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1.
Front Immunol ; 15: 1330549, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38433831

RESUMO

Background: Vaccination against COVID-19 is highly effective in preventing severe disease and hospitalization, but primary COVID mRNA vaccination schedules often differed from those recommended by the manufacturers due to supply chain issues. We investigated the impact of delaying the second dose on antibody responses to COVID mRNA-vaccines in a prospective cohort of health-care workers in Quebec. Methods: We recruited participants from the McGill University Health Centre who provided serum or participant-collected dried blood samples (DBS) at 28-days, 3 months, and 6 months post-second dose and at 28-days after a third dose. IgG antibodies to SARS-CoV2 spike (S), the receptor-binding domain (RBD), nucleocapsid (N) and neutralizing antibodies to the ancestral strain were assessed by enzyme-linked immunosorbent assay (ELISA). We examined associations between long (≤89 days) versus short (<89 days) between-dose intervals and antibody response through multivariable mixed-effects models adjusted for age, sex, prior covid infection status, time since vaccine dose, and assay batch. Findings: The cohort included 328 participants who received up to three vaccine doses (>80% Pfizer-BioNTech). Weighted averages of the serum (n=744) and DBS (n=216) cohort results from the multivariable models showed that IgG anti-S was 31% higher (95% CI: 12% to 53%) and IgG anti-RBD was 37% higher (95% CI: 14% to 65%) in the long vs. short interval participants, across all time points. Interpretation: Our study indicates that extending the covid primary series between-dose interval beyond 89 days (approximately 3 months) provides stronger antibody responses than intervals less than 89 days. Our demonstration of a more robust antibody response with a longer between dose interval is reassuring as logistical and supply challenges are navigated in low-resource settings.


Assuntos
Formação de Anticorpos , COVID-19 , Humanos , Estudos Prospectivos , Vacinas contra COVID-19 , RNA Viral , COVID-19/prevenção & controle , SARS-CoV-2 , Anticorpos Neutralizantes , Imunoglobulina G , RNA Mensageiro
2.
Eur Rev Med Pharmacol Sci ; 28(4): 1314-1326, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38436165

RESUMO

OBJECTIVE: Pulmonary arterial hypertension (PAH) represents an important vascular complication of mixed connective tissue disease (MCTD) and systemic sclerosis (SSc). Microvascular involvement in these diseases can be investigated by means of nailfold capillaroscopy (NFC). Microvascular involvement detected in the nailfold bed is the mirror of the microvascular damage occurring in the entire body, further indicating the involvement of the target organs. The aim of this study was to evaluate the microvascular involvement in MCTD patients with or without PAH, compared to that found in SSc patients with or without PAH. PATIENTS AND METHODS: This cross-sectional study was performed in the Department of Internal Medicine and Department of Rheumatology, Timișoara, Romania, during the time period between January 2017 and December 2022, on a group of 26 patients with MCTD and 26 SSc patients. Antinuclear antibodies, anti-U1-RNP, anti-Scl 70, anti-centromere, anti-cardiolipin antibodies (aCL) (IgM, IgG), anti-ß2-glycoprotein I (aß2GPI) (IgM, IgG) antibodies, and lupus anticoagulant (LAC) were determined in both the groups. PAH was evaluated through cardiac ultrasonography, determining the sPAP (systolic pulmonary artery pressure). Nailfold capillaroscopy was performed using a USB Digital Microscope and 2.0-megapixel digital camera recording capillaries density, giant capillaries, enlarged capillaries, capillaries hemorrhages, avascular areas, ramified/bushy capillaries scores. Data were recorded and presented as mean ± standard deviation. Statistical analyses were performed using the Student's t-test, ANOVA test, and Pearson's correlation. Differences were considered statistically significant if p-value < 0.05. RESULTS: Among the MCTD patients, PAH was identified in 12 patients (46.15%), while among the SSc patients PAH was identified in 14 patients (53.84%). Development of PAH in MCTD patients was associated with lower capillaries density (p-value < 0.00001), higher scores of giant capillaries, ramified/bushy capillaries, and capillary hemorrhages (p-value < 0.00001, for each of them). Anti-U1-RNP, aCL, aß2GPI antibodies and LAC were also found to be involved in PAH-associated MCTD development. Unlike MCTD patients, SSc patients with PAH presented with lower capillaries density and ramified/bushy capillaries scores (p-value < 0.05). CONCLUSIONS: The MCTD patients who presented significant NFC abnormalities (especially active and late scleroderma-like capillaroscopic pattern) are prone to PAH development. Capillary density reduction is the most important factor associated with the occurrence of PAH. Differences in NFC findings (especially capillary density and ramified/bushy capillaries) were detected among patients with MCTD and SSc having PAH.


