Serum IgG Research Articles

Aspergillus fumigatus binding IgA and IgG1 are increased in bronchoalveolar lavage fluid of horses with neutrophilic asthma.

Equine asthma (EA) is a common lower airway disease in horses, but whether its pathogenesis is allergic is ambiguous. Extrinsic stimuli like hay dust induce acute exacerbation of clinical signs and sustained local neutrophilic inflammation in susceptible horses. Aspergillus fumigatus is an EA stimulus, but it is unclear if it merely acts as an IgE-provoking allergen. We aimed to comprehensively analyze immunoglobulin (Ig) isotypes in EA, elucidating their binding to different A. fumigatus antigens, and their quantities systemically in serum and locally in bronchoalveolar lavage fluid (BALF). Serum and BALF from healthy horses (HE, n = 18) and horses with mild-moderate asthma (MEA, n = 20) or severe asthma (SEA, n = 24) were compared. Ig isotype (IgG1, IgG3/5, IgG4/7, IgG6, IgA, and IgE) binding to nine antigens (A.fumigatus lysate, and recombinant Asp f 1, Asp f 7, Asp f 8, dipeptidyl-peptidase 5, class II aldolase/adducin domain protein, glucoamylase, beta-hexosaminidase, and peptide hydrolase) was compared by enzyme-linked immunosorbent assays. Total Ig isotype contents were determined by bead-based assays. MEA and SEA differed from HE but hardly from each other. Compared to HE, asthmatic horses showed increased anti-A. fumigatus binding of IgG (BALF and serum) and IgA (BALF). Serum and BALF IgE binding and total IgE contents were similar between HE and EA. Single antigens, as well as A. fumigatus lysate, yielded similar Ig binding patterns. Serum and BALF IgG1 binding to all antigens was increased in SEA and to several antigens in MEA. Serum IgG4/7 binding to two antigens was increased in SEA. BALF IgA binding to all antigens was increased in SEA and MEA. Total BALF IgG1 and IgG4/7 contents were increased in SEA, and serum IgG4/7 content was increased in MEA compared to HE. Yet, total isotype contents differentiated EA and HE less clearly than antigen-binding Ig. A. fumigatus immunogenicity was confirmed without identification of single dominant antigens here. A. fumigatus provoked elevated BALF IgG1 and IgA binding, and these isotypes appear relevant for neutrophilic EA, which does not support allergy. BALF Ig isotype differentiation beyond IgE is crucial for a comprehensive analysis of immune responses to fungi in EA pathogenesis.

Genistein Promotes M2 Macrophage Polarization via Aryl Hydrocarbon Receptor and Alleviates Intestinal Inflammation in Broilers with Necrotic Enteritis.

The aryl hydrocarbon receptor (AhR) is a transcription factor that regulates the immune system through complicated transcriptional programs. Genistein, an AhR ligand, exhibits anti-inflammatory properties. However, its role in modulating immune responses via the AhR signaling pathway remains unclear. In this study, 360 male Arbor Acre broilers (1-day-old) were fed a basal diet supplemented with 40 or 80 mg/kg genistein and infected with or without Clostridium perfringens (Cp). Our results demonstrated that genistein ameliorated Cp-induced intestinal damage, as reflected by the reduced intestinal lesion scores and improved intestinal morphology and feed-to-gain ratio. Moreover, genistein increased intestinal sIgA, TGF-β, and IL-10, along with elevated serum IgG, IgA, and lysozyme levels. Genistein improved intestinal AhR and cytochrome P450 family 1 subfamily A member 1 (CYP1A1) protein levels and AhR+ cell numbers in Cp-challenged broilers. The increased number of AhR+CD163+ cells in the jejunum suggested a potential association between genistein-induced AhR activation and anti-inflammatory effects mediated through M2 macrophage polarization. In IL-4-treated RAW264.7 cells, genistein increased the levels of AhR, CYP1A1, CD163, and arginase (Arg)-1 proteins, as well as IL-10 mRNA levels. This increase was attenuated by the AhR antagonist CH223191. In summary, genistein activated the AhR signaling pathway in M2 macrophages, which enhanced the secretion of anti-inflammatory cytokines and attenuated intestinal damage in Cp-infected broilers Cp.

Agalactosyl IgG induces liver fibrogenesis via Fc gamma receptor 3a on human hepatic stellate cells.

The relevance of aberrant serum IgG N-glycosylation in liver fibrosis has been identified; however, its causal effect remains unclear. Because hepatic stellate cells (HSCs) contribute substantially to liver fibrosis, we investigated whether and through which mechanisms IgG N-glycosylation affects the fibrogenic properties of HSCs. Analysis of serum IgG1 N-glycome from 151 patients with chronic hepatitis B or liver cirrhosis revealed a positive correlation between Ishak fibrosis grading and IgG1 with agalactosyl N-glycoforms on the crystallizable fragment (Fc). Fc gamma receptor (FcγR) IIIa was observed in cultured human HSCs and HSCs in human liver tissues, and levels of FcγRIIIa in HSCs correlated with the severity of liver fibrosis. Additionally, agalactosyl IgG treatment caused HSCs to have a fibroblast-like morphology, enhanced migration and invasion capabilities, and enhanced expression of the FcγRIIIa downstream tyrosine-protein kinase SYK. Furthermore, agalactosyl IgG treatment increased fibrogenic factors in HSCs, including transforming growth factor (TGF)-β1, total collagen, platelet-derived growth factor subunit B and its receptors, pro-collagen I-α1, α-smooth muscle actin, and matrix metalloproteinase 9. These effects were more pronounced in HSCs that stably expressed FCGR3A and were reduced in FCGR3A knockout cells. Agalactosyl IgG and TGF-β1 each increased FCGR3A in HSCs. Furthermore, serum TGF-β1 concentrations in patients were positively correlated with agalactosyl IgG1 levels and liver fibrosis severity, indicating a positive feedback loop involving agalactosyl IgG, HSC-FcγRIIIa, and TGF-β1. In conclusion, agalactosyl IgG promotes fibrogenic characteristics in HSCs through FcγRIIIa. © 2024 The Pathological Society of Great Britain and Ireland.

