) have anti-inflammatory properties. Here, we explored the role of anti-PC in hospitalized versus non-hospitalized obese. One-hundred-and-twenty-eight obese (BMI ≥ 30 kg/m2) individuals (59.8 (± 5.5) years, 53.9% women) from the Malmö Diet and Cancer Cardiovascular Cohort were examined and IgM, IgG1 and IgG2 anti-PC were analyzed by ELISA. Individuals with at least one recorded history of hospitalization prior to study baseline were considered hospitalized obese (HO). Associations between IgM, IgG1 and IgG2 anti-PC and HO (n = 32)/non-hospitalized obese (NHO) (n = 96), but also with metabolic syndrome and diabetes were analysed using logistic regressions. Both IgM and IgG1 anti-PC were inversely associated with HO, also after controlling for age and sex. When further adjusted for waist circumference, systolic blood pressure, glucose levels and smoking status, only IgG1 anti-PC remained significantly associated with HO. In multivariate models, each 1 standard deviation of increment in anti-PC IgG1 levels was inversely associated with prevalence of HO (odds ratio 0.57; CI 95% 0.33-0.98; p = 0.044). IgG2 anti-PC did not show any associations with HO. Low levels of IgM and IgG1 anti-PC are associated with higher risk of being a HO individual independent of sex and age, IgG1 anti-PC also independently of diabetes and metabolic syndrome. The anti-inflammatory properties of these antibodies may be related to inflammation in obesity and its complications.