Assuntos
Síndrome Antifosfolipídica , Hipertensão Pulmonar , Doença Mista do Tecido Conjuntivo , Hipertensão Arterial Pulmonar , Escleroderma Sistêmico , Humanos , Hipertensão Pulmonar/diagnóstico por imagem , Angioscopia Microscópica , Doença Mista do Tecido Conjuntivo/complicações , Estudos Transversais , Escleroderma Sistêmico/complicações , Imunoglobulina G , Hemorragia , Imunoglobulina M
3.
Eur Rev Med Pharmacol Sci ; 28(4): 1624-1631, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38436195

RESUMO

OBJECTIVE: Cancer patients are among the high-risk groups where COVID-19 infection tends to be severe and can lead to increased mortality. Therefore, they are included in the priority groups for COVID-19 vaccination. This study aimed to compare the levels of SARS-CoV-2 immunoglobulin G (IgG) antibodies following two different COVID-19 vaccinations between hematology-oncology patients and healthcare personnel and to identify factors associated with these antibody levels. PATIENTS AND METHODS: A prospective study was conducted with 91 hematology-oncology patients (cancer group) and 75 healthcare personnel (control group) from January 2020 to June 2023. The cancer and control groups comprised adults who had received a booster dose, with either a single dose of BNT162b2 or two doses of CoronaVac™ spaced one month apart, following their primary vaccination with two doses of either CoronaVac™ or BNT162b2. Four weeks after the administration of the booster dose, levels of SARS-CoV-2 IgG antibodies were assessed using an ELISA kit. Antibody levels above 50 AU/mL were accepted as signifying seropositivity. RESULTS: The median SARS-CoV-2 IgG antibody level was lower in the cancer group compared to the control group (4,509 vs. 7,268, p = 0.004), while the rate of seroconversion was similar between the groups (97.8% vs. 100%, p = 0.564). In the cancer group, no association was found between SARS-CoV-2 IgG antibody levels and age, sex, comorbidity, type of malignancy, stage and duration, or type of vaccine. CONCLUSIONS: In cancer patients, the seroconversion positivity rate was about 98%. However, antibody responses were still lower compared to the control group. No difference was detected in antibody levels among cancer patients based on the type of vaccine.


Assuntos
COVID-19 , Neoplasias , Adulto , Humanos , Vacina BNT162 , Vacinas contra COVID-19 , SARS-CoV-2 , Estudos Prospectivos , COVID-19/prevenção & controle , Vacinação , Anticorpos Antivirais , Imunoglobulina G
4.
J Med Virol ; 96(3): e29479, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38425270

RESUMO

Infection with influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a significant risk to human life, health, and the global economy. Vaccination is one of the most effective strategies in the fight against infectious viruses. In this study, we, for the first time, have evaluated the immunogenicity and protective effect of an influenza/SARS-CoV-2 Omicron subunit combined vaccine adjuvanted with MF59 and administered to BALB/c mice. Results showed that the combined vaccine induced high levels of IgG, IgG1 , and IgG2a antibodies, as well as influenza A H1N1/California/2009 virus-specific hemagglutination-inhibiting antibodies in BALB/c mice. Moreover, this subunit combined vaccine induced high titers of neutralization antibodies against SARS-CoV-2 Omicron sublineage BA.5 pseudovirus and effectively reduced the viral load of authentic SARS-CoV-2 Omicron sublineage BA.5.2 in the cell culture supernatants. These results suggested that this subunit combined vaccine achieved protective effect against both H1N1 A/California/07/2009 strain and SARS-CoV-2 Omicron BA.5.2 variant. It is therefore expected that this study will establish the scientific foundation for the next-step development of combined vaccines against other strains or variants of IAV and SARS-CoV-2.


Assuntos
COVID-19 , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A , Vacinas contra Influenza , Influenza Humana , Animais , Camundongos , Humanos , SARS-CoV-2 , Camundongos Endogâmicos BALB C , COVID-19/prevenção & controle , Vacinas Combinadas , Imunoglobulina G , Anticorpos Antivirais , Anticorpos Neutralizantes
5.
Methods Mol Biol ; 2761: 1-26, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38427225

RESUMO

Detection of merely apoptosis does not reveal the type of central nervous system (CNS) cells that are dying in the CNS diseases and injuries. In situ detection and estimation of amount of apoptosis specifically in neurons or glial cells (astrocytes, oligodendrocytes, and microglia) can unveil valuable information for designing therapeutics for protection of the CNS cells and functional recovery. A method was first developed and reported from our laboratory for in situ detection and estimation of amount of apoptosis precisely in neurons and glial cells using in vitro and in vivo models of CNS diseases and injuries. This is a combination of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and double immunofluorescent labeling (DIFL) or simply TUNEL-n-DIFL method for in situ detection and estimation of amount of apoptosis in a specific CNS cell type. An anti-digoxigenin (DIG) IgG antibody conjugated with 7-amino-4-methylcoumarin-3-acetic acid (AMCA) for blue fluorescence, fluorescein isothiocyanate (FITC) for green fluorescence, or Texas Red (TR) for red fluorescence can be used for in situ detection of apoptotic cell DNA, which is earlier labeled with TUNEL using alkali-stable DIG-11-dUTP. A primary anti-NeuN (neurons), anti-GFAP (astrocytes), anti-MBP (oligodendrocytes), or anti-OX-42 (microglia) IgG antibody and a secondary IgG antibody conjugated with one of the above fluorophores (other than that of ani-DIG antibody) are used for in situ detection of apoptosis in a specific CNS cell type in the mixed culture and animal models of the CNS diseases and injuries.