Application of Interferon-γ Release Assay in the Assessment of T-Cell Immunity to SARS-CoV-2 Antigens in the Cohort of Pediatric Patients with Juvenile Idiopathic Arthritis.

Background: an accurate assessment of the immunity against SARS-CoV-2 can facilitate a better understanding and management of not only the recent coronavirus but similar pathogens as well. Objective: the aim of this study was to evaluate T-cell immunity with reference to antibody titers in a group of pediatric patients with autoimmune arthritides utilizing the widely known Interferon-γ Release Assay (IGRA). Materials and Methods: This study was conducted in the cohort of 55 children suffering from Juvenile Idiopathic Arthritis (JIA). This research analyzed the SARS-CoV-2 T-cell response measured by a specific quantitative IGRA, followed by a serological ELISA test measuring the presence and quantity of IgG, IgM, and IgA antibodies in serum. Results: The cellular response to SARS-CoV-2 measured by the IGRA test significantly correlated with the antibody titers, IgA (p < 0.00003, R = 0.537), IgG (p < 0.0001, R = 0.668), and IgG nucleocapsid protein (NCP) (p < 0.003, R = 0.0399), with no correlation with IgM levels. The antibody levels in patients receiving biological agents were significantly lower compared to the rest of the cohort (p = 0.0369), while traditional disease-modifying antirheumatic drugs had no such effect. Limitations: the main limitation of the research is the small sample size, mostly due to the specific cohort of patients and the lack of a healthy control. Conclusions: IGRA appears to be a viable tool in the accurate evaluation of T-cell responses to SARS-CoV-2, and serodiagnostics alone is not always sufficient in the assessment of immune responses.

Mikulicz’s disease combined with IgG4-related hypophysitis: a case report

BackgroundIgG4-related diseases are very uncommon, and its diagnosis and treatment are complicated as it encompasses multiple disciplines.Case presentation: A 77-year-old woman was admitted with a jaw mass and nausea and vomiting. Laboratory tests showed elevated serum IgG4, pituitary MRI suggested thickening of the pituitary stalk, and head and neck CT suggested orbital and mandibular masses. Patients with mandibular mass were diagnosed with Mikulicz’s disease with IgG4-related hypophysitis. We found no other evidence of causing thickening of the pituitary stalk. She was given oral prednisolone 30 mg daily, and her nausea and vomiting improved significantly, and the mandibular and ocular masses decreased in size.ConclusionMikulicz’s disease combined with IgG4-related hypophysitis is a rare case of IgG4-RD in elderly women. IgG4-RD is one of the causes of head and neck exocrine gland mass and pituitary stalk thickening in the elderly.

Results of the study of factors predicting the risk of the development of grade III radiation-induced mucositis during radiation or chemoradiation therapy in patients with oral cavity and oropharynx cancer.

