-
Molecular Therapy : the Journal of the... May 2024Single monoclonal antibodies (mAbs) can be expressed in vivo through gene delivery of their mRNA formulated with liponanoparticles (mRNA/LNP). However, delivery of a mAb...
Single monoclonal antibodies (mAbs) can be expressed in vivo through gene delivery of their mRNA formulated with liponanoparticles (mRNA/LNP). However, delivery of a mAb combination could be challenging due to risk of heavy and light variable chain mispairing. We evaluated the pharmacokinetics of a three mAb combination against Staphylococcus aureus first in single chain variable fragment scFv-Fc and then in immunoglobulin G 1 (IgG1) format in mice. Intravenous delivery of each mRNA/LNP or the trio (1 mg/kg each) induced functional antibody expression after 24 hours (10-100 μg/ml) with 64 to 78% cognate-chain paired IgG expression after 3 days, and an absence of non-cognate chain pairing for scFv-Fc. We did not observe reduced neutralizing activity for each mAb compared to the level of expression of chain-paired mAbs. Delivery of the trio mRNA protected mice in a S. aureus induced dermonecrosis model. Intravenous administration of the three mRNA in non-human primates achieved peak serum IgG levels ranging between 2.9-13.7 μg/ml with a half-life of 11.8-15.4 days. These results suggest nucleic acid delivery of mAb combinations holds promise and may be a viable option to streamline development of therapeutic antibodies.
PubMed: 38822525
DOI: 10.1016/j.ymthe.2024.05.036 -
PloS One 2024Considering the differences in molecular structure and function, the effects of β-1,3-glucans from Euglena gracilis and β-1,3/1,6-glucans from Saccharomyces cerevisiae...
Considering the differences in molecular structure and function, the effects of β-1,3-glucans from Euglena gracilis and β-1,3/1,6-glucans from Saccharomyces cerevisiae on immune and inflammatory activities in dogs were compared. Four diets were compared: control without β-glucans (CON), 0.15 mg/kg BW/day of β-1,3/1,6-glucans (Β-Y15), 0.15 mg/kg BW/day of β-1,3-glucans (Β-S15), and 0.30 mg/kg BW/day of β-1,3-glucans (Β-S30). Thirty-two healthy dogs (eight per diet) were organized in a block design. All animals were fed CON for a 42-day washout period and then sorted into one of four diets for 42 days. Blood and faeces were collected at the beginning and end of the food intake period and analysed for serum and faecal cytokines, ex vivo production of hydrogen peroxide (H2O2) and nitric oxide (NO), phagocytic activity of neutrophils and monocytes, C-reactive protein (CRP), ex vivo production of IgG, and faecal concentrations of IgA and calprotectin. Data were evaluated using analysis of covariance and compared using Tukey's test (P<0.05). Dogs fed Β-Y15 showed higher serum IL-2 than dogs fed Β-S30 (P<0.05). A higher phagocytic index of monocytes was observed in dogs fed the B-S15 diet than in those fed the other diets, and a higher neutrophil phagocytic index was observed for B-S15 and B-Y15 than in dogs fed the CON diet (P<0.05). Monocytes from dogs fed B-S15 and B-S30 produced more NO and less H2O2 than those from the CON and B-Y15 groups (P<0.05). Despite in the reference value, CRP levels were higher in dogs fed B-S15 and B-S30 diets (P<0.05). β-1,3/1,6-glucan showed cell-mediated activation of the immune system, with increased serum IL-2 and neutrophil phagocytic index, whereas β-1,3-glucan acted on the immune system by increasing the ex vivo production of NO by monocytes, neutrophil phagocytic index, and serum CRP. Calprotectin and CRP levels did not support inflammation or other health issues related to β-glucan intake. In conclusion, both β-glucan sources modulated some immune and inflammatory parameters in dogs, however, different pathways have been suggested for the recognition and action of these molecules, reinforcing the necessity for further mechanistic studies, especially for E. gracilis β-1,3-glucan.