Assuntos
Apoptose , Doenças do Sistema Nervoso Central , Animais , Marcação In Situ das Extremidades Cortadas , Apoptose/genética , Neuroglia , Neurônios/metabolismo , Doenças do Sistema Nervoso Central/metabolismo , Modelos Animais de Doenças , Imunoglobulina G/metabolismo
6.
Ophthalmic Plast Reconstr Surg ; 40(2): e58-e62, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38427841

RESUMO

IgG4-related disease is an uncommon multisystem inflammatory disease characterized by tissue infiltration by IgG4 plasma cells, extensive fibrosis, and sclerosing inflammation. Diffuse orbital involvement extending to the orbital apex and cavernous sinus has been reported, but a solitary well-circumscribed lesion at the apex has not been previously reported. Herein, we report a unique case of IgG4-related orbital disease presenting as a solitary well-circumscribed orbital apex lesion causing subacute visual decline in a 45-year-old male. MRI demonstrated bilateral lacrimal gland and infraorbital nerve enlargement and an 18 × 7 mm left orbital apex lesion demonstrating homogeneous contrast enhancement and isointense signal on T2. He was initially treated with tapering systemic corticosteroid therapy with improvement in his vision; however, he experienced visual deterioration 3 months later with recurrent inflammation. He subsequently commenced high-dose systemic corticosteroid therapy and rituximab infusions with improvement of left visual acuity to 6/7.5 + 2.


Assuntos
Doença Relacionada a Imunoglobulina G4 , Doenças Orbitárias , Masculino , Humanos , Pessoa de Meia-Idade , Doença Relacionada a Imunoglobulina G4/complicações , Doença Relacionada a Imunoglobulina G4/diagnóstico , Imunoglobulina G , Doenças Orbitárias/diagnóstico , Doenças Orbitárias/tratamento farmacológico , Corticosteroides , Inflamação
7.
Front Immunol ; 15: 1358178, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38469303

RESUMO

The prevalence of food allergy is rising and is estimated to approach 10%. Red meat allergy is the first known food allergy elicited by immunoglobulin E (IgE) antibodies recognizing a carbohydrate. Due to the loss of function of the alpha-1,3-galactosyltransferase (GGTA1) gene in humans, the disaccharide galactose-α-1,3-galactose (α-Gal) cannot be synthesized and therefore became immunogenic. IgE sensitization is elicited through the skin by repetitive tick bites transmitting α-Gal. The underlying mechanisms regarding innate and adaptive immune cell activation, including the B-cell isotype switch to IgE, are poorly understood, requiring further research and physiologically relevant animal models. Here, we describe a new animal model of red meat allergy using percutaneous α-Gal sensitization of gene-edited GGTA1-deficient pigs. Total and α-Gal-specific IgG, IgG1, IgG2, IgG4, and IgE levels were tracked. Further key factors associated with allergic skin inflammation, type 2 immunity, and allergy development were measured in PBMCs and skin samples. Significant increases in α-Gal-specific IgG1 and IgE levels indicated successful sensitization to the allergen α-Gal. Intracutaneous sensitizations with α-Gal recruited lymphocytes to the skin, including elevated numbers of T helper 2 (Th2) cells. Finally, α-Gal-sensitized pigs not only recognized α-Gal as non-self-antigen following α-Gal exposure through the skin but also developed anaphylaxis upon antigen challenge. Based on the similarities between the porcine and human skin, this new large animal model for α-Gal allergy should help to unveil the consecutive steps of cutaneous sensitization and aid the development of prophylactic and treatment interventions.