Today, a number of methods and ways of prevention and treatment of radiation- -induced mucositis of the oral cavity and oropharynx have been developed, but the represented approaches are still not effective enough. Therefore, to increase the effectiveness of the prevention and treatment of radiation-induced mucositis, it is necessary to approach this problem comprehensively and individually, and to evaluate the factors affecting the development of mucositis. In this single-center prospective controlled non-randomized clinical trial, the results of clinical observation of the development of complications of radiation and chemoradiation therapy in 105 patients with a newly diagnosed squamous cell cancer of the oral cavity and oropharynx were analyzed. Factors affecting the risk of the development of grade III radiation-induced mucositis including the age, gender of the patients, their general condition before the treatment according to World Health Organisation scales, type of the treatment and its doses, additional use of immunotherapy with alpha/beta defensins, characteristic signs of the tumor process and all indices of the immune status of the patients before the treatment have been analyzed. The method of construction and analysis of one-factor logistic regression models, where 24 indices were analyzed as factorial features, showed that the reduction of the risk of the development of grade III radiation-induced mucositis is predicted by several factors: immunotherapy, gender, serum concentrations of IgG and IgA. A decrease (P &lt; 0.001) in the risk of the development of grade III radiation-induced mucositis was revealed if immunotherapy with alpha/beta defensins (with a total dose of 40 mg) was included into the treatment scheme (relative odds (RO) 0.05; 95% reference interval (RI) 0.02-0.18), in comparison with patients of the groups where it was not present or this immune agent was used in a total dose of 60 mg (P = 0.001, RO 0.06; 95% RI 0.01-0.30). The next factorial sign was gender, namely the risk of the development of grade III radiation-induced mucositis was lower for men (P = 0.003; RO 0.15; 95% RI 0.04-0.53) compared to women. An increase (P = 0.024) in the risk of the development of grade III radiation-induced mucositis with an increase in the initial level of IgG serum concentration was revealed, (RO 1.08; 95% RI 1.01-1.16) for each 1 mg/mL, as well as an increase (P = 0.044) in the possibility of the appearance of grade III radiation-induced mucositis with an increase in the serum concentration of IgA (RO 1.23; 95% RI 1.01-1.50) for every 1 mg/mL also before the beginning of the treatment. Multifactorial analysis has also confirmed that the risk of the development of grade III radiation-induced mucositis increases (P = 0.008) with a high serum IgG concentration before the treatment or with an increase in this index during therapy (RO 1.13; 95% RI 1.03-1.09) for every 1 mg/mL (when standardized by other risk factors). It was determined that when standardizing according to other factors (gender, IgG level), the risk of the development of grade III radiation-induced mucositis in the use of the immune agent alpha/beta defensins in a total dose of 40 mg per course decreases (P &lt; 0.001; RO 0.08; 95% RI 0.02-0.27) compared to patients with oral cavity and oropharynx cancer who were not treated with immunotherapy. The risk of the development of grade III radiation-induced mucositis also decreases (P = 0.001) in the use of immunotherapy in a higher dose, i.e. 60 mg per course (RO 0.03; 95% RI 0.004-0.24 compared to patients whose treatment did not include immunotherapy (when standardized by other factors). As a result of this controlled clinical study, some factors were determined in addition to the radiation as those affecting the risk of the development of grade III radiation-induced mucositis in patients with oral cavity and oropharynx cancer during special treatment. These factors comprise the inclusion of immunotherapy with alpha/beta defensins into the specific treatment; gender, and baseline levels of serum IgG and IgA concentrations suggest a pattern in which the higher the serum IgG and IgA concentrations are before the start of the treatment, the greater is the likelihood of severe radiation-induced mucositis degree during special therapy. The results of the study of humoral state of the immune system in patients with oral cavity and oropharynx cancer before the beginning of chemoradiation therapy can be used as prognostic risk factors for the development of severe gamma-irradiation-induced mucositis of the oropharyngeal area, as well as an indication for the use of immunotherapeutic agents (in particular, alpha/beta defensins) that are able to polarize the immune response towards type 1 T-helpers through their immunomodulatory action.

Blood-stage malaria vaccine candidate RH5.1/Matrix-M in healthy Tanzanian adults and children; an open-label, non-randomised, first-in-human, single-centre, phase 1b trial

A blood-stage Plasmodium falciparum malaria vaccine would provide a second line of defence to complement partially effective or waning immunity conferred by the approved pre-erythrocytic vaccines. RH5.1 is a soluble protein vaccine candidate for blood-stage P falciparum, formulated with Matrix-M adjuvant to assess safety and immunogenicity in a malaria-endemic adult and paediatric population for the first time. We did a non-randomised, phase 1b, single-centre, dose-escalation, age de-escalation, first-in-human trial of RH5.1/Matrix-M in Bagamoyo, Tanzania. We recruited healthy adults (aged 18-45 years) and children (aged 5-17 months) to receive the RH5.1/Matrix-M vaccine candidate in the following three-dose regimens: 10 μg RH5.1 at 0, 1, and 2 months (Adults 10M), and the higher dose of 50 μg RH5.1 at 0 and 1 month and 10 μg RH5.1 at 6 months (delayed-fractional third dose regimen; Adults DFx). Children received either 10 μg RH5.1 at 0, 1, and 2 months (Children 10M) or 10 μg RH5.1 at 0, 1, and 6 months (delayed third dose regimen; Children 10D), and were recruited in parallel, followed by children who received the dose-escalation regimen (Children DFx) and children with higher malaria pre-exposure who also received the dose-escalation regimen (High Children DFx). All RH5.1 doses were formulated with 50 μg Matrix-M adjuvant. Primary outcomes for vaccine safety were solicited and unsolicited adverse events after each vaccination, along with any serious adverse events during the study period. The secondary outcome measures for immunogenicity were the concentration and avidity of anti-RH5.1 serum IgG antibodies and their percentage growth inhibition activity (GIA) in vitro, as well as cellular immunogenicity to RH5.1. All participants receiving at least one dose of vaccine were included in the primary analyses. This trial is registered at ClinicalTrials.gov, NCT04318002, and is now complete. Between Jan 25, 2021, and April 15, 2021, we recruited 12 adults (six [50%] in the Adults 10M group and six [50%] in the Adults DFx group) and 48 children (12 each in the Children 10M, Children 10D, Children DFx, and High Children DFx groups). 57 (95%) of 60 participants completed the vaccination series and 55 (92%) completed 22 months of follow-up following the third vaccination. Vaccinations were well-tolerated across both age groups. There were five serious adverse events involving four child participants during the trial, none of which were deemed related to vaccination. RH5-specific T cell and serum IgG antibody responses were induced by vaccination and purified total IgG showed in vitro GIA against P falciparum. We found similar functional quality (ie, GIA per μg RH5-specific IgG) across all age groups and dosing regimens at 14 days after the final vaccination; the concentration of RH5.1-specific polyclonal IgG required to give 50% GIA was 14·3 μg/mL (95% CI 13·4-15·2). 11 children were vaccinated with the delayed third dose regimen and showed the highest median anti-RH5 serum IgG concentration 14 days following the third vaccination (723 μg/mL [IQR 511-1000]), resulting in all 11 who received the full series showing greater than 60% GIA following dilution of total IgG to 2·5 mg/mL (median 88% [IQR 81-94]). The RH5.1/Matrix-M vaccine candidate shows an acceptable safety and reactogenicity profile in both adults and 5-17-month-old children residing in a malaria-endemic area, with all children in the delayed third dose regimen reaching a level of GIA previously associated with protective outcome against blood-stage P falciparum challenge in non-human primates. These data support onward efficacy assessment of this vaccine candidate against clinical malaria in young African children. The European and Developing Countries Clinical Trials Partnership; the UK Medical Research Council; the UK Department for International Development; the National Institute for Health and Care Research Oxford Biomedical Research Centre; the Division of Intramural Research, National Institute of Allergy and Infectious Diseases; the US Agency for International Development; and the Wellcome Trust.