Topics: Animals; Dogs; Euglena gracilis; beta-Glucans; Saccharomyces cerevisiae; Feces; Inflammation; Male; Nitric Oxide; Cytokines; C-Reactive Protein; Hydrogen Peroxide; Phagocytosis; Neutrophils; Female; Immunoglobulin G; Glucans; Monocytes
PubMed: 38820480
DOI: 10.1371/journal.pone.0304833 -
PloS One 2024Health personnel (HP) are on the frontlines during response to public health emergencies like COVID-19. This risk of exposure suggests the need for safety in responding...
SARS-CoV-2 active infection and antibodies amongst health personnel during the outbreak in Cameroon: Strengthening the health system for response to future public health emergencies.
BACKGROUND
Health personnel (HP) are on the frontlines during response to public health emergencies like COVID-19. This risk of exposure suggests the need for safety in responding to any pandemic. Therefore, to ascertain the rate of SARS-CoV-2 infection and immunity, and their determinants amongst HP become relevant.
METHODS
A cross sectional health facility-based study was carried-out amongst HP in the Centre Region of Cameroon from 1st February to 30th June 2021. Characteristics and access to preventive tools were collected using face-to-face administered questionnaire. Nasopharyngeal swabs and whole blood were collected for PCR, IgG and IgM testing respectively. STATA version 17 software was used for data analysis. Determinants of COVID-19 infection were explored by estimating crude and adjusted Odd Ratio.
RESULTS
Out of 510 HP reached, 458 were enrolled with mean age of 35 (±10) years. Thirty-four (7.4%) were PCR-positive to SARS-CoV-2 with 73.5% being clinicians versus 9 (26.4%) non-clinicians (p = 0.05). Sero-positivity to SARS-CoV-2 IgG/IgM was 40.2% (184/458), with 84.2% being clinicians versus 29 (15.8%) non-clinicians (p = 0.733). Amongst the 34 HP with PCR-positivity, 16 (47%) had no antibodies, while, 15 (44%) were IgG only. An estimate of HP (43.7%) had at least an evidence of PCR, IgG or IgM contact to COVID-19. Determinants of PCR-positivity was being clinical staff (AOR = 0.29, P = 0.039); and that of IgG/IgM were being non clinical staff (AOR = 0.41, p = 0.018) and regular use of face masks (AOR = 0.44, p = 0.001). HP trained on IPC (24%) were mainly from peripheral level (74.7%, p = 0.002).
CONCLUSION
Active infections were within the range of pandemic control (<10%). However, around two-fifths of participants have had contact with the virus, indicating that HP remains a population at risk of COVID-19 and other similarly-transmitted epidemic prone diseases, and also an important source of transmission. There is need of vaccine to achieve protectiveness, and optimal response also requires capacity building to improve the health system when challenged by a future pandemic.
Topics: Humans; COVID-19; Cameroon; Health Personnel; Male; Adult; Female; SARS-CoV-2; Cross-Sectional Studies; Antibodies, Viral; Middle Aged; Public Health; Disease Outbreaks; Immunoglobulin G; Immunoglobulin M
PubMed: 38820301
DOI: 10.1371/journal.pone.0304477 -
The Journal of Experimental Medicine Aug 2024Th17 cell plasticity is crucial for development of autoinflammatory disease pathology. Periodontitis is a prevalent inflammatory disease where Th17 cells mediate key...