Assuntos
Anafilaxia , Hipersensibilidade Alimentar , Humanos , Animais , Suínos , Galactose , Edição de Genes , Imunoglobulina E , Imunoglobulina G
8.
Front Immunol ; 15: 1347871, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38469305

RESUMO

The antibody- FcγRIIIa interaction triggers key immunological responses such as antibody dependent cellular cytotoxicity (ADCC), making it highly important for therapeutic mAbs. Due to the direct glycan-glycan interaction with FcγRIIIa receptor, differences in antibody glycosylation can drastically influence the binding affinity. Understanding the differential binding of mAb glycoforms is a very important, yet challenging task due to the co-existence of multiple glycoforms in a sample. Affinity liquid chromatography (AC) and affinity capillary electrophoresis (ACE) hyphenated with mass spectrometry (MS) can provide glycoform-resolved affinity profiles of proteins based on their differences in either dissociation (AC) or equilibrium (ACE) constants. To cross-validate the affinity ranking provided by these complementary novel approaches, both techniques were benchmarked using the same FcγRIIIa constructs. Both approaches were able to assess the mAb - FcγRIIIa interaction in a glycoform selective manner and showed a clear increase in binding for fully versus hemi-fucosylated mAbs. Also, other features, such as increasing affinity with elevated galactosylation or the binding affinity for high mannose glycoforms were consistent. We further applied these approaches to assess the binding towards the F158 allotype of FcγRIIIa, which was not reported before. The FcγRIIIa F158 allotype showed a very similar profile compared to the V158 receptor with the strongest increase in binding due to afucosylation and only a slight increase in binding with additional galactosylation. Both techniques showed a decrease of the binding affinity for high mannose glycoforms for FcγRIIIa F158 compared to the V158 variant. Overall, both approaches provided very comparable results in line with orthogonal methods proving the capabilities of separation-based affinity approaches to study FcγR binding of antibody glycoforms.


Assuntos
Imunoglobulina G , Receptores de IgG , Receptores de IgG/metabolismo , Imunoglobulina G/metabolismo , Manose , Benchmarking , Anticorpos Monoclonais/metabolismo , Polissacarídeos/metabolismo , Espectrometria de Massas
9.
Ren Fail ; 46(1): 2323160, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38466632

RESUMO

Anti-glomerular basement membrane (GBM) disease is a rare autoimmune condition characterized by the presence of positive anti-GBM autoantibodies, linear deposition of immunoglobulin G (IgG) along the GBM and severe kidney injury. In a limited number of cases, the association of anti-GBM disease with other glomerulonephritis has been reported. Herein, we present the case of a 66-year-old female patient with progressive worsen kidney function and decreased urine output. A renal biopsy revealed crescent glomerulonephritis with lineal IgG deposition along the GBM and mesangial IgA deposition, which supported the diagnosis of concurrent anti-GBM disease and IgA nephropathy (IgAN). In an extensive literature review, we identified a total of thirty-nine patients were reported anti-GBM disease combined with IgAN. The clinical characteristics of these patients demonstrate that the anti-GBM disease combined with IgAN tends to be milder with a more indolent course and a better prognosis than the classic anti-GBM disease, and its potential pathogenesis deserves to be further explored.


Assuntos
Doença Antimembrana Basal Glomerular , Glomerulonefrite por IGA , Glomerulonefrite , Feminino , Humanos , Idoso , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/diagnóstico , Doença Antimembrana Basal Glomerular/complicações , Doença Antimembrana Basal Glomerular/diagnóstico , Autoanticorpos , Imunoglobulina G
10.
BMC Neurosci ; 25(1): 16, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38468222

RESUMO

BACKGROUND: Myelin oligodendrocyte glycoprotein-associated disorders (MOGAD) is an autoimmune central nervous system disease. Antigen-specific immune tolerance using nanoparticles such as Polylactic-co-glycolic acid (PLGA) have recently been used as a new therapeutic tolerization approach for CNS autoimmune diseases. We examined whether MOG1-125 conjugated with PLGA could induce MOG-specific immune tolerance in an experimental autoimmune encephalitis (EAE) mouse model. EAE was induced in sixty C57BL/6 J wild-type mice using MOG1-125 peptide with complete Freund's Adjuvant. The mice were divided into 12 groups (n = 5 each) to test the ability of MOG1-125 conjugated PLGA intervention to mitigate the severity or improve the outcomes from EAE with and without rapamycin compared to antigen alone or PLGA alone. EAE score and serum MOG-IgG titers were compared among the interventions.Kindly check and confirm the processed Affiliation “4” is appropriate.I confirmed the Aff 4.Affiliation: Corresponding author information have been changed to present affiliation. Kindly check and confirm.I checked and confirmed the Corresponding author's information. RESULTS: Mice with EAE that were injected intraperitoneally with MOG1-125 conjugated PLGA + rapamycin complex showed dose-dependent mitigation of EAE score. Intraperitoneal and intravenous administration resulted in similar clinical outcomes, whereas 80% of mice treated with subcutaneous injection had a recurrence of clinical score worsening after approximately 1 week. Although there was no significant difference in EAE scores between unconjugated-PLGA and MOG-conjugated PLGA, serum MOG-IgG tended to decrease in the MOG-conjugated PLGA group compared to controls. CONCLUSION: Intraperitoneal administration of PLGA resulted in dose-dependent and longer-lasting immune tolerance than subcutaneous administration. The induction of immune tolerance using PLGA may represent a future therapeutic option for patients with MOGAD.