In silico study to explore the mechanism of Toxoplasma-induced inflammation and target therapy based on sero and salivary Toxoplasma

We aimed to assess salivary and seroprevalence of Toxoplasma immunoglobulins in risky populations and evaluate drug docking targeting TgERP. A cross-sectional study was conducted in Alexandria University hospitals’ outpatient clinics. 192 participants were enrolled from September 2022 to November 2023. Anti-Toxoplasma IgG and IgM were determined in serum and saliva by ELISA. An in-Silico study examined TgERP’s protein–protein interactions (PPIs) with pro-inflammatory cytokine receptors, anti-inflammatory cytokine, cell cycle progression regulatory proteins, a proliferation marker, and nuclear envelope integrity-related protein Lamin B1. Our findings revealed that anti-T. gondii IgG were detected in serum (66.1%) and saliva (54.7%), with 2.1% of both samples were positive for IgM. Salivary IgG had 75.59% sensitivity, 86.15% specificity, 91.40% PPV, 64.40% NPP, 79.17% accuracy and fair agreement with serum IgG. On the other hand, the sensitivity, specificity, PPV, NPV, and accuracy in detecting salivary IgM were 75.0%, 99.47%, 75.0%, 99.47%, and 98.96%. AUC 0.859 indicates good discriminatory power. Examined synthetic drugs and natural products can target specific amino acids residues of TgERP that lie at the same binding interface with LB1 and Ki67, subsequently, hindering their interaction. Hence, salivary samples can be a promising diagnostic approach. The studied drugs can counteract the pro-inflammatory action of TgERP.

The effect of modified Qiyuan paste on mice with low immunity and sleep deprivation by regulating GABA nerve and immune system

BackgroundLow immunity and sleep disorders are prevalent suboptimal health conditions in contemporary populations, which render them susceptible to the infiltration of pathogenic factors. LJC, which has a long history in traditional Chinese medicine for nourishing the Yin and blood and calming the mind, is obtained by modifying Qiyuan paste. Dendrobium officinale Kimura et Migo has been shown to improve the immune function in sleep-deprived mice. In this study, based on the traditional Chinese medicine theory, LJC was prepared by adding D. officinale Kimura et Migo to Qiyuan paste decoction.MethodsIndicators of Yin deficiency syndrome, such as back temperature and grip strength, were measured in each group of mice; furthermore, behavioral tests and pentobarbital sodium-induced sleep tests were performed. An automatic biochemical analyzer, enzyme-linked immunosorbent assay kit, and other methods were used to determine routine blood parameters, serum immunoglobulin (IgG, IgA, and IgM), cont (C3, C4), acid phosphatase (ACP) and lactate dehydrogenase (LDH) levels in the spleen, serum hemolysin, and delayed-type hypersensitivity (DTH) levels. In addition, serum levels of γ-aminobutyric acid (GABA) and glutamate (Glu) were detected using high-performance liquid chromatography (HPLC). Hematoxylin–eosin staining and Nissl staining were used to assess the histological alterations in the hypothalamus tissue. Western blot and immunohistochemistry were used to detect the expressions of the GABA pathway proteins GABRA1, GAD, GAT1, and GABAT1 and those of CD4+ and CD8+ proteins in the thymus and spleen tissues.ResultsThe findings indicated that LJC prolonged the sleep duration, improved the pathological changes in the hippocampus, effectively upregulated the GABA content in the serum of mice, downregulated the Glu content and Glu/GABA ratio, enhanced the expressions of GABRA1, GAT1, and GAD, and decreased the expression of GABAT1 to assuage sleep disorders. Importantly, LJC alleviated the damage to the thymus and spleen tissues in the model mice and enhanced the activities of ACP and LDH in the spleen of the immunocompromised mice. Moreover, serum hemolysin levels and serum IgG, IgA, and IgM levels increased after LJC administration, which manifested as increased CD4+ content, decreased CD8+ content, and enhanced DTH response. In addition, LJC significantly increased the levels of complement C3 and C4, increased the number of white blood cells and lymphocytes, and decreased the percentage of neutrophils in the blood.ConclusionsLJC can lead to improvements in immunocompromised mice models with insufficient sleep. The underlying mechanism may involve regulation of the GABA/Glu content and the expression levels of GABA metabolism pathway-related proteins in the brain of mice, enhancing their specific and nonspecific immune functions.Graphical

Immunogenicity, reactogenicity, and IgE-mediated immune responses of a mixed whole-cell and acellular pertussis vaccine schedule in Australian infants: A randomised, double-blind, noninferiority trial.