Th17 cell plasticity is crucial for development of autoinflammatory disease pathology. Periodontitis is a prevalent inflammatory disease where Th17 cells mediate key pathological roles, yet whether they exhibit any functional plasticity remains unexplored. We found that during periodontitis, gingival IL-17 fate-mapped T cells still predominantly produce IL-17A, with little diversification of cytokine production. However, plasticity of IL-17 fate-mapped cells did occur during periodontitis, but in the gingiva draining lymph node. Here, some Th17 cells acquired features of Tfh cells, a functional plasticity that was dependent on IL-6. Notably, Th17-to-Tfh diversification was important to limit periodontitis pathology. Preventing Th17-to-Tfh plasticity resulted in elevated periodontal bone loss that was not simply due to increased proportions of conventional Th17 cells. Instead, loss of Th17-to-Tfh cells resulted in reduced IgG levels within the oral cavity and a failure to restrict the biomass of the oral commensal community. Thus, our data identify a novel protective function for a subset of otherwise pathogenic Th17 cells during periodontitis.
Topics: Th17 Cells; Animals; Periodontitis; Cell Plasticity; Interleukin-17; Mice; Interleukin-6; Mice, Inbred C57BL; T Follicular Helper Cells; Gingiva; Immunoglobulin G; Alveolar Bone Loss
PubMed: 38819409
DOI: 10.1084/jem.20232015 -
Frontiers in Pediatrics 2024Children with autoimmune hepatitis (AIH) often present with symptoms similar to those of other liver diseases. This study consists of a comparison between the clinical...
BACKGROUND
Children with autoimmune hepatitis (AIH) often present with symptoms similar to those of other liver diseases. This study consists of a comparison between the clinical and histological characteristics of AIH and those of other four AIH-like liver diseases [i.e, drug-induced liver injury (DILI), gene deficiency, infectious liver disease and other etiology of liver disease], as well as an evaluation of the AIH scoring system's diagnostic performance.
METHODS
All children with AIH-like liver disease at our center from January 2013 to December 2022 were included. The clinical and histological characteristics of the AIH group were retrospectively analyzed and compared with those of the other four groups.
RESULTS
A total of 208 children were included and divided into AIH group (18 patients), DILI group (38 patients), gene deficiency group (44 patients), infectious liver disease group (74 patients), and other etiology group (34 patients). The antinuclear antibodies (ANA) ≥ 1:320 rate was significantly higher in the AIH compared to the other four groups after multiple testing correction (< 0.0125), while patients with positive antibodies to liver-kidney microsomal-1 (anti-LKM1, = 3) and smooth muscle antibodies (SMA, = 2) were only observed in the AIH group. The positive rates of antibodies to liver cytosol type1 (anti-LC1) and Ro52 were higher than those in the other four groups. The serum immunoglobulin G (IgG) and globulin levels, as well as the proportions of portal lymphoplasmacytic infiltration, lobular hepatitis with more than moderate interface hepatitis, and lobular hepatitis with lymphoplasmacytic infiltration, were significantly higher in the AIH group than in the other four groups after multiple testing correction (< 0.0125). The cirrhosis rate in the AIH group was higher than that in the DILI and infectious liver disease groups (< 0.0125). Both the simplified (AUC > 0.73) and the revised systems (AUC > 0.93) for AIH have good diagnostic performance, with the latter being superior (< 0.05).
CONCLUSION
Positive autoantibodies (ANA ≥ 1:320 or anti-LKM1 positive, or accompanied by SMA, anti-LC1 or Ro-52 positive) and elevated serum IgG or globulin levels contribute to early recognition of AIH. The presence of lobular hepatitis with more than moderate interface hepatitis and lymphoplasmacytic infiltration contribute to the diagnosis of AIH.
PubMed: 38818349
DOI: 10.3389/fped.2024.1377333 -
Wellcome Open Research 2024We have previously demonstrated that older residents of long-term care facilities (LTCF) in the UK show levels of anti-spike antibodies that are comparable to the...
BACKGROUND
We have previously demonstrated that older residents of long-term care facilities (LTCF) in the UK show levels of anti-spike antibodies that are comparable to the general population following primary series and booster vaccination for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, data on the humoral response to other SARS-CoV-2 proteins associated with natural infection are scarce in this vulnerable population.