Assuntos
Encefalite , Encefalomielite Autoimune Experimental , Doença de Hashimoto , Poliésteres , Humanos , Camundongos , Animais , Glicoproteína Mielina-Oligodendrócito/efeitos adversos , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/tratamento farmacológico , Camundongos Endogâmicos C57BL , Glicóis/efeitos adversos , Sirolimo/farmacologia , Imunoglobulina G/efeitos adversos
11.
Int J Mol Sci ; 25(5)2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38473808

RESUMO

Antibodies to DNA are a diverse set of antibodies that bind sites on DNA, a polymeric macromolecule that displays various conformations. In a previous study, we showed that sera of normal healthy subjects (NHS) contain IgG antibodies to Z-DNA, a left-handed helix with a zig-zig backbone. Recent studies have demonstrated the presence of Z-DNA in bacterial biofilms, suggesting a source of this conformation to induce responses. To characterize further antibodies to Z-DNA, we used an ELISA assay with brominated poly(dGdC) as a source of Z-DNA and determined the isotype of these antibodies and their binding properties. Results of these studies indicate that NHS sera contain IgM and IgA as well as IgG anti-Z-DNA antibodies. As shown by the effects of ionic strength in association and dissociation assays, the anti-Z-DNA antibodies bind primarily by electrostatic interactions; this type of binding differs from that of induced anti-Z-DNA antibodies from immunized animals which bind by non-ionic interactions. Furthermore, urea caused dissociation of NHS anti-Z-DNA at molar concentrations much lower than those for the induced antibodies. These studies also showed IgA anti-Z-DNA antibodies in fecal water. Together, these studies demonstrate that antibodies to Z-DNA occur commonly in normal immunity and may arise as a response to Z-DNA of bacterial origin.


Assuntos
DNA Forma Z , Animais , Humanos , Voluntários Saudáveis , Anticorpos Antinucleares , Imunoglobulina G , Imunoglobulina A
12.
MAbs ; 16(1): 2303781, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38475982

RESUMO

Early identification of antibody candidates with drug-like properties is essential for simplifying the development of safe and effective antibody therapeutics. For subcutaneous administration, it is important to identify candidates with low self-association to enable their formulation at high concentration while maintaining low viscosity, opalescence, and aggregation. Here, we report an interpretable machine learning model for predicting antibody (IgG1) variants with low viscosity using only the sequences of their variable (Fv) regions. Our model was trained on antibody viscosity data (>100 mg/mL mAb concentration) obtained at a common formulation pH (pH 5.2), and it identifies three key Fv features of antibodies linked to viscosity, namely their isoelectric points, hydrophobic patch sizes, and numbers of negatively charged patches. Of the three features, most predicted antibodies at risk for high viscosity, including antibodies with diverse antibody germlines in our study (79 mAbs) as well as clinical-stage IgG1s (94 mAbs), are those with low Fv isoelectric points (Fv pIs < 6.3). Our model identifies viscous antibodies with relatively high accuracy not only in our training and test sets, but also for previously reported data. Importantly, we show that the interpretable nature of the model enables the design of mutations that significantly reduce antibody viscosity, which we confirmed experimentally. We expect that this approach can be readily integrated into the drug development process to reduce the need for experimental viscosity screening and improve the identification of antibody candidates with drug-like properties.


Assuntos
Anticorpos Monoclonais , Imunoglobulina G , Anticorpos Monoclonais/química , Viscosidade , Imunoglobulina G/química , Mutação , Ponto Isoelétrico
13.
AAPS J ; 26(2): 33, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38478197

RESUMO

The clinical use of therapeutic monoclonal antibodies (mAbs) for the treatment of cancer, inflammation, and other indications has been successfully established. A critical aspect of drug-antibody pharmacokinetics is immunogenicity, which triggers an immune response via an anti-drug antibody (ADA) and forms drug/ADA immune complexes (ICs). As a consequence, there may be a reduced efficacy upon neutralization by ADA or an accelerated drug clearance. It is therefore important to understand immunogenicity in biological therapies. A drug-like immunoglobulin G (IgG) was radiolabeled with tritium, and ICs were formed using polyclonal ADA, directed against the complementary-determining region of the drug-IgG, to investigate in vivo biodistribution in rodents. It was demonstrated that 65% of the radioactive IC dose was excreted within the first 24 h, compared with only 6% in the control group who received non-complexed 3H-drug. Autoradiographic imaging at the early time point indicated a deposition of immune complexes in the liver, lung, and spleen indicated by an increased radioactivity signal. A biodistribution study confirmed the results and revealed further insights regarding excretion and plasma profiles. It is assumed that the immune complexes are readily taken up by the reticuloendothelial system. The ICs are degraded proteolytically, and the released radioactively labeled amino acids are redistributed throughout the body. These are mainly renally excreted as indicated by urine measurements or incorporated into protein synthesis. These biodistribution studies using tritium-labeled immune complexes described in this article underline the importance of understanding the immunogenicity induced by therapeutic proteins and the resulting influence on biological behavior.