In many countries, infant vaccination with acellular pertussis (aP) vaccines has replaced use of more reactogenic whole-cell pertussis (wP) vaccines. Based on immunological and epidemiological evidence, we hypothesised that substituting the first aP dose in the routine vaccination schedule with wP vaccine might protect against IgE-mediated food allergy. We aimed to compare reactogenicity, immunogenicity, and IgE-mediated responses of a mixed wP/aP primary schedule versus the standard aP-only schedule. OPTIMUM is a Bayesian, 2-stage, double-blind, randomised trial. In stage one, infants were assigned (1:1) to either a first dose of a pentavalent wP combination vaccine (DTwP-Hib-HepB, Pentabio PT Bio Farma, Indonesia) or a hexavalent aP vaccine (DTaP-Hib-HepB-IPV, Infanrix hexa, GlaxoSmithKline, Australia) at approximately 6 weeks old. Subsequently, all infants received the hexavalent aP vaccine at 4 and 6 months old as well as an aP vaccine at 18 months old (DTaP-IPV, Infanrix-IPV, GlaxoSmithKline, Australia). Stage two is ongoing and follows the above randomisation strategy and vaccination schedule. Ahead of ascertainment of the primary clinical outcome of allergist-confirmed IgE-mediated food allergy by 12 months old, here we present the results of secondary immunogenicity, reactogenicity, tetanus toxoid IgE-mediated immune responses, and parental acceptability endpoints. Serum IgG responses to diphtheria, tetanus, and pertussis antigens were measured using a multiplex fluorescent bead-based immunoassay; total and specific IgE were measured in plasma by means of the ImmunoCAP assay (Thermo Fisher Scientific). The immunogenicity of the mixed schedule was defined as being noninferior to that of the aP-only schedule using a noninferiority margin of 2/3 on the ratio of the geometric mean concentrations (GMR) of pertussis toxin (PT)-IgG 1 month after the 6-month aP. Solicited adverse reactions were summarised by study arm and included all children who received the first dose of either wP or aP. Parental acceptance was assessed using a 5-point Likert scale. The primary analyses were based on intention-to-treat (ITT); secondary per-protocol (PP) analyses were also performed. The trial is registered with ANZCTR (ACTRN12617000065392p). Between March 7, 2018 and January 13, 2020, 150 infants were randomised (75 per arm). PT-IgG responses of the mixed schedule were noninferior to the aP-only schedule at approximately 1 month after the 6-month aP dose [GMR = 0·98, 95% credible interval (0·77 to 1·26); probability (GMR > 2/3) > 0·99; ITT analysis]. At 7 months old, the posterior median probability of quantitation for tetanus toxoid IgE was 0·22 (95% credible interval 0·12 to 0·34) in both the mixed schedule group and in the aP-only group. Despite exclusions, the results were consistent in the PP analysis. At 6 weeks old, irritability was the most common systemic solicited reaction reported in wP (65 [88%] of 74) versus aP (59 [82%] of 72) vaccinees. At the same age, severe systemic reactions were reported among 14 (19%) of 74 infants after wP and 8 (11%) of 72 infants after aP. There were 7 SAEs among 5 participants within the first 6 months of follow-up; on blinded assessment, none were deemed to be related to the study vaccines. Parental acceptance of mixed and aP-only schedules was high (71 [97%] of 73 versus 69 [96%] of 72 would agree to have the same schedule again). Compared to the aP-only schedule, the mixed schedule evoked noninferior PT-IgG responses, was associated with more severe reactions, but was well accepted by parents. Tetanus toxoid IgE responses did not differ across the study groups. Trial registered at the Australian and New Zealand Clinical 207 Trial Registry (ACTRN12617000065392p).

Autoantigen Exposure in Murine Fetuses Elicited Nonpathogenic Autoimmunity

Autoimmunity refers to the presence of autoantibodies and autoreactive lymphocytes against the structural molecules of an individual's cells or tissues, known as self-antigens or autoantigens. It might exist in the absence of autoimmune disease. However, how autoimmunity develops remains a mystery, despite the discovery of autoantibodies in human cord blood. Murine fetuses on day 14 of gestation were subjected to intraperitoneal injection of murine thyroid peroxidase (TPO) peptides or collagen type II (CII) at graded doses via transuterine approach. Postnatally, the recipients were examined for autoantibodies by ELISA and autoreactive lymphocytes by in vitro incorporation of tritium and for the development of autoimmune thyroiditis or arthritis. At one month of age, the recipients did not secrete significant levels of anti-TPO or CII IgG2a in sera until a dose of 0.5 µg TPO or 5.0 µg CII was injected in utero. Serum anti-TPO or CII IgG2a persisted for at least two to four months postnatally. In recipients with elevated autoantibodies, their lymphocytes also showed proliferative responses specifically to TPO or CII. However, the development of autoantibodies and autoreactive lymphocytes was not associated with inflammatory cell infiltration of thyroid glands or paw joints even though anti-TPO or CII IgG2a was enhanced by postnatal TPO or CII challenge. Fetal exposure to free autoantigens could be immunogenic, shedding new light on the in utero origin of autoantibodies and autoreactive lymphocytes. The development of autoimmunity requires a threshold intensity of autoantigen exposure in the fetus.

Pathogenic roles of follicular helper T cells in IgG4-related disease and implications for potential therapy.