METHODS
We measured quantitative levels of anti-nucleocapsid antibodies in blood samples taken from LTCF residents and staff after initial and repeat SARS-CoV-2 infections, between December 2020 and March 2023. Data on SARS-CoV-2 infection and vaccination were obtained through linkage to national datasets. Linear mixed effects models were used to investigate anti-nucleocapsid antibody levels, using log10 scale, in relation to time from most recent infection. This included evaluation of associations between repeat infection, staff/resident status, age, sex, Omicron infection and vaccination history and peak antibody level and slope of decline with time.
RESULTS
We analysed 405 antibody observations from 220 residents and 396 observations from 215 staff. Repeat infection was associated with 8.5-fold (95%CI 4.9-14.8-fold) higher initial (peak) median anti-nucleocapsid antibody level, with steeper subsequent slope of decline. There were no significant differences in antibody level associated with resident (vs. staff) status or age, but Omicron infection was associated with 3.6-fold (95%CI 2.4-5.4-fold) higher levels. There was stronger evidence of waning of antibody levels over time in a sensitivity analysis in which observations were censored in cases with suspected undetected repeat infection.
CONCLUSIONS
We found similar levels of anti-nucleocapsid antibody in residents and staff of LTCFs. Repeat infection and infection with an Omicron strain were associated with higher peak values. There was evidence of waning of anti-nucleocapsid antibody levels over time.
PubMed: 38818129
DOI: 10.12688/wellcomeopenres.20750.1 -
Turkish Journal of Medical Sciences 2023In this cross-sectional study, it was aimed to test the predictive value of noncriteria antiphospholipid antibodies (aPL) in addition to the global antiphospholipid...
BACKGROUND/AIM
In this cross-sectional study, it was aimed to test the predictive value of noncriteria antiphospholipid antibodies (aPL) in addition to the global antiphospholipid syndrome score (GAPSS) in predicting vascular thrombosis (VT) in a cohort of patients with APS and aPL (+) systemic lupus erythematosus (SLE).
MATERIAL AND METHODS
This study included 50 patients with primary APS, 68 with SLE/APS, and 52 with aPL (+) SLE who were classified according to VT as VT ± pregnancy morbidity (PM), PM only or aPL (+) SLE. Antiphospholipid serology consisting of lupus anticoagulant (LA), anticardiolipin (aCL) immunoglobulin G (IgG)/IgM/IgA, antibeta2 glycoprotein I (aβ2GPI) IgG/IgM/IgA, antiphosphatidylserine/prothrombin (aPS/PT) IgG/IgM and antidomain-I (aDI) IgG was determined for each patient. The GAPSS and adjusted GAPSS (aGAPSS) were calculated for each patient, as previously defined. Logistic regression analysis was carried out with thrombosis as the dependent variable and high GAPSS, aCL IgA, aβ2GPI IgA, and aDI IgG as independent variables.
RESULTS
The mean GAPSS and aGAPSS of the study population were 11.6 ± 4.4 and 9.6 ± 3.8. Both the VT ± PM APS (n = 105) and PM only APS (n = 13) groups had significantly higher GAPSS and aGAPSS values compared to the aPL (+) SLE (n = 52) group. The patients with recurrent thrombosis had higher aGAPSS but not GAPSS than those with a single thrombotic event. The computed area under the receiver operating characteristic curve demonstrated that a GAPSS ≥13 and aGAPSS ≥10 had the best predictive values for thrombosis. Logistic regression analysis including a GAPSS ≥13, aCL IgA, aβ2GPI IgA, and aDI IgG showed that none of the factors other than a GAPSS ≥13 could predict thrombosis.
CONCLUSION
Both the GAPSS and aGAPSS successfully predict the thrombotic risk in aPL (+) patients and aCL IgA, aβ2GPI IgA, and aDI IgG do not contribute to high a GAPSS or aGAPSS.