Assuntos
Anticorpos Monoclonais , Complexo Antígeno-Anticorpo , Distribuição Tecidual , Trítio , Imunoglobulina G
14.
Front Immunol ; 15: 1329805, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38481993

RESUMO

mRNA vaccine technologies introduced following the SARS-CoV-2 pandemic have highlighted the need to better understand the interaction of adjuvants and the early innate immune response. Type I interferon (IFN-I) is an integral part of this early innate response that primes several components of the adaptive immune response. Women are widely reported to respond better than men to tri- and quadrivalent influenza vaccines. Plasmacytoid dendritic cells (pDCs) are the primary cell type responsible for IFN-I production, and female pDCs produce more IFN-I than male pDCs since the upstream pattern recognition receptor Toll-like receptor 7 (TLR7) is encoded by X chromosome and is biallelically expressed by up to 30% of female immune cells. Additionally, the TLR7 promoter contains several putative androgen response elements, and androgens have been reported to suppress pDC IFN-I in vitro. Unexpectedly, therefore, we recently observed that male adolescents mount stronger antibody responses to the Pfizer BNT162b2 mRNA vaccine than female adolescents after controlling for natural SARS-CoV-2 infection. We here examined pDC behaviour in this same cohort to determine the impact of IFN-I on anti-spike and anti-receptor-binding domain IgG titres to BNT162b2. Through flow cytometry and least absolute shrinkage and selection operator (LASSO) modelling, we determined that serum-free testosterone was associated with reduced pDC IFN-I, but contrary to the well-described immunosuppressive role for androgens, the most bioactive androgen dihydrotestosterone was associated with increased IgG titres to BNT162b2. Also unexpectedly, we observed that co-vaccination with live attenuated influenza vaccine boosted the magnitude of IgG responses to BNT162b2. Together, these data support a model where systemic IFN-I increases vaccine-mediated immune responses, yet for vaccines with intracellular stages, modulation of the local IFN-I response may alter antigen longevity and consequently improve vaccine-driven immunity.


Assuntos
Vacinas contra Influenza , Interferon Tipo I , Humanos , Masculino , Feminino , Adolescente , Interferon-alfa , Vacinas contra Influenza/metabolismo , Receptor 7 Toll-Like/metabolismo , Androgênios/metabolismo , Vacina BNT162 , Vacinas de mRNA , Interferon Tipo I/metabolismo , Vacinação , Células Dendríticas , Imunoglobulina G/metabolismo
15.
Front Immunol ; 15: 1322879, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38482020

RESUMO

Orf virus (ORFV) is a large DNA virus that can harbor and efficiently deliver viral antigens in swine. Here we used ORFV as a vector platform to deliver chimeric hemagglutinins (HA) of Influenza A virus of swine (IAV-S). Vaccine development against IAV-S faces limitations posed by strain-specific immunity and the antigenic diversity of the IAV-S strains circulating in the field. A promising alternative aiming at re-directing immune responses on conserved epitopes of the stalk segment of the hemagglutinin (HA2) has recently emerged. Sequential immunization with chimeric HAs comprising the same stalk but distinct exotic head domains can potentially induce cross-reactive immune responses against conserved epitopes of the HA2 while breaking the immunodominance of the head domain (HA1). Here, we generated two recombinant ORFVs expressing chimeric HAs encoding the stalk region of a contemporary H1N1 IAV-S strain and exotic heads derived from either H6 or H8 subtypes, ORFVΔ121cH6/1 and ORFVΔ121cH8/1, respectively. The resulting recombinant viruses were able to express the heterologous protein in vitro. Further, the immunogenicity and cross-protection of these vaccine candidates were assessed in swine after sequential intramuscular immunization with OV-cH6/1 and OV-cH8/1, and subsequent challenge with divergent IAV-S strains. Humoral responses showed that vaccinated piglets presented increasing IgG responses in sera. Additionally, cross-reactive IgG and IgA antibody responses elicited by immunization were detected in sera and bronchoalveolar lavage (BAL), respectively, by ELISA against different viral clades and a diverse range of contemporary H1N1 IAV-S strains, indicating induction of humoral and mucosal immunity in vaccinated animals. Importantly, viral shedding was reduced in nasal swabs from vaccinated piglets after intranasal challenge with either Oh07 (gamma clade) or Ca09 (npdm clade) IAV-S strains. These results demonstrated the efficiency of ORFV-based vectors in delivering chimeric IAV-S HA-based vaccine candidates and underline the potential use of chimeric-HAs for prevention and control of influenza in swine.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza , Vírus do Orf , Infecções por Orthomyxoviridae , Animais , Suínos , Hemaglutininas/genética , Infecções por Orthomyxoviridae/prevenção & controle , Vírus da Influenza A Subtipo H1N1/genética , Anticorpos Antivirais , Imunoglobulina G , Epitopos
16.
Radiol Cardiothorac Imaging ; 6(2): e230105, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38483247