IgG4-related disease (IgG4-RD) is a recently described autoimmune disorder characterized by elevated serum IgG4 levels and tissue infiltration of IgG4+ plasma cells in multiple organ systems. Recent advancements have significantly enhanced our understanding of the pathological mechanism underlying this immune-mediated disease. T cell immunity plays a crucial role in the pathogenesis of IgG4-RD, and follicular helper T cells (Tfh) are particularly important in germinal center (GC) formation, plasmablast differentiation, and IgG4 class-switching. Apart from serum IgG4 concentrations, the expansion of circulating Tfh2 cells and plasmablasts may also serve as novel biomarkers for disease diagnosis and activity monitoring in IgG4-RD. Further exploration into the pathogenic roles of Tfh in IgG4-RD could potentially lead to identifying new therapeutic targets that offer more effective alternatives for treating this condition. In this review, we will focus on the current knowledge regarding the pathogenic roles Tfh cells play in IgG4-RD and outline potential therapeutic targets for future clinical intervention.

Intranasal SARS-CoV-2 Omicron variant vaccines elicit humoral and cellular mucosal immunity in female mice

In order to prevent the emergence and spread of future variants of concern of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), developing vaccines capable of stopping transmission is crucial. The SARS-CoV-2 vaccine NDV-HXP-S can be administered live intranasally (IN) and thus induce protective immunity in the upper respiratory tract. The vaccine is based on Newcastle disease virus (NDV) expressing a stabilised SARS-CoV-2 spike protein. NDV-HXP-S can be produced as influenza virus vaccine at low cost in embryonated chicken eggs. The NDV-HXP-S vaccine was genetically engineered to match the Omicron variants of concern (VOC) BA.1 and BA.5 and tested as an IN two or three dose vaccination regimen in female mice. Furthermore, female mice intramuscularly (IM) vaccinated with mRNA-lipid nanoparticles (LNPs) were IN boosted with NDV-HXP-S. Systemic humoral immunity, memory T cell responses in the lungs and spleens as well as immunoglobulin A (IgA) responses in distinct mucosal tissues were characterised. NDV-HXP-S Omicron variant vaccines elicited high mucosal IgA and serum IgG titers against respective SARS-CoV-2 VOC in female mice following IN administration and protected against challenge from matched variants. Additionally, antigen-specific memory B cells and local T cell responses in the lungs were induced. Host immunity against the NDV vector did not interfere with boosting. Intramuscular vaccination with mRNA-LNPs was enhanced by IN NDV-HXP-S boosting resulting in improvement of serum neutralization titers and induction of mucosal immunity. We demonstrate that NDV-HXP-S Omicron variant vaccines utilised for primary immunizations or boosting efficiently elicit humoral and cellular immunity. The described induction of systemic and mucosal immunity has the potential to reduce infection and transmission. This work was partially funded by the NIAIDCenters of Excellence for Influenza Research and Response (CEIRR) and by the NIAID Collaborative Vaccine Innovation Centers and by institutional funding from the Icahn School of Medicine at Mount Sinai. See under Acknowledgements for details.

Colostrum Replacement and Serum IgG Concentrations in Beef Calves Delivered by Elective Cesarean Section.

Assistance during calving and cesarean section (C-section) are important risk factors for the failure of transfer of passive immunity (FTPI) in beef calves, which increases the risk of morbidity and mortality in beef calves during the preweaning period. Colostrum replacement recommendations for beef calves, and especially for those delivered by C-section, are unavailable. The objective of this study was to determine whether or not colostrum replacement or supplementation with a commercially available product could increase serum IgG concentrations in beef calves delivered by elective C-section, compared to beef calves that nursed colostrum naturally. An elective C-section was performed in 32 pregnant beef cows and first-calf heifers. Immediately after delivery, newborn calves were randomly assigned to one of three different treatment groups. Group A calves (n = 7) were fed one packet of a commercial colostrum replacer (CR) product providing 60 g of IgG within 30 min of life. A second packet of the same CR was fed at 6 h of life. Group B calves (n = 13) were fed the same CR at the same frequency as group A; however, these calves were reunited with their dams after the second CR feeding to allow additional nursing of maternal colostrum. Group C calves (n = 12) were united with their dams immediately after surgery without colostrum intervention. Serum IgG levels at 48 h of life were greater in group C calves and in calves born to multiparous cows. Based on the results of this study, neither colostrum replacement nor supplementation result in higher serum IgG concentrations in beef calves delivered by elective C-section compared with natural nursing.

Identification of novel biomarkers for anti-Toxoplasma gondii IgM detection and the potential application in rapid diagnostic fluorescent tests.