Topics: Humans; Antiphospholipid Syndrome; Female; Adult; Male; Thrombosis; Cross-Sectional Studies; Antibodies, Antiphospholipid; Risk Assessment; Middle Aged; Lupus Erythematosus, Systemic; Pregnancy; Antibodies, Anticardiolipin
PubMed: 38813003
DOI: 10.55730/1300-0144.5671 -
Frontiers in Immunology 2024To explore the clinical characteristics and treatment outcomes of children with central nervous system (CNS) involvement in eosinophilic granulomatosis with polyangiitis... (Review)
Review
OBJECTIVE
To explore the clinical characteristics and treatment outcomes of children with central nervous system (CNS) involvement in eosinophilic granulomatosis with polyangiitis (EGPA).
METHODS
A child who presented with EGPA complicated by CNS involvement was admitted to our hospital in June 2023. The clinical features were analyzed retrospectively, and relevant literatures were reviewed to provide a comprehensive overview of this condition.
RESULTS
A ten-year-old girl, who had a history of recurrent cough and asthma accompanied by peripheral blood eosinophilia for eight months, was admitted to our hospital. On admission, spotted papules were visible on her hands and feet, bilateral pulmonary rales were audible. The laboratory examination revealed that the proportion of eosinophils (EOS) exceeded 10% of white blood cells, the anti-neutrophil cytoplasmic antibody (MPO-ANCA) was positive, the immunoglobulin G level was 15.80g/L, and the immunoglobulin E level was greater than 2500.00IU/mL. The imaging examination showed multiple patchy and nodular high-density shadows in both lungs as well as sinusitis. Pulmonary function tests indicated moderate ventilation and diffusion dysfunction. Bone marrow cytology demonstrated a significant increase in the proportion of eosinophils. Skin pathology confirmed leukocytoclastic vasculitis. During the hospitalization, the child had a convulsion. The magnetic resonance imaging (MRI) scan of the brain showed multiple abnormal signal shadows in the bilateral cerebral cortex and the electroencephalogram (EEG) showed epileptic waves. Following the administration of methylprednisolone pulse therapy in combination with cyclophosphamide treatment, her cough and asthma resolved, the skin rash disappeared without any further convulsions. We found that only a young EGPA patient with CNS involvement had been previously reported. The previously reported case began with long-term fever, weight loss, and purpuric rash. Both patients responded well to treatment with glucocorticoids and cyclophosphamide, experiencing significant improvement in their clinical symptoms and normalization of their peripheral blood eosinophils.
CONCLUSION
The diagnosis of EGPA in children can be challenging. When a child is affected by EGPA, it is essential to remain vigilant for signs of CNS involvement. The treatment with glucocorticoids and cyclophosphamide is effective in managing EGPA in children.
Topics: Humans; Female; Child; Churg-Strauss Syndrome; Treatment Outcome; Granulomatosis with Polyangiitis; Cyclophosphamide; Antibodies, Antineutrophil Cytoplasmic
PubMed: 38812515
DOI: 10.3389/fimmu.2024.1406424 -
Frontiers in Immunology 2024HIV-1 infection may produce a detrimental effect on the immune response. Early start of antiretroviral therapy (ART) is recommended to preserve the integrity of the...
INTRODUCTION
HIV-1 infection may produce a detrimental effect on the immune response. Early start of antiretroviral therapy (ART) is recommended to preserve the integrity of the immune system. In fact, people with HIV (PWH) and normal CD4/CD8 ratio appear not to be more susceptible to severe forms of COVID-19 than the general population and they usually present a good seroconversion rate in response to vaccination against SARS-CoV-2. However, few studies have fully characterized the development of cytotoxic immune populations in response to COVID-19 vaccination in these individuals.
METHODS
In this study, we recruited PWH with median time of HIV-1 infection of 6 years, median CD4/CD8 ratio of 1.0, good adherence to ART, persistently undetectable viral load, and negative serology against SARS-CoV-2, who then received the complete vaccination schedule against COVID-19. Blood samples were taken before vaccination against COVID-19 and one month after receiving the complete vaccination schedule.