RESUMO

Immunoglobulin 4 (IgG4)-related disease is a chronic immune-mediated fibroinflammatory disorder. Involvement of the vascular system, including large- and medium-sized vessels, is increasingly recognized. The varied appearances of vascular involvement reflect the sequela of chronic inflammation and fibrosis and can include aortitis and periaortitis with resultant complications such as aneurysm formation and dissection. A diagnosis of IgG4-related large vessel involvement should be considered when there is known or suspected IgG4-related disease elsewhere. Other organs that are typically affected in IgG4-related disease include the lacrimal and salivary glands, thyroid, pancreas, biliary tree, lungs, kidneys, and meninges. Diagnosis typically requires careful correlation with clinical, imaging, serum, and pathologic findings. Patients may be managed with corticosteroid therapy or the anti-CD20 monoclonal antibody, rituximab, if needed. The varied clinical presentations and imaging features of large vessel involvement are discussed herein. Keywords: Vascular, Inflammation, Aorta, IgG4-related Vessel Involvement © RSNA, 2024.


Assuntos
Doença Relacionada a Imunoglobulina G4 , Humanos , Doença Relacionada a Imunoglobulina G4/diagnóstico por imagem , Imunoglobulina G , Imagem Multimodal , Aorta , Inflamação
17.
Parasit Vectors ; 17(1): 121, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38468307

RESUMO

BACKGROUND: Onchocerciasis is endemic in 14 of Sierra Leone's 16 districts with high prevalence (47-88.5%) according to skin snips at baseline. After 11 rounds of mass treatment with ivermectin with good coverage, an impact assessment was conducted in 2017 to assess the progress towards eliminating onchocerciasis in the country. METHODS: A cluster survey was conducted, either integrated with lymphatic filariasis (LF) transmission assessment survey (TAS) or standalone with the LF TAS sampling strategy in 12 (now 14) endemic districts. Finger prick blood samples of randomly selected children in Grades 1-4 were tested in the field using SD Bioline Onchocerciasis IgG4 rapid tests. RESULTS: In total, 17,402 children aged 4-19 years in 177 schools were tested, and data from 17,364 children aged 4-14 years (14,230 children aged 5-9 years) were analyzed. Three hundred forty-six children were confirmed positive for Ov-16 IgG4 antibodies, a prevalence of 2.0% (95% CI 1.8-2.2%) in children aged 4-14 years with prevalence increasing with age. Prevalence in boys (2.4%; 95% CI 2.1-2.7%) was higher than in girls (1.6%; 95% CI 1.4-1.9%). There was a trend of continued reduction from baseline to 2010. Using data from children aged 5-9 years, overall prevalence was 1.7% (95% CI 1.5-1.9%). The site prevalence ranged from 0 to 33.3% (median prevalence = 0.0%): < 2% in 127 schools, 2 to < 5% in 34 schools and ≥ 5% in 16 schools. There was a significant difference in average prevalence between districts. Using spatial analysis, the Ov-16 IgG4 antibody prevalence was predicted to be < 2% in coastal areas and in large parts of Koinadugu, Bombali and Tonkolili Districts, while high prevalence (> 5%) was predicted in some focal areas, centered in Karene, Kailahun and Moyamba/Tonkolili. CONCLUSIONS: Low Ov-16 IgG4 antibody prevalence was shown in most areas across Sierra Leone. In particular, low seroprevalence in children aged 5-9 years suggests that the infection was reduced to a low level after 11 rounds of treatment intervention. Sierra Leone has made major progress towards elimination of onchocerciasis. However, attention must be paid to those high prevalence focal areas.


Assuntos
Filariose Linfática , Oncocercose , Criança , Feminino , Humanos , Masculino , Filariose Linfática/diagnóstico , Filariose Linfática/tratamento farmacológico , Filariose Linfática/epidemiologia , Imunoglobulina G , Ivermectina/uso terapêutico , Oncocercose/diagnóstico , Oncocercose/tratamento farmacológico , Oncocercose/epidemiologia , Prevalência , Testes de Diagnóstico Rápido , Estudos Soroepidemiológicos , Serra Leoa/epidemiologia , Pré-Escolar , Adolescente , Adulto Jovem
18.
Trials ; 25(1): 175, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38468338