Toxoplasmosis, while often asymptomatic and prevalent as a foodborne disease, poses a considerable mortality risk for immunocompromised individuals during pregnancy. Point-of-care serological tests that detect specific IgG and IgM in patient sera are critical for disease management under limited resources. Despite many efforts to replace the T. gondii total lysate antigens (TLAs) by recombinant antigens (rAgs) in commercial kits, while IgG detection provides significant specificity and sensitivity, IgM detection remains comparatively low in sensitivity. In this study, we attempted to identify novel antigens targeting IgM in early infection, thereby establishing an IgM on-site detection kit. Using two-dimensional gel electrophoresis (2DE) and mouse serum immunoblotting, three novel antigens, including EF1γ, PGKI, and GAP50, were indicated to target T. gondii IgM. However, rAg EF1γ was undetectable by IgM of mice sera in Western blotting verification experiments, and ELISA coated with PGKI did not eliminate cross-reactivity, in contrast to GAP50. Subsequently, the lateral flow reaction employing a strip coated with 0.3 mg/mL purified rAg GAP50 and exhibited remarkable sensitivity compared with the conventional ELISA based on tachyzoite TLA, which successfully identified IgM in mouse sera infected with tachyzoites, ranging from 103 to 104 at 5 dpi and 104 at 7 dpi, respectively. Furthermore, by using standard T. gondii-infected human sera from WHO, the limit of detection (LOD) for the rapid fluorescence immunochromatographic test (FICT) using GAP50 was observed at 0.65 IU (international unit). These findings underline the particular immunoreactivity of GAP50, suggesting its potential as a specific biomarker for increasing the sensitivity of the FICT in IgM detection.

The extracellular serine protease from Staphylococcus epidermidis elicits a type 2-biased immune response in atopic dermatitis patients.

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease with skin barrier defects and a misdirected type 2 immune response against harmless antigens. The skin microbiome in AD is characterized by a reduction in microbial diversity with a dominance of staphylococci, including Staphylococcus epidermidis (S. epidermidis). To assess whether S. epidermidis antigens play a role in AD, we screened for candidate allergens and studied the T cell and humoral immune response against the extracellular serine protease (Esp). To identify candidate allergens, we analyzed the binding of human serum IgG4, as a surrogate of IgE, to S. epidermidis extracellular proteins using 2-dimensional immunoblotting and mass spectrometry. We then measured serum IgE and IgG1 binding to recombinant Esp by ELISA in healthy and AD individuals. We also stimulated T cells from AD patients and control subjects with Esp and measured the secreted cytokines. Finally, we analyzed the proteolytic activity of Esp against IL-33 and determined the cleavage sites by mass spectrometry. We identified Esp as the dominant candidate allergen of S. epidermidis. Esp-specific IgE was present in human serum; AD patients had higher concentrations than controls. T cells reacting to Esp were detectable in both AD patients and healthy controls. The T cell response in healthy adults was characterized by IL-17, IL-22, IFN-γ, and IL-10, whereas the AD patients' T cells lacked IL-17 production and released only low amounts of IL-22, IFN-γ, and IL-10. In contrast, Th2 cytokine release was higher in T cells from AD patients than from healthy controls. Mature Esp cleaved and activated the alarmin IL-33. The extracellular serine protease Esp of S. epidermidis can activate IL-33. As an antigen, Esp elicits a type 2-biased antibody and T cell response in AD patients. This suggests that S. epidermidis can aggravate AD through the allergenic properties of Esp.

A case of variant of GBS with positive serum ganglioside GD3 IgG antibody

BackgroundAcute bulbar palsy-plus (ABPp) syndrome is an unusual variant of Guillain-Barré syndrome (GBS). Anti-GT1a and anti-GQ1b antibodies have been reported in patients with ABPp, but without reports related to GD3 antibodies.MethodsClinical data of a patient diagnosed as ABPp syndrome were reviewed clinically. And we summarized the GBS patients with ABP and facial paralysis reported in the literature.ResultsWe reported a 13-year-old girl presented with asymmetric bifacial weakness, bulbar palsy and transient limb numbness, and had positive serum IgG anti-GD3 antibody. Through reviewing the GBS patients with ABP and facial paralysis reported previously, we found that facial palsy could be unilateral or bilateral. The bilateral facial palsy could present successively or simultaneously, and could be symmetrical or asymmetrical. Other common symptoms included ophthalmoplegia, sensory abnormality and ataxia. IgG anti-GT1a and IgG anti-GQ1b antibodies were the most frequent. Most of the patients had full recovery within two weeks to one year of follow-up.ConclusionsWe reported a patient with asymmetric bifacial palsy and bulbar palsy, which seemed to fit the diagnosis of ABPp syndrome. This was the first report of ABPp variant of GBS with positive serum ganglioside GD3 IgG antibody.

Gastrointestinal Cytomegalovirus Infection in a Transplantation Recipient With a Negative Serum Viral Load: Case Report

Kidney transplant recipients are vulnerable to infections, especially cytomegalovirus (CMV) disease. It is recommended that clinicians plan their prophylaxis and therapeutic regimens based on viral load testing. CMV viral load monitoring testing provides useful information for identifying virologic response and possible antiviral resistance. Due to the paucity of medical literature on guiding viral therapy in cases of CMV tissue disease with nondetectable serum viral load, we intend to provide physicians with evidence on how to guide medical therapy in these cases. A 49-year-old Hispanic male recipient of a kidney transplant from a cadaver donor presented to the emergency department with anorexia, asthenia, diarrhea, weight loss, and supraclavicular and mediastinal adenomegalies at 2 months post-transplantation. Both patients were serum IgG- and IgM-positive for CMV, which classified them as intermediate risk for developing CMV disease or tissue-invasive disease (donor-positive/recipient-positive [D+/R+]). The patient was induced with basiliximab and methylprednisolone and received maintenance therapy with tacrolimus, mycophenolic acid, and prednisone. Real-time polymerase chain reaction analyses were performed due to suspicion for BK virus, B19 parvovirus, Epstein-Barr virus, and CMV, with an undetectable viral load for all. A biopsy specimen taken from the gastrointestinal tract confirmed CMV infection, which was corroborated through immunocytochemistry. Histopathologic testing is a possible option for patients with CMV tissue disease symptoms but no detectable serum viral load. Clinical observation is fundamental when viral monitoring is difficult.