RESULTS
PWH produced high levels of IgG against SARS-CoV-2 in response to vaccination that were comparable to healthy donors, with a significantly higher neutralization capacity. Interestingly, the cytotoxic activity of PBMCs from PWH against SARS-CoV-2-infected cells was higher than healthy donors before receiving the vaccination schedule, pointing out the pre-existence of activated cell populations with likely unspecific antiviral activity. The characterization of these cytotoxic cell populations revealed high levels of Tgd cells with degranulation capacity against SARS-CoV-2-infected cells. In response to vaccination, the degranulation capacity of CD8+ T cells also increased in PWH but not in healthy donors.
DISCUSSION
The full vaccination schedule against COVID-19 did not modify the ability to respond against HIV-1-infected cells in PWH and these individuals did not show more susceptibility to breakthrough infection with SARS-CoV-2 than healthy donors after 12 months of follow-up. These results revealed the development of protective cell populations with broad-spectrum antiviral activity in PWH with normal CD4/CD8 ratio and confirmed the importance of early ART and treatment adherence to avoid immune dysfunctions.
Topics: Humans; SARS-CoV-2; COVID-19; HIV Infections; Male; Female; Middle Aged; Adult; CD4-CD8 Ratio; COVID-19 Vaccines; CD8-Positive T-Lymphocytes; Antibodies, Viral; HIV-1; Cytotoxicity, Immunologic; Immunoglobulin G; T-Lymphocytes, Cytotoxic; Vaccination
PubMed: 38812512
DOI: 10.3389/fimmu.2024.1362621 -
Frontiers in Immunology 2024Vaccine effectiveness against SARS-CoV-2 infection has been somewhat limited due to the widespread dissemination of the Omicron variant, its subvariants, and the immune...
BACKGROUND
Vaccine effectiveness against SARS-CoV-2 infection has been somewhat limited due to the widespread dissemination of the Omicron variant, its subvariants, and the immune response dynamics of the naturally infected with the virus.
METHODS
Twelve subjects between 3-17 years old (yo), vaccinated with two doses of CoronaVac, were followed and diagnosed as breakthrough cases starting 14 days after receiving the second dose. Total IgGs against different SARS-CoV-2 proteins and the neutralizing capacity of these antibodies after infection were measured in plasma. The activation of CD4 and CD8 T cells was evaluated in peripheral blood mononuclear cells stimulated with peptides derived from the proteins from the wild-type (WT) virus and Omicron subvariants by flow cytometry, as well as different cytokines secretion by a Multiplex assay.
RESULTS
2 to 8 weeks post-infection, compared to 4 weeks after 2 dose of vaccine, there was a 146.5-fold increase in neutralizing antibody titers against Omicron and a 38.7-fold increase against WT SARS-CoV-2. Subjects showed an increase in total IgG levels against the S1, N, M, and NSP8 proteins of the WT virus. Activated CD4 T cells showed a significant increase in response to the BA.2 subvariant (p<0.001). Finally, the secretion of IL-2 and IFN-γ cytokines showed a discreet decrease trend after infection in some subjects.
CONCLUSION
SARS-CoV-2 infection in the pediatric population vaccinated with an inactivated SARS-CoV-2 vaccine produced an increase in neutralizing antibodies against Omicron and increased specific IgG antibodies for different SARS-CoV-2 proteins. CD4 T cell activation was also increased, suggesting a conserved cellular response against the Omicron subvariants, whereas Th1-type cytokine secretion tended to decrease.
CLINICAL TRIAL REGISTRATION
clinicaltrials.gov #NCT04992260.
Topics: Adolescent; Child; Child, Preschool; Female; Humans; Male; Antibodies, Neutralizing; Antibodies, Viral; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; COVID-19; COVID-19 Vaccines; Cytokines; Immunoglobulin G; SARS-CoV-2; Vaccination; Follow-Up Studies
PubMed: 38812507
DOI: 10.3389/fimmu.2024.1372193