RESUMO

BACKGROUND: The demand for plasma products is growing, necessitating an increase in plasma collection by plasmapheresis. While the 20th edition of the European Guidelines permits plasma donors in Europe to donate with 96-h donation intervals, the potential short- and long-term consequences of high-frequency plasma donations on donor health remain unknown. This study aims to measure the effect of plasma donation frequency on plasma protein composition, including total serum protein (TSP) and immunoglobulin G (IgG), in Norwegian male blood donors. METHODS: This randomized controlled trial (RCT) included 120 male blood donors who were randomized into two intervention groups and one control group: high-frequency plasma donors (HFPDs) who donated 650 mL of plasma 3 times every 2 weeks, whereas regular-frequency plasma donors (RFPDs) who donated 650 mL of plasma 1 time every 2 weeks. The control group consisted of whole blood donors. The primary outcomes are the concentrations of TSP and IgG. DISCUSSION: The findings from this study may have implications for recommendations related to donor health and plasma donation frequencies and may contribute to supporting the strategic independence of plasma products in Norway and Europe without compromising donor health. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05179200 . Registered December 20th, 2021.


Assuntos
Doadores de Sangue , Plasmaferese , Masculino , Humanos , Plasmaferese/métodos , Imunoglobulina G , Tempo , Europa (Continente) , Ensaios Clínicos Controlados Aleatórios como Assunto
19.
Lupus Sci Med ; 11(1)2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38471722

RESUMO

OBJECTIVE: Celastrol is a bioactive constituent extracted from Tripterygium wilfordii (thunder god vine). It has been demonstrated to have a therapeutic effect on experimental disease models for chronic inflammatory and immune disorders. In the present study, we investigated whether and how celastrol exerts a regulatory effect on the autoimmune response in MRL/lpr mice. METHODS: We performed an in vivo study to determine the therapeutic effects of celastrol in MRL/lpr mice and then further investigated the underlying mechanism of celastrol in the regulation of the autoimmune response in MRL/lpr mice. RESULTS: Celastrol showed a therapeutic effect in MRL/lpr mice by preventing the enlargement of the spleen and lymph nodes, alleviating renal injury, and reducing the levels of ANA and anti-double-stranded DNA antibodies. Furthermore, celastrol suppressed the in vivo inflammatory response in MRL/lpr mice by reducing the serum levels of multiple cytokines, including interleukin (IL)-6, tumour necrosis factor (TNF) and interferon (IFN)-γ, and the production of multiple antibody subsets, including total IgG, IgG1 and IgG2b. In vitro, celastrol reduced anti-CD3 antibody stimulation-induced T helper 1 and TNF-producing cells in CD4+ T cells of MRL/lpr mice. In addition, celastrol significantly affected B cell differentiation and prevented the generation of plasma cells from B cells in MRL/lpr mice by reducing the frequency of activated and germinal centre B cells. Celastrol treatment also affected T cell differentiation and significantly reduced central memory T cell frequencies in MRL/lpr mice. Importantly, celastrol treatment specifically promoted apoptosis of CD138+ but not CD138- T cells to suppress autoimmune T cell accumulation in MRL/lpr mice. CONCLUSIONS: Celastrol exerted therapeutic effects on lupus by specifically promoting apoptosis of autoimmune T cells and preventing the progression of autoimmune response.


Assuntos
Autoimunidade , Lúpus Eritematoso Sistêmico , Triterpenos Pentacíclicos , Camundongos , Animais , Humanos , Camundongos Endogâmicos MRL lpr , Apoptose , Imunoglobulina G
20.
Int J Mol Sci ; 25(5)2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38473828

RESUMO

Limbic encephalitis (LE) due to anti-leucine-rich glioma-inactivated 1 (LGI1) antibodies is an autoimmune disease characterized by distinct clinical features unique to LGI1 LE, such as faciobrachial dystonic seizures. However, it is unclear whether an additional disease-related LGI1 antigen-specific T cell response is involved in the pathogenesis of this disease. To address this question, we studied the effect of recombinant LGI1 on the proliferation and effector-specific cytokine production (IFN-γ, IL-5, IL-10, and IL-17) of peripheral blood mononuclear cells (PBMCs) from patients with LGI1 LE and healthy controls. We observed that recombinant LGI1 stimulated the proliferation of PBMCs from patients with LGI1 LE, but not from healthy controls. Cytokine measurement of cell culture supernatants from PBMCs incubated with recombinant LGI1 revealed a highly significant increase in IL-10 release in PBMCs from patients with LGI1 LE in comparison with healthy controls. These results suggest that LGI1-mediated stimulation of PBMCs from patients with LGI1 LE leads to the establishment of an IL-10-dominated immunosuppressive cytokine milieu, which may inhibit Th1 differentiation and support B cell proliferation, IgG production, and IgG subclass switching.


Assuntos
Doenças Autoimunes do Sistema Nervoso , Glioma , Encefalite Límbica , Humanos , Leucina , Peptídeos e Proteínas de Sinalização Intracelular , Leucócitos Mononucleares/patologia , Interleucina-10 , Imunoglobulina G
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