Idiopathic hypertrophic pachymeningitis: Features of 9 patients and a literature review

Introduction: Idiopathic hypertrophic pachymeningitis (IHP) is a rare disorder presenting with headache, cranial and spinal neuropathy. This study is to explore the clinical, laboratory and imaging changes; treatment; and clinical outcomes of idiopathic hypertrophic pachymeningitis (IHP). Methods: This was a retrospective evaluation of 9 patients (5 men and 4 women; mean age: 53.6 years), their clinical features, laboratory tests, cerebral spinal fluid (CSF) analysis, MRI results, pathological features, treatment and clinical outcomes from a tertiary centre in Qingdao, North East China. The serum IgG4 was negative for all the cases. Results: Headache was the most common symptom (7/9), followed by oculomotor, trigeminal, abducens and facial nerve neuropathies, and limb numbness in one case. Two cases showed increased ESR and CRP, and four were positive for ANA or anti-SSA antibodies. On CSF analysis, 2/7 had increased pressure, and 4/7 showed lymphocytosis and high protein levels. MRI revealed a thickening and enhancement of the dura, mainly involving bilateral tentorium (85%), falx cerebri (57%), and cerebellar hemisphere (57%). The tissue biopsy of dura mater in three cases showed thickened collagen fibers, lymphocytosis and focal necrosis, with similar but not identical features to IgG4-related sclerosing disease. Most patients were treated with corticosteroids, and 79% showed improvement. The abnormal thickness and enhancement of the dura mater disappeared in one case. Conclusion: Gadolinium-enhanced MRI serves as the key preliminary investigation for the diagnosis and evaluation of the clinical course for IHP. Majority of patients have good respond to steroid.

OPTec: A phase 2 study to evaluate outpatient (OP) step-up administration of teclistamab (Tec), a BCMA-targeting bispecific antibody, in patients (pts) with relapsed/refractory multiple myeloma (RRMM).

7528 Background: Tec is the only approved BCMA×CD3 bispecific antibody with personalized, weight-based dosing for triple-class exposed RRMM. In the MajesTEC-1 study, Tec showed deep, durable responses and a manageable safety profile. Cytokine release syndrome (CRS) occurred in 72% of pts during Cycles 1-2, and 33% of pts had recurrent CRS grade (gr) ≤3 (gr 3, 0.6%). Tocilizumab (Toci) is used to manage CRS. In a separate MajesTEC-1 cohort, pts who received prophylactic Toci (proToci) experienced less CRS, compared with pts who did not (26% vs 72%). Administering the Tec step-up dosing (SUD) regimen in the OP setting may make Tec more accessible, especially at community centers. Therefore, we are investigating whether proToci can reduce the incidence and severity of CRS associated with Tec and facilitate safe OP administration. Methods: This single-arm, non-randomized, multicenter, prospective study (NCT05972135) will evaluate proToci in pts treated with Tec using an OP SUD regimen. The primary endpoint is the overall incidence of CRS. Secondary endpoints include recurrent CRS gr ≥3, and any gr infections, neurotoxicity (NT) including ICANS, neutropenia, and efficacy. Eligible pts are ≥18 years with RRMM and ≥4 prior lines of therapy. Pts with rapidly progressing MM, CNS involvement, active infection, or contraindication to Toci are excluded. Toci 8 mg/kg IV is administered 2 to 4 hours prior to SUD 1 of Tec in an OP setting. The Tec SUD regimen consists of 0.06 mg/kg subcutaneously (SC), 0.3 mg/kg SC 2 to 4 days later, and 1.5 mg/kg SC 1 week after SUD 1. Tec 1.5 mg/kg SC is then given weekly for 12 cycles (28-day) or until MM progression or unacceptable toxicity. Pts with ≥PR after 6 mo can receive 1.5 mg/kg SC biweekly. IVIG is allowed in pts with serum IgG &lt;400 mg/dL. Results: Ten pts will be enrolled at 4 Sarah Cannon / US Oncology community sites in a safety and PK/PD cohort, followed by 40 pts at 12 sites. After the first 6 pts, a Data Review Committee (DRC) meeting was held. Median age was 74 (56 to 83) yrs; half of pts were male. Pts had received a median of 4.5 (4 to 6) prior therapies. One pt with diffuse bony lesions had an SAE of bilateral leg weakness and pain unrelated to Toci or Tec, did not complete the SUD regimen, and died on C1D40 of unknown causes. The other 5 pts completed the SUD regimen per protocol. AEs in &gt;1 pt were fatigue, headache and neutropenia (2 each). Gr 2 hypotension (1 pt) and gr 1 confusion and dizziness (1 pt each) were not felt due to CRS or ICANS. Stopping criteria (gr &gt;3 CRS or NT/ICANS) were not met. The DRC recommended proceeding with enrollment. Conclusions: Initial results indicate that proToci prior to SUD 1 of Tec may mitigate the risk of CRS. Enrollment is ongoing to determine if proToci may make Tec safe to give in an OP setting and increase accessibility in community centers. The full safety cohort will be presented at ASCO. Clinical trial information: NCT05972